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FAMILIAL ADENOMATOUS POLYPOSIS: ONE GENE. MANY MANIFESTATIONS.

ALPHABET SOUP: FROM HERE TO THERE AND BACK AGAIN…AGAIN

Part III of this series looked at Familial Adenomatous Polyposis (FAP) and the genetics underlying the disease. Part IV will examine the ways in which this knowledge can be used to diagnose and treat patients and family members affected by FAP.

Genotype To Diagnosis: From Appearance To Discovery

The Laboratory Story: Unraveling The Alphabet Soup Of Genetic Mutations

As ninety six percent of Adenomatous Polyposis Coli (APC) gene mutations in FAP result in a truncated protein product, the protein truncation test (PTT) has been developed to identify the area of the mutant APC gene which produces the abnormal protein. The APC gene mutation causes a premature termination of translation. Translation is the process whereby the nucleic code is translated into amino acids. The protein truncation test is also known as in vitro synthesized protein assay (IVSP). The DNA to be tested is extracted from lymphocytes in whole blood. The PTT has been found to be successful in confirming a diagnosis in eighty five percent of cases. Failure to diagnose FAP by PTT does not exclude the diagnosis and the clinician should not rely on a negative test result and falsely reassure the patient at this point. (27) In those fifteen percent of mutations missed by PTT, electrophoretic migration is used to find the undiscovered mutation. This sequential testing using two techniques has become commonplace and has a high sensitivity and high specificity. (28) If testing is successful in identifying a mutant APC protein, the mutated nucleotides causing the truncation can be precisely identified with gene sequence analysis. This may provide valuable information as to both diagnosis and phenotypic expression of the disease. The mutational information can also be used for comparison with family members being tested for the same mutation.

Predictive gene testing of unaffected family members has become an important tool in the screening of families with members at risk for FAP. PTT, electrophoretic migration testing or direct gene sequencing tests of DNA from whole blood samples can identify and confirm the diagnosis in both symptomatic and asymptomatic patients with a family history of the disease. This is especially useful in young patients or in those who do not wish to undergo an intensive clinical screening process.

Genetic Testing For Individuals And Family Members With Clinically Proven FAP

Prior to embarking on genetic testing, genetic counseling and informed consent should be given to patients and appropriate family members. In individuals affected with the clinical stigmata of FAP, the PTT is the first step toward making a definitive diagnosis (figure 1(28)). Electrophoretic migration testing may be used to further study the APC gene if the PTT fails uncover a mutation. If either test is APC mutation-positive, surveillance is started as outlined below. If possible, genetic sequencing should be performed so as to further elucidate the phenotype risk. The mutant codon location information is used in genetic testing of family members to determine if they have the identical mutation. First degree family members are at a fifty percent risk of carrying the mutation and should be counseled.

If no mutation is identified in a patient with the phenotypic appearance of FAP, the patient is APC mutation-negative. As the PTT and electrophoretic migration tests are highly sensitive for an APC mutation, patients with polyposis or related manifestations of the disease should be evaluated for a mutation in a different gene on a chromosome other than chromosome five. An MYH mutation should be suspected and gene analysis using DNA sequencing techniques can be performed to evaluate for this. No matter the result, continued intensive surveillance of the patient is performed because malignant degeneration of the polyps may occur. Additionally, the negative tests have no predictive value for family members, and further family testing for an APC mutation is likely to be unrewarding. However, as there may be a mutation on a different chromosome, first degree relatives should undergo colorectal surveillance every year between the ages of 12 and 25, every other year between the ages of 25 and 35, and every third year between the ages of 35 and 50. After age 50, healthy family members are considered to be unaffected… (29)

Genetic Testing For Clinically Normal Family Members Under Age 50, With Clinically Proven FAP In A Relative.

With respect to family members without observable disease, who are under the age of fifty, and who belong to an FAP kindred, a genetic evaluation should be performed (figure 2(28)). Genetic counseling should be recommended, with informed consent obtained prior to any genetic testing.

In individuals with a known mutation previously identified in a family member, a PTT is performed. Electrophoretic migration testing can be performed if the PTT is negative. If either test is positive, the patient is an FAP mutation carrier and is at high risk for colorectal cancer. FAP surveillance is instituted. All first degree relatives have a fifty percent risk of carrying the mutation, and they should be evaluated.

If all testing is APC mutation-negative in family members whose relative(s) has a known mutation, the patient and all other mutation- negative family members are not at risk for FAP and surveillance is as for the general population.

In patients of an FAP kindred whose family mutation status is unavailable, PTT and if necessary, electrophoretic migration testing is performed. In those testing positive, germline analysis is performed and surveillance is as for patients with FAP. Family members of this newly diagnosed patient should be evaluated. It should be noted that thirty percent of FAP patients have a new, spontaneous mutation, and the parents of this patient will not be carriers of the mutation. They will test APC mutation-negative. However, descendents of the patient are at a fifty percent risk for carrying the mutant gene and should be tested even though their grandparents may have tested negative.

As protein testing is highly sensitive, if a mutation is not detected, the patient in question most likely does not have an APC mutation. However, another as of yet undefined mutation may exist, and the patient must not be falsely reassured that he is mutation free or disease free. (28) Colorectal surveillance should be continued. The patient should consider having the originally affected relative tested to evaluate for an APC mutation or other mutation.

Using genetic testing, detection rates in AFAP are almost one hundred percent.

From Diagnosis To Screening And Surveillance

The Physician On The Frontlines

Genetic testing can guide screening and surveillance recommendations. The risk of colorectal disease can be evaluated with genetic testing and shown to be either that of the general population at three percent, or that of patients with untreated FAP at one hundred percent.

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In patients with known FAP, routine endoscopic surveillance should begin at age eleven with a flexible sigmoidoscopy. The rationale for this limited exam is that polyps usually do not appear until puberty and are most commonly left sided in eighty four percent of patients. Colonoscopic surveillance should be started at age fourteen and continued yearly for life. Patients should be counseled and prepared for a prophylactic colectomy. Genetic counseling should be offered regarding the risks to future offspring. In first-degree relatives without an identified mutation, screening should be performed at the time of initial genetic testing, but no later than age fifteen. As the genetic testing is highly sensitive, an APC mutation negative patient should undergo future surveillance in the same manner as in colorectal cancer surveillance in the general population. The traditional approach with respect performing a prophylactic colectomy for FAP has been that it should be performed by age twenty five in patients with polyps, although the choice this age is arbitrary and many affected individuals have undergone operative prophylaxis by the age of twenty. (30,31) It is now recommended that operative intervention be undertaken as soon as polyposis is discovered. Without treatment, there is close to a one hundred per cent risk for the development of colorectal cancer by age forty. In patients undergoing an early prophylactic procedure, long term survival rates are between eighty seven to ninety four per cent. In patients presenting with an established malignancy, ten year survival rates are forty per cent. (32,33) The pendulum seems to be swinging toward earlier prophylactic colectomy, possibly within two years of the discovery of the disease.

In AFAP, full colonoscopic screening should begin at age twenty as this entity has a later age of onset, with polyps found more commonly in the proximal colon. The screening interval is similar to those in patients with FAP.

Upper gastrointestinal surveillance should begin at age twenty and continue for the lifetime of the patient at intervals between one and five years, depending upon the findings. Alternatively, surveillance can begin at the same time as a diagnosis of FAP is secured. Strict attention must be paid to performing a thorough duodenal inspection using both straight viewing and side viewing endoscopes. Although the lifetime risk of forming duodenal adenomas approaches one hundred percent, less than thirty percent of duodenal adenomas in crease in size, number or histology. If surgical intervention is to be undertaken, the entire gastrointestinal tract must be evaluated prior to the intervention. (34,35)

From Screening And Surveillance To Therapy

The Surgeon On The Frontlines: Surgical Prophylaxis And Treatment

Prior to any operative intervention, histopathological confirmation of FAP is mandatory so as not to confuse FAP with other polyposis syndromes which look like FAP, but which may not require radical operative treatment.

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With operative intervention, the goal is to remove as much of the colorectal mucosa as possible. Currently, three operations are available to treat FAP. None of them cures the underlying disease. The aim of each is to remove as much susceptible tissue as possible, while retaining normal colorectal functioning.

Laparoscopic Or Open Proctocolectomy With An End Ileostomy

A proctocolectomy with an end ileostomy provides the most complete future colorectal cancer risk reduction but requires the creation of a permanent stoma. This is an unpopular option because of the permanent stoma. Young patients are unlikely to choose this approach. However, total abdominal colectomy with a proctectomy is the procedure of choice in patients with a distal rectal carcinoma. It is also an option in patients who cannot undergo a rectal or anal anastomosis because of intraoperative technical difficulties (the planned reconstruction will not reach the anastomotic site due to anatomic considerations or infiltrative mesenteric desmoid disease) or poor sphincter function. A variation on this operation involves creating a continent ileostomy, or Kock pouch. In this procedure, a reservoir is created using the terminal ileum. A nipple valve is constructed and brought out through the abdominal wall. Ideally, there is no need to wear an ostomy appliance as the reservoir holds the intestinal contents until the patient performs a self-catheterization, usually four to six times per day. When not in use, the ostomy is covered with a band aid. The esthetic and cosmetic advantages are obvious. However, the procedure is associated with prolapse of the nipple. The Kock pouch is rarely used.

Laparoscopic Or Open Total Abdominal Colectomy With An Ileorectal Anastomosis.

A total abdominal colectomy with an ileorectal anastomosis may be used in patients with few rectal adenomas or in patients with AFAP, as AFAP usually spares the rectum. A total abdominal colectomy with an ileorectal anastomosis is relatively easy to perform, usually does not require a temporary protective ileostomy, restores intestinal continuity and achieves good functional results. The risks of erectile and ejaculatory dysfunction that may occur in a more extensive operation secondary to operative nerve trauma during the pelvic dissection are largely avoided. Female fertility is preserved as well. Patients must submit to regular, lifelong endoscopic surveillance with removal of any new rectal polyps. However, repeated endoscopic polyp removal may lead to rectal scarring, stenosis and poor rectal functioning.

The risk of developing a malignancy in the remaining rectal mucosa is estimated to be between zero percent (36) and thirty two percent. (37) This development would require a completion proctectomy. Factors that seem to be associated with this risk are having greater than twenty polyps in the rectum or colon cancer resected before or during the colectomy. In a St. Mark’s series, the cumulative risk of developing a malignancy in the retained rectum was ten percent at twenty years, increasing to greater than thirty percent at thirty five years. The report concluded that the means of surveillance must be improved or that the patients must undergo a complete proctocolectomy at an earlier age. (38) Even with increased surveillance, other studies have echoed these results, thus calling into question the use of the total abdominal colectomy with ileorectal anastomosis for treatment of FAP. Given that the more aggressive and complete proctocolectomy with a restorative ileal pouch-anal anastomosis (IPAA) is associated with a greater morbidity, studies have looked at features that might guide the surgeon in choosing to perform a total abdominal colectomy with an ileorectal anastomosis, rather than a proctocolectomy with an IPAA. The two factors which helped exclude patients from having an ileorectal anastomosis were the severity of colorectal polyposis, (39) and the location of the mutation on the APC gene. The risk of the development of a second carcinoma was greater if the mutation was located between codons 1250 and 1500, especially at codon 1309, a known “hot spot”. None of the patients with AFAP and mutations in codons 0 to 200, or greater than 1500 required a secondary proctectomy. (40) These studies conclude that it is reasonable to perform a total abdominal colectomy with ileorectal anastomosis in young patients with less than twenty rectal adenomas, less than one thousand colonic adenomas (considered to be mild disease), and in FAP with mutations in codons 0 to 200 or greater than 1500. Lifetime surveillance is required with the understanding that a future proctectomy may be required.

Laparoscopic Proctocolectomy with an ileal pouch-anal anastomosis

The third treatment option for FAP is a laparoscopic total abdominal proctocolectomy with an ileal pouch-anal anastomosis (IPAA), with or without a rectal mucosectomy. This type of pouch is also known as a J-pouch. Potential advantages include restored intestinal continuity with a new rectal reservoir, or neo-rectum, in those patients who do not want an end ileostomy, and an almost complete removal of the at-risk colorectal tissue. This approach is favored in situations where there is extensive polyposis, greater than twenty rectal polyps, polyps that cannot be controlled endoscopically, adenomatous dysplasia or carcinoma at any location in the large intestine, in patients with a history of desmoid tumors in whom the operative risk is higher due to the desmoid disease and in whom another operative procedure would potentially be fraught with problems, or in those patients with APC mutations associated with an increased rectal cancer risk. However, patients must be carefully selected as those with poor preoperative sphincter function, especially the elderly, may have poor functional results after IPAA. Additionally, anatomic considerations or infiltrative mesenteric desmoid disease may make the creation of an IPAA technically difficult or impossible, requiring a temporary or permanent ileostomy. Preoperatively, the patient must be prepared for this eventuality.

The operation itself is associated with a greater blood loss and an increased risk of immediate postoperative sepsis. Local sepsis is associated with pouch failure requiring excision of the pouch. A longer hospital stay is not uncommon. Longer term complications include the possibility of postoperative anal stenosis with troublesome functional symptoms, and increased stool frequency both during the day and nighttime. Stool frequency is often associated with perianal skin irritation. Urinary and sexual functioning may be compromised after this extensive dissection due to disruption of the autonomic pathways.

Other disadvantages include the unsuspected retention of rectal mucosa and the new, potentially occult development of rectal polyps. In patients undergoing an IPAA, continued endoscopic surveillance is mandatory as pouch adenomas can develop in the small intestinal pouch mucosa in thirty per cent of patients. Additionally, a small, but unknown number of patients may develop cancer in the pouch, at the site of the anastomosis or in the anal transition zone. The carcinomas can be locally advanced (T4) or not (T1, T2). (41) Continued lifetime surveillance is mandatory.

A Cleveland Clinic prospective study found the risk of developing adenomas in the pouch, anal transition zone or at the anastomotic staple line to be twice as high in a stapled IPAA as in a hand-sewn anastomosis (twenty eight percent versus fourteen percent). The study found that the postoperative development of adenomas was related to the severity of the colonic polyposis prior to operative intervention. However, the incidence of cancer development was minimal in both techniques, although the study stated that this may have been due to a short follow up period. The article concluded that the risk of future neoplasia must be balanced against the relatively better functional outcome with an IPAA. (42)

…And Back Again

A clinician who is knowledgeable in mutational genetics and who cares for patients at the early part of the diagnostic algorithm is in an ideal position to do a tremendous service for those patients and family members presenting with signs and symptoms pointing to a diagnosis of familial adenomatous polyposis. With advances in early detection, and with the concomitant improvement in survival rates and functional outcomes, operative intervention in patients with known or newly diagnosed familial adenomatous polyposis or attenuated familial adenomatous polyposis is gratifying for the patient, the family, any newly diagnosed relatives, the astute physician who first considers and confirms the diagnosis, and the surgeon who performs the preventative or curative operative procedure. Further improvements in early detection will enhance our ability to diagnose and treat this family of genetic disorders.

REFERENCES

27. Giardello, F.M., Brensinger, J.D., Peterson, G.M. et al. “The Use And Interpretation Of Commercial APC Gene Testing For Familial Adenomatous Polyposis.” New England Journal Of Medicine 336 (1997): 823-827

28. Wong Et Al., N. “Genetic Counseling And Interpretation Of Genetic Tests In Familial Adenomatous Polyposis And Hereditary Nonpolyposis Colorectal Cander.”Diseases Of The Colon And Rectum 44 (2001): 271-79.

29. Rabelo, R., W. Foulkes, and P. H. Gordon. “Role Of Molecular Diagnostic Testing In Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer.” Diseases Of The Colon And Rectum 44 (2001): 437-46.

30. Peterson, G. M. “Genetic Counseling And Predictive Testing in Familial Adenomatous Polyposis.” Seminars In Colon And Rectal Surgery 6 (1995): 55-60.

31. Karen, P., Nugent, M.A., “Total Colectomy And Ileorectal Anastomosis.”Pathology: Phillips, R, K., Et Al. London: Edward Arnold, 19954 80-91.

32. Bertario, L., S. Presciuttini, and P. Sala. “Causes Of Death And Postsurgical Survival In Familial Adenomatous Polyposis: Results From The Italian Registry.” Seminars In Surgical Oncology 10 (1994): 225-34.

33. Heiskanen, I. Et Al. “Impact Of Screening Examinations On Survival In Familial Adenomatous Polyposis.” Scandinavian Journal Of Gastroenterology 35 (2000): 1284-287.

34. Burke, C. A., G. J. Beck, J. M. Church, and R. W. Van Stolk. “The Natural History of Duodenal And Ampullary Adenomas In Patients With Familial Adenomatous Polyposis Followed In An Endoscopic Surveillance Program.” Gatrointestinal Endoscopy 49 (1999): 358-64.

35. Brosens Et Al., L. A. “Prevention And Management Of Duodenal Polyps in Familial Adenomatous Polyposis.” Gut 54 (2005): 1034-043.

36. Gingold, B. S., Jagelman, D. J., and R. D. Turnbull, R.D., “Surgical Management OF Familial Adenomatous Polyposis And Gardner’s Syndrome.” American Journal Of Surgery137 (1979): 54-56.

37. Bess, M. A., Adson, L. R. Elveback, A. A., and Moertel, C. G., “Rectal Cancer Following Colectomy For Polyposis.” Archive Of Surgery 115 (1980): 460-67

38. Bussey, H. J., Eyers, S. M. Ritchie, M., and J. M. Thompson. “The Rectum In Adenomatous Polyposis.” British Journal Of Surgery 72. [supplement] (1985): S29-31.

39. Chruch, J. Et Al. “Predicting Polyposis Severity By Proctoscopy: How Reliable Is It?” Disease Of The Colon And Rectum 44 (2001): 1249-254

40. Bulow, C., and H. Vasen Et Al. “Ileorectal Anastomosis Is Appropriate For A Subset Of Patients With Familial Adenomatous Polyposis.” Gastroenterology 119 (2000): 1454-460.

41. Nivatvongs, Santhat. “Part III: Colorectal Disorders.” Principles And Practice of Surgery For The Colon, Rectum and Anus. Informa Healthcare USA. 466-87.

42. Remzi, F. H., J. M. Church, and J. Bast et al. “Mucosectomy vs. stapled ileal pouch—anal anastomosis in patients with familial adenomatous polyposis.” Diseases Of The Colon And Rectum 44 (2001): 1590-596.

The post Colon and Rectal Cancer (Inherited): Part 4 appeared first on LAcolon.

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FAMILIAL ADENOMATOUS POLYPOSIS: ONE GENE. MANY MANIFESTATIONS.

MAKING SENSE OF THE ALPHABET SOUP THAT IS THE GENETIC CODE.

Parts I and II of this series looked at the genetics, diagnosis and treatment of hereditary nonpolyposis colorectal cancer.

Part III will examine familial adenomatous polyposis and the damage caused by this inherited disease. Emphasis is placed on the genetics of the disease and how knowledge of the mutational pattern can help the clinician secure a diagnosis, and begin treatment. Look alike diseases, those looking like familial adenomatous polyposis but arising from a mutation on a different gene will also be considered.

Part IV will evaluate the surveillance and surgical options for patients and family members affected by familial adenomatous polyposis. With an understanding of the genetics underlying familial adenomatous polyposis, the clinician on the frontlines of diagnosis and treatment will be able to help the patient and family members begin to struggle with, and overcome some of the dreaded consequences associated with this virulent disease.

Genotype to Phenotype: From Genetics To Appearance

Familial adenomatous polyposis (FAP), an inherited disorder, is responsible for one percent of all colorectal malignancies. Caused by a mutation in a single gene, the Adenomatosis Polyposis Coli (APC) gene, FAP can lead to a radical change in the structure and functioning of the body. How can a seemingly small change in the genotype so drastically alter the phenotype in such a lethal manner? The answer is in the genetic realm where proteins are produced. A mutant gene produces abnormal proteins which lead to disease.

A nucleotide, is formed by the combination of a five carbon sugar, one or more phosphates and one of the purine or pyrimidine nucleobases guanine, adenine, cytosine, or thymine. A tri-nucleotide sequence, also known as a triplet or codon, codes for and produces a specific amino acid using processes called transcription and translation. A long sequence of codons with a start codon and a stop codon defines a single gene, which codes for many amino acids. These amino acids bond together to form a protein. Proteins participate in every process within the cell. Proteins are the building blocks of enzymes and they also make up the structural or mechanical elements of body cells and tissues. Proteins play integral roles in cellular signaling, cellular division, and cell death or apoptosis. Each protein is considered to be the protein product of its parent gene.

The gene is a long-term storage area for the genetic code, or DNA, and all of the genes form a set of blueprints used by the body to control cellular structure and functioning. Many genes reside on a linear stretch of DNA and the entire length of these genes plus the intervening, non-coding portions form a chromosome. Humans have 46 chromosomes (the common fruit fly has 8 and goldfish have 104). Human chromosome five has between nine hundred and one thousand three hundred genes. One of these is the Adenomatosis Polyposis Coli gene.

In both FAP and sporadic colorectal cancers, a mutation of the APC gene is one of the earliest events leading to polyp formation, and subsequent malignant degeneration. This is known as the adenoma-carcinoma sequence. (1) Six hundred mutations have been discovered in the APC gene. The APC protein is made up of 2,843 amino acids. A mutation in any one of the six hundred APC codons can lead to disease through the production of a defective, malfunctioning, truncated APC protein product. The ubiquitous APC protein belongs to the family of suppressor proteins and is commonly found in the cell cytoplasm. It interacts with several other cytoplasmic proteins, including ß-catenin. ß-catenin may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once an epithelial layer is complete. Normally, the APC protein binds to, and down-regulates ß-catenin through destruction of the ß-catenin. Because of truncation or shortening of the now malfunctioning APC protein, ß-catenin may enter the nucleus and actually stimulate cell proliferation. This begins a neoplastic cascade and malignant transformation through unchecked cellular division. The result of this is polyp and tumor growth. The APC protein is highly concentrated in colonic mucosa. (2)

Different mutant codons within the APC gene may code for different forms of FAP or attenuated familial adenomatous polyposis (AFAP), and also code for the development of extra-colonic tumors. In other words, the mutation at the genotype level is translated into a somatic mutation, deformity or neoplasm at the phenotype level. For example, “mutations between codons 1301 and 2011 are associated with a six fold increase in desmoid tumors relative to the low risk region. Codons 1250-1464 are associated with severe polyposis and earlier onset cancer. Duodenal adenoma risk and extracolonic manifestations are highest between codons 976 and1067.”(3) Mutations associated with AFAP are located on either end of this large APC gene, (figure 1). (4) Mutations found in the APC gene of patients with FAP or AFAP are similar to those found in patients with sporadic colorectal cancer. However, in contradistinction to the acquired sporadic colorectal carcinoma, the APC mutation in the inherited disease is present at birth. (5)

Phenotype To Diagnosis: From Appearance To Discovery

The Phenotype Story: The Many Faces Of FAP

Familial adenomatous polyposis is a rare autosomal dominant disorder characterized by the pancolonic formation of hundreds or thousands of polyps which develop at an early age. It is associated with at least eight other malignancies. The APC gene mutation has a high penetrance rate, meaning that individuals with the mutated gene (the genotype) will almost surely develop polyps (the phenotype).

In the average, untreated patient the natural history of the disease is: (6)

• Age of appearance of adenomas: 23 years
• Age of onset of symptoms: 33 years
• Age of diagnosis of adenomas: 36 years
• Age of diagnosis of carcinomas: 39 years (65 years in the general population)
• Age of death from carcinomas: 42 years (71 years in the general population)

Sixty five percent of patients who present with symptoms of FAP already have a colorectal carcinoma.

There is an almost one hundred per cent risk of developing colon cancer if patients with familial adenomatous polyposis remain untreated. Therefore, early diagnosis and treatment are of paramount importance.

Eighty per cent of patients will have a family history of FAP or AFAP, with a known, precisely located mutation, heightening diagnostic suspicion and making the diagnosis of FAP straightforward. However, twenty per cent of patients will have a de-novo mutation in an unknown gene location. In these patients who are unaware of their disease, symptoms generally begin when the polyposis is complete, at an average age of thirty three years.

Rectal bleeding and diarrhea are the commonest presentations. As the symptoms call attention to the need for evaluation, colonoscopy is the surest way to detect the disease. Extracolonic manifestations of disease (see below) may also be discovered on physical examination and call attention to the diagnosis. The diagnosis is secured with histopathological confirmation of adenomatous polyps. Affected patients have as few as one hundred colonic polyps and may have thousands of polyps carpeting large sections of the colon. Polyp size can range from microscopic to greater than one centimeter; however most of the polyps are small. The smaller adenomas may require the use of indigo carmine or narrow-band imaging to be discovered. In contrast to HNPCC, where the disease is predominantly located proximal to the splenic flexure, FAP commonly affects the left side of the colon. Rectal carcinoma occurs in fifty nine percent of patients. However, the entire colon must be examined as rectal sparing has been reported. (7) Twenty four percent of patients have a sigmoid malignancy, and the remainder of cases shows more proximal disease. (8)

In FAP, there is a lifetime risk of developing associated desmoid tumors (15%), duodenal cancer (4%), thyroid cancer (2%), brain cancer (2%), ampullary cancer (1.7%), pancreatic cancer (1.7%), hepatoblastoma (1.6%), or gastric cancer (0.6%) and early diagnostic questioning and subsequent evaluation must focus on these areas.(9) Esophagogastroduodenoscopy may often disclose fundic gland polyps which might point the clinician to search in the direction of a defective APC gene. Suitable radiographic examinations such as CT scanning or MRI evaluation may be employed in the search for extracolonic disease.

Clinical Variants of Familial Adenomatous Polyposis

Attenuated Familial Adenomatous Polyposis

Attenuated Familial Adenomatous Polyposis (AFAP) is characterized by the formation of fewer, more proximal polyps developed at a later age. (10,11) Clinically, AFAP has been recognized relatively recently. It may be a variant of FAP, or may be a disease in its own right.

Securing a diagnosis of AFAP is more challenging but must be considered in younger patients with between ten and one hundred proximally located colonic polyps. The polyps are often flat. An upper gastrointestinal examination must be performed in patients with FAP or AFAP, as eighty to ninety per cent will develop duodenal or periampullary adenomas. The polyps are commonly flat. They are diagnosed at an average age of forty four years. The carcinomas in AFAP develop at age fifty six compared with FAP in which the average age at diagnosis is ten or fifteen years earlier. It is possible that the differential in age of onset of the polyposis and malignant transformation between FAP and AFAP is due to a lack of earlier recognition of AFAP by physicians and patients, rather than being a true difference in the age of onset. (5)

It is often difficult to distinguish between FAP and AFAP based solely on the number of polyps seen on examination. In a single family with a single mutation, the number of colonic polyps in each family member may vary widely. In fact, there is evidence that AFAP and FAP may not be separate diseases, but different manifestations of a single entity. Extracolonic disease is similar in both forms of polyposis. Genetically, FAP and AFAP are associated with a large number of different APC mutations. Clinically, patients with fewer than one hundred polyps may have FAP, AFAP or HNPCC. In a single family, patients may present with widely differing clinical manifestations. “The definition of AFAP, “multiple, but fewer than one hundred synchronous colorectal adenomas, is one that suffers from an arbitrary imposition of a finite number of polyps combined with a spectrum of subtle variations.”(5) Even though the polyps in AFAP are predominantly right sided and the mutation is usually located on either end of the APC gene, the underlying disease remains FAP. (5) AFAP simply may be a form of FAP with mild expression.

Turcot’s Syndrome:

Turcot’s Syndrome describes the association of colorectal adenomatous polyposis with central nervous system tumors, specifically, cerebellar medulloblastomas. Two thirds of patients have an APC gene mutation and one third have a mutation in a mismatch repair gene. Mismatch repair genes are commonly associated with hereditary nonpolyposis colorectal cancer, and Turcot’s Syndrome may be a disease that has several underlying genetic etiologies.

APC I1307K

Three hundred sixty thousand American Ashkenazy Jews are carriers of a mutant gene located on codon 1307 of the APC gene. This represents five percent of the Ashkenazy population. People carrying this mutation, known as APC I1307K, are at a 1.7 times greater risk of colorectal neoplasia compared with those who do not have this mutation. Additionally there are greater numbers of adenomas and colorectal cancers in this group, with a younger age at diagnosis. It is estimated that APC I1307K is responsible for up to four percent of all Ashkenazy Jewish colorectal cancers. Although the impact of this mutation is not fully understood at this time, it is thought that genetic testing of this entire population, irrespective of a family history of colorectal cancer, followed by appropriate clinical screening and surveillance might benefit the mutation carriers who are expected to develop colorectal cancer. (12)

Gardner’s Syndrome.

Gardner’s Syndrome is the association of FAP with epidermoid cysts, osteomas and fibromas (now called desmoid tumors). Colorectal polyposis was later added to the syndrome. Gardner’s Syndrome is thought to be FAP with an extraintestinal feature. As this seems to be the case in most clinical presentations of FAP, Gardner’s Syndrome is no longer considered to be a distinct entity.

MYH mutations: A Look Alike, But A Different Gene.

MYH polyposis is a condition resembling FAP on a phenotypic level but which results from a mutation on a gene other than the APC gene. The MYH gene is located on the short arm of chromosome one. Being inherited in an autosomal recessive manner means that both alleles, or both copies of the MYH gene must be mutant to cause the phenotypic expression of disease. MYH is usually associated with a smaller number of colorectal polyps, but some cases have been reported presenting with hundreds of colorectal adenomatous polyps; hence, the inclusion of MYH polyposis in the family of inheritable colonic polyposis syndromes. In patients with clinical disease, in whom no APC mutation is identified, a diagnosis of MYH polyposis should be considered and should be evaluated using gene analysis of a whole blood sample. Although malignant transformation of the polyps does occur, the exact incidence of this transformation is unknown. Treatment and surveillance is as for patients with FAP.

Other Look Alikes: Rare But Troublesome

Peutz-Jeghers Syndrome, Juvenile Polyposis, Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, and Metaplastic Polyposis are all rare inherited syndromes with varying presentations, varying types of polyps and variable degrees of risk for the development of a malignancy. The common phenotypic disorder linking them together is the development of gastrointestinal polyposis. The polyps become manifest at differing ages and have differing malignant potentials. The key point for the clinician to keep in mind is that the polyps’ histopathological features must be identified so as to appropriately guide surveillance and treatment. Genetic counseling is an integral part of the care in these patients.

Extracolonic Manifestations of Familial Adenomatous Polyposis

Endoderm Derived Disease

FAP affects the entire body and may give rise to extracolonic neoplasms derived from the embryologic endoderm, ectoderm or mesoderm. (Table 1) (13) The etiology of the extracolonic manifestations is not clear and may involve the APC gene, other genes or environmental factors. There is inconclusive data that suggests that the codon location of the APC mutation may have a phenotypic effect. (14) Death from extracolonic disease in patients with FAP is now more common than death from colorectal carcinoma. (15)

The prevalence of gastric polyps ranges from thirty four percent to one hundred percent. Most are hyperplastic polyps and a few are adenomatous and are located in the antrum. Malignant transformation rarely occurs. There is evidence that the adenomatous polyps are located in areas that have been exposed to bile through reflux. (16,17,18)

Duodenal polyps are found in over ninety percent of FAP patients. They are often located in the periampullary region. They vary in number, size and morphology. However, they are almost always adenomas. The concern in these patients relates to the potential for malignant transformation of these adenomas. Up to thirty five percent of patients with FAP have been found to have a duodenal or periampullary carcinoma. However, other studies have reported a much lower incidence of carcinoma (9)After desmoid tumors, periampullary carcinoma is the second leading cause of death in patients with FAP. (15)

Small intestinal adenomas and carcinomas occur rarely and the risk of developing a malignant lesion is small.

Mesoderm Derived Disease

Desmoid tumors arise from benign fibroaponeurotic tissue. They are thought to be true neoplasms as opposed to a fibroblastic reaction. They are locally invasive. Commonly, they cause pressure on surrounding structures and erosions of adjacent tissue. Small bowel obstructions are common and are also the result of local growth. The most common symptom in patients with an intraabdominal desmoid tumor is a painful mass, with pain being secondary to a small bowel obstruction. Desmoid tumors have been observed in fourteen percent of patients undergoing laparotomy for FAP (19). They are even more common in patients undergoing a repeat laparotomy. (20) Growth rates range from indolent to rapid. Although rare, spontaneous regression has been noted. In up to thirty eight percent of cases of laparotomy, a desmoid tumor interfered with the planned procedure. Treatment is controversial, empirical and difficult, especially with desmoid involvement with abdominal vessels, the ureters or the mesentery. Because of a high rate of recurrence, it is felt that a conservative approach, including the use of combinations of non-steroidal anti-inflammatory drugs and/or anti-neoplastic agents is warranted, with operative treatment reserved for patients having life threatening complications such as local invasion into vital structures. (21) Death as a result of desmoid disease is from local invasion into a vascular structure, sepsis resulting from an enteric fistula or as the result of the attempted therapeutic operation. (22)

Osteomas may occur in any bone, particularly in the facial bones. They are benign, cause symptoms due to local growth and are sometimes identified prior to the diagnosis of FAP. Dental abnormalities such as unerupted or supernumerary teeth, dentigerous cysts or odontomas occur often in FAP and their appearance is diagnostically useful. (21,23)

Ectodermal Disease

Ectodermal lesions associated with a mutated APC gene involve the eye, the skin or the brain.

Congenital hypertrophy of retinal pigment epithelium (CHRPE) is considered to be a marker for FAP, and is restricted to a mutation in codons 463 to 1444. The lesion is a hamartoma, which is a collection of cellular elements normally found at the site, but presenting as a disordered mass of histologically normal tissue. CHRPE is asymptomatic and benign. It is best viewed on indirect ophthalmoscopy through a dilated pupil. As a marker for FAP, it has a seventy nine percent sensitivity rate and a ninety five percent specificity rate. (24,25) In other words, patients presenting with CHRPE will most likely have FAP.

Epidermoid cysts are found on the limbs, face and scalp. They may be found in up to half of patients with FAP. They are rarely found in children except in FAP, and may appear even prior to the development of colorectal polyps. The association is strong enough such that any child with an epidermoid cyst should undergo a sigmoidoscopy after age fourteen. Histologically, the cyst is made up of a thin layer of squamous cells and may be asymptomatic or may present as a painful nodule.

Although also found in patients with hereditary nonpolyposis colorectal cancer, medulloblastomas are more often found in FAP. This association bears the name of Turcot’s syndrome, after Jacques Turcot, the Canadian surgeon who discovered this new extracolonic manifestation of FAP. Although rare, Turcot’s syndrome is usually fatal, with death occurring at an average age of twenty. In two studies, seventy five percent of patients died from the medulloblastoma and sixteen percent died from colorectal cancer. (26,27)

Part IV of this series will evaluate the surveillance and surgical options for patients and family members affected by familial adenomatous polyposis.

REFERENCES

1. Fearon, E. R., and B. Vogelstein. “A Model For Colorectal Tumourigenesis.” Cell 61 (1990): 759-67.

2. Schnitzler, M., T. Dwight, and D. J. Marsh. “Quantitation of AOC Messenger RNA in Human Tissues.” Biochem Biophys Res Commun 217 (95): 385-92.

3. Bertario, L. “Multiple Approach To The Exploration Of Genotype-Phenotype Correlations In Familial Adenomatous Polyposis.” Journal Of Clinical Oncology 21 (2003): 1698-707.

4. Chung, D. C. “A 45 Year Old Woman With A Family History Of Colonic Cancer And Polyps.” New England Journal of Medicine 349 (2003): 1750-760.

5. Nivatvongs, Santhat. “Part III: Colorectal Disorders.” Principles And Practice of Surgery For The Colon, Rectum and Anus. Informa Healthcare USA. 466-87.

6. Busey, H. J,. “Familial Polyposis Coli. Family Studies, Histopathology, Differential Diagnosis and Results of Treatment.” Johns Hopkins University Press (1975).

7. Bussey, H. J., M. A. Christensen, A. G. Thorson, and T. Williams. “Familial Polyposis: Colon Cancer In The Absence Of Rectal Polyps.” British Journal of Surgery 76 (1989): 744.

8. Bulow, S. “The Risk of Developing Rectal Cancer After Colectomy and Ileorectal Anastomosis In Danish Patients With Polyposis Coli.” Diseases of the Colon and Rectum 27 (1984): 726-29.

9. Galiatsatos, P., and W. D. Foulkes. “Familial Adenomatous Polyposis.” American Journal Of Gastroenterology 101 (2006): 385-98.

10. Spiro, L., S. Olschwang, and J. Groden Et Al. “Alleles of the APC Gene: An Attenuated Form of Familial Polyposis Coli.” Cell 75 (1993): 951-57.

11. Lynch, H. T., T. Smyrk, and T. McGinn Et Al. “Attenuated Familial Adenomatous Polyposis (AFAP). A Phenotypically and Genotypically Distinct Variant of FAP.” Cancer 76 (1995): 2427-433.

12. Gryfe, R., N. Di Nicola, G. Lal, S. Gallinger, and M. Redston. “Inherited Colorectal Polyposis And Cancer Risk Of The APC I1307K Polymorphism.” American Journal of Human Genetics 64 (1999): 378-84.

13. Bret, M. C., M. J. Hershman, and G. Glazer. “Other Manifestations Of Familial Adenomatous Polyposis.” In: Phillips, Spigelman and Thompson editors., Familial Adenomatous Polyposis And Other Polyposis Syndromes (1994): 143-58.

14. Powell, S. M. “Clinical Applications Of Molecular Genetics In Colorectal Cancer.”Seminars In Colorectal Surgery 6 (1995): 2-18.

15. Belchetz, L. A., T. Berk, B. V. Bapat, Z. Cohen, and S. Gallinger. “Changing Causes Of Mortality In Patients With Familial Adenomatous Polyposis.” Diseases Of The Colon And Rectum 39 (1996): 384-87.

16. Utsunomiya, J., T. Maki, and T. Iwama. “Gastric Lesions In Familial Polyposis Coli.”Cancer 34 (1974): 645-754.

17. Arcello, P. W., A. J. Asbun, and M. C. Veidenheimer Et Al. “Gastroduodenal Polyps in Familial Adenomatous Polyposis.” Surgical Endoscopy 40 (1996): 418-21.

18. Wallace, M. H., and R. K. Phillips. “Upper Gastrointestinal Disease In Patients With Familial Adenomatous Polyposis.” British Journal Of Surgery 85 (1998): 742-50

19. Heiskanen, I.., and H. J. Jarvinen. “Occurrence Of Desmoid Tumors In Familial Adenomatous Polyposis And Results of Treatment.” International Journal Of Colorectal Disease 11 (1996): 157-62

20. Clark, S. K., K. F. Neale, R. K. Phillips, and J. C. Landgrebe. “Desmoid Tumors Complicating Familial Adenomatous Polyposis.” British Journal Of Surgery 99 (86): 1185-189

21. Campbell, W. J., R. A. Spence, and T. G. Parks. “Familial Adenomatous Polyposis [a Review].” British Journal Of Surgery 6 (1995): 2-18.

22. Church, J. M. “Desmoid Tumors in Patients With Familial Adenomatous Polyposis.”Seminars In Colon and Rectal Surgery 6 (1995): 29-32

23. Talbot, I. C. “Familial Adenomatous Polyposis And Other Polyposis Syndromes.”Pathology: Phillips, R, K., Et Al. London: Edward Arnold, 1995. 15-25.

24. Giardiello Et Al., F. M. “APC Mutations And Extraintestinal Gene Phenotye of Familial Adenomatous Polyposis.” Gut 40 (1997): 521-25.

25. Campbell, W. J., R. A. Spence, and T. J. Parks. “Giardiello Et Al., F. M. “APC Mutations And Extraintestinal Gene Phenotye of Familial Adenomatous Polyposis.[review].”British Journal Of Surgery 81 (1994): 1722-73.

26. Turcot, J., J. P. Despres, and F. St Pierre. “Malignant Tumors Of The Central Nervous System Associated With Familial Polyposis OF The Colon.” Diseases Of The Colon And Rectum 2 (1959): 465-68.

27. Matsui, T., and N. Hayasi Et Al. “A Father And Son With Turcot’s Syndrome. Report Of Two Cases Evidence For Autosomal Inheritance.” Diseases Of The Colon And Rectum 41 (1998): 797-81

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Hereditary Nonpolyposis Colorectal Cancer: From Diagnosis to Treatment

In this four-part series, Part 1 reviewed the basic pathologic and genetic concepts underlying hereditary nonpolyposis colorectal cancer. This second part defines the clinical challenges facing the clinician who is at the forefront of diagnostic and treatment efforts. Parts 3 and 4 will examine familial adenomatous polyposis and related polyposis syndromes.

To Screen: Who, When and How

With steady advances in the understanding of the genetics controlling inherited colorectal cancer, the clinician is now in the position of securing a diagnosis before the disease has transitioned from a simple DNA error to a complex multiorgan disease.

The evaluation of inherited colorectal cancers often begins when a patient presents with a family history suggestive of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Syndrome. The diagnosis of HNPCC may also be suggested in the postoperative period on finding a poorly differentiated tumor with mucin, signet ring cells, or tumor-infiltrating lymphocytes. This leads to further investigation. The pathologist and then the geneticist are often the first physicians to diagnose HNPCC. How should screening and evaluation of the patient and family members proceed?

Mass screening of the general population is impractical, and because molecular sampling of all colorectal tumors is likewise unreasonable, much attention has been focused on finding more efficient tools to aid in the initial identification of at-risk populations before or after operative intervention. Screening techniques have used various combinations of family history, tumor pathology, evaluation of tumor microsatellite instability (MSI), immunohistochemistry (IHC) staining, or whole blood gene sequencing. (These genetic tests were discussed in Part 1 of this series.) A coherent screening strategy is needed that is based on current understanding of HNPCC at both the clinical and molecular levels.

Clinical Evaluation

Investigation begins with the construction of a family pedigree. Beginning with the 1990 Amsterdam criteria,¹ also known as the “3-2-1” rule, attempts have been made to develop clinical screening criteria to distinguish patients with sporadic colorectal cancer from those patients with inherited colorectal cancer, known as hereditary nonpolyposis colorectal cancer, or Lynch I Syndrome. The criteria evolved into the Amsterdam-2 criteria in 1998. The Amsterdam-2 criteria were created to include patients with Lynch II Syndrome, or inherited colorectal cancer associated with one or more extracolonic neoplasms. In women with Lynch II, there is a 50% to 70% lifetime risk for developing endometrial cancer, with the average age at diagnosis being 46 years.² Other malignancies associated with Lynch II are ovarian cancer (3%-13%); gastric cancer (2%-13%); transitional cell carcinoma of the ureter and renal pelvis (1%-12%); small bowel cancer occurring most commonly in the duodenum and jejunum (4%-7%); central nervous system tumors, most often glioblastomas (1%-4%); and hepatobiliary cancer (2%).³

The Amsterdam-2 criteria are:

• 3 or more relatives with a Lynch Syndrome–associated cancer;
• 2 or more successive generations affected;
• 1 or more relatives diagnosed before age 50 years;
• One family member should be a first-degree relative of the other 2 members.

Familial adenomatous polyposis should be excluded in cases of colorectal carcinoma; tumors should be verified by pathologic examination.

As the clinical guidelines evolved, so did the understanding of the genetics underlying HNPCC. The Bethesda Guidelines were developed in 1996 to help determine which colorectal tumors should be tested for MSI.⁴

Presently, both the Amsterdam-2 criteria and the Bethesda Guidelines are in clinical use. The Bethesda Guidelines for proceeding with further clinical and genetic evaluation of patients suspected of harboring a mismatch repair (MMR) mutation include the following⁵:

• Colorectal carcinoma diagnosed in a patient who is less than 50 years old;
• Presence of a synchronous or metachronous colorectal carcinoma or other Lynch Syndrome–associated tumors, regardless of age (a synchronous tumor is discovered at the same time as the original tumor, in the same organ system and of the same pathologic type as the original tumor; a metachronous tumor is of the same pathologic type as the original tumor, in the same organ system and develops more than 12 months after the date of discovery of the original tumor);
• Colorectal carcinoma with high MSI histology (MSI-H) or lack of IHC staining diagnosed in a patient less than 60 years old;
• Colorectal carcinoma diagnosed in one or more first-degree relatives with a Lynch Syndrome–associated tumor, with one of the cancers being diagnosed in a patient less than 50 years old; and
• Colorectal carcinoma diagnosed in 2 or more first- or second-degree relatives with Lynch Syndrome–associated tumors, regardless of age.

The clinician must balance the ideal need to screen and find all individuals affected by HNPCC, whether this is the patient or family member(s), against the psychological and financial costs of testing. Various approaches to the molecular evaluation are based on prescreening the at-risk population using the Amsterdam-2 criteria, the Bethesda Guidelines, or variations of these clinical guidelines combined with some form of genetic evaluation.⁶

The authors use an approach that combines the most relevant features of all available techniques. The approach is based on clinical identification of individuals at risk for an inherited colorectal cancer followed by a genetic evaluation at the molecular level. This strategy may not be available in all institutions. The strategy is separated into a testing scheme for patients with tumor tissue available for analysis (Figure 1) and a strategy for patients from whom tissue is not available tor testing (Figure 2). It is important to note that in patients who are undergoing IHC testing and/or germline analysis, specific genetic information may be uncovered. Patients must give informed consent before undergoing this testing, and genetic counseling must be available. A caveat regarding the use of the algorithm approach: There are other algorithms which do not use MSI testing, but employ IHC as the only initial molecular evaluation before germline analysis. This approach has the advantages of being easier to perform than MSI testing and may be more widely available for clinical use. However, IHC testing has the disadvantage of being unable to distinguish Familial Colorectal Cancer Type X from a non-informative test result. Surveillance for each of these entities is different.

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The initial step in the evaluation is to determine whether the patient or family member meets the Amsterdam-2 criteria, the Bethesda Guidelines, or has a suspicious history which does not meet the strict clinical screening criteria.

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When Tumor Tissue Is Available

If tumor tissue is available, it is first tested for MSI (Figure 1). This test is highly sensitive at 98%, and any patient who is MSI-stable (MSI-S) or MSI-low (MSI-L), most likely does not have HNPCC. Further molecular testing of this group is unhelpful, yielding little new information. However, this group of patients carries a diagnosis of Familial Colorectal Cancer Type X, which has an inherited etiology as the origin of the tumor, caused by an unknown genetic mutation. Patients in this group appear to have a lower overall incidence of colorectal cancer and a lower risk for non-colorectal cancers than families with documented HNPCC.⁷ The colorectal cancers seem to occur at a later age as well. Surveillance in this group of patients is different from that in patients with a diagnosis of HNPCC. It is started five or 10 years earlier than the earliest diagnosed colorectal cancer in the family, and conducted no less often than every five years. Aggressive endometrial cancer screening is not necessary and is not supported by data in this group of patients.

Tumors that are MSI-H are subjected to IHC staining, searching for the identification of the mutant gene. If IHC staining is normal, with normal protein expression of the known MMR genes, the test is considered non-informative. However, both the patient and family members are followed as if they carried a diagnosis of HNPCC. Even though the test is noninformative, emphasis is placed on intensive surveillance so as not to miss any patients in this group who might have HNPCC. The major disadvantage of this approach is that patients who, in fact, do not have HNPCC may undergo screening and continued intensive surveillance as if they were carriers of the mutation. This has obvious psychological and financial costs as well as the downside of any morbidity associated with the surveillance procedures.

Patients or family members without tumor protein staining by IHC undergo germline sequencing of the newly discovered mutant MMR gene. If germline testing confirms the mutation, this patient or family member is identified as having HNPCC and undergoes surveillance as described below. Finding a mutation in a known MMR gene is the sine qua non for diagnosing true HNPCC.

A patient who has previously undergone a segmental colon resection for what was thought to be sporadic disease now carries an additional diagnosis of HNPCC. Consideration must be given to continued intensive lifetime colorectal surveillance, or to a repeat operation with resection of the remaining colorectal tissue. Surveillance of other organ systems is indicated and is detailed below.

As MLH1 hypermethylation accounts for 20% of all sporadic colorectal cancers, tumors demonstrating high MSI and absent MLH1 staining on IHC, and in whom no MMR gene mutation is found on germline analysis, will undergo testing looking for sporadic, non-inherited disease, or an epigenetic mutation. Attention is focused on MLH1 because, with few exceptions, it is the methylated gene commonly associated with sporadic colorectal cancer. An epigenetic mutation is one in which the underlying DNA sequence is normal and a change, such as nucleotide hypermethylation, has occurred on top of this normal DNA sequence. This change, although affecting gene function, is not considered to be inherited. The βRAF gene is involved in cell signaling. When the βRAF gene mutates, cell growth and function are affected. Patients without protein staining for MLH1 who test positive on both of these tests are considered to have sporadic, non-inherited disease. Surveillance for this group and family members is the same as for the general population.

If the hypermethylation and βRAF tests are negative, the genetic test results are considered to be non-informative and further surveillance is the same as for patients with HNPCC.

When Tumor Tissue Is Not Available

In patients who meet the clinical screening criteria or guidelines, without tissue for study (the patient has previously undergone a tumor resection and the tissue is not available, or in family members of patients with known HNPCC), germline MMR gene analysis is the first and only molecular evaluation performed (Figure 2).

If there is a family history of a known specific genetic mutation, this gene is sequenced in the patient. Testing for an already known mutant gene avoids having to laboriously analyze all MMR genes. If a mutation is confirmed, a diagnosis of HNPCC is made and surveillance proceeds appropriately. If the patient’s family has no clinical findings of disease, this patient is considered to be a carrier of the HNPCC mutation. Surveillance proceeds as for patients with HNPCC. Descendants of this patient must be screened as well.

If a mutation is not found, the patient is considered to not have HNPCC and surveillance is carried out as for the general population. Descendants of the patient also do not have the mutation.

In patients without tissue for study and in whom there is no available genetic information, analysis of all MMR genes is performed. If a mutation is found, a diagnosis of HNPCC is made and surveillance proceeds accordingly. Again, finding a mutation in a known MMR gene is the sine qua non for diagnosing true HNPCC. If a mutation is not found, this patient or family member is considered to have a non-informative test and surveillance proceeds as if a diagnosis of HNPCC has been confirmed. The patient undergoes surveillance as if an HNPCC mutation exists.

Importantly, if there is a high index of suspicion of inherited colorectal cancer in patients not meeting the Bethesda Guidelines or the Amsterdam-2 criteria, testing is begun as if malignant disease exists.

Because the genetics of all inherited colorectal cancers are not completely understood, parts of the diagnostic algorithm involve tests with lower than optimal sensitivities. Emphasis has been placed on screening and surveillance as if the patient or family member has a Lynch tumor or is an HNPCC carrier, so as not to miss disease in the patient under study.

Understanding Surgical Options

Intensive Watchful Waiting or Surgical Prophylaxis In Patients Without Evidence of Disease?

After using clinical screening guidelines to direct evaluation and molecular testing, patients without detectable disease who have an HNPCC-associated mutation or who are to undergo surveillance as if they were known HNPCC mutation carriers should begin full colonic surveillance every one to 2 years beginning at age 20, or 10 years earlier than the youngest age of onset of colorectal cancer in the family, whichever is earlier. This should continue to age 40, at which time surveillance should be conducted annually. Accelerated carcinogenesis occurs in HNPCC and a tiny colonic adenoma may emerge as a carcinoma within 2 to 3 years, as opposed to the 8 to 10 years this process may take in the general population. It is for this reason that annual colonoscopic surveillance should begin at the age of 40. The entire colon must be evaluated, as tumors tend to occur in the more proximal colon.⁸

Because endometrial cancer is the most common extracolonic malignancy, women at risk for HNPCC should have an annual transvaginal ultrasound with consideration given to regular endometrial biopsies and evaluation of CA-125 levels after age 25. Female patients should be made aware of the value of prophylactic hysterectomy and oophorectomy, especially after the childbearing years are completed.

Upper gastrointestinal endoscopy should be performed regularly. Families having a predilection for genitourinary tumors should undergo ultrasound and urine cytology screening every 2 years beginning at age 25. However, prophylactic intervention is not recommended.

The risk–benefit ratio for prophylactic colectomy versus lifetime endoscopic surveillance in carriers of the HNPCC mutation is equivocal. Not all carriers will develop disease and operative intervention carries morbidity. Therefore, recommendations for surgical intervention in asymptomatic patients are complex. In the most straightforward case, a prophylactic resection is indicated in those patients with an MMR mutation in whom surveillance is not technically possible, in noncompliant patients, or in those with a personal preference for prophylactic operative intervention.⁹ The goal of a prophylactic resection is to remove as much at-risk tissue as possible while retaining normal colorectal functioning. Even with a prophylactic resection, patients remain at risk for the development of extracolonic neoplasms, and continued surveillance is necessary.

Understanding Surgical Options

The Surgeon

In patients with an HNPCC-associated MMR mutation and a dysplastic adenoma or a colorectal cancer, a choice exists between a segmental resection, a proctocolectomy with a permanent ileostomy, a total abdominal colectomy with an ileorectal anastomosis, or a proctocolectomy with an ileal pouch–anal anastomosis (IPAA). There are advantages and disadvantages with each option.

First, a thorough evaluation should be undertaken to locate any sites of extracolonic disease that could be removed concomitantly during a colonic resection, or which would suggest widespread, late-stage disease precluding a colonic resection for cure. In patients whose tumors are MSI-H and/or lacking IHC staining for MLH1, and in whom germline analysis does not reveal an MMR gene mutation, hypermethylation testing and βRAF mutation testing should be performed to rule out sporadic colorectal cancer. A standard oncologic segmental resection would be the obvious operative choice in patients with sporadic disease.

The ideal operative approach attempts to balance the need for removing as much at-risk tissue as possible against the side effects associated with a more radical extirpation. The functional results are generally considered to be better with a greater amount of colon or rectum left intact. Conversely, not removing all of the colorectal mucosa exposes the patient to a 45% increased risk for a metachronous lesion.

Four Choices

In patients with an HNPCC lesion, a proctocolectomy with an end ileostomy will remove all at-risk tissue and will prevent the development of a metachronous colorectal lesion. However, this will leave the patient with a permanent stoma and is not a popular choice among young patients. This operative approach is not without morbidity.

A total abdominal colectomy with an ileorectal anastomosis removes most of the colonic tissue while attempting to preserve normal rectal reservoir function. The remaining rectum is at risk for the development of a second cancer and will require frequent surveillance for the lifetime of the patient, as there is a 12% incidence of the development of a rectal cancer at 10 years postoperatively.^10,11

A proctocolectomy with an IPAA removes almost all colorectal tissue. However, microscopic islands of mucosa may remain and are subject to malignant transformation. Lifetime proctoscopic examinations are necessary. Frequent daytime and nocturnal bowel movements can strongly impact the postoperative quality of life. Sexual function may be affected with extended resections, and immediate postoperative morbidity is higher as well. Pouch failure requiring excision of the pouch may occur and is more common after local sepsis in the postoperative period.

What about the possibility of performing a more limited, segmental resection? It has been shown that a segmental resection is associated with a higher rate of development of a second colorectal cancer, a shorter period of time to the development of the colorectal cancer, and a similarly shorter period of time to a second operative resection compared with a primary operative procedure of a total abdominal colectomy with an ileorectal reconstruction or a proctocolectomy with an IPAA. These results are not surprising, as leaving in place a greater amount of colorectal tissue with a segmental resection exposes the remaining at-risk tissue to the same genetic forces that caused the original cancer.¹² However, this is not the entire story, as an extended resection is associated with a higher postoperative morbidity rate. This rate increases in older patients undergoing a more radical procedure.

Segmental Resection and Extended Resection: Postoperative Quality of Life And Life Expectancy

When evaluating quality-of-life results in patients undergoing a total abdominal colectomy with an ileorectal anastomosis, subjects were found to have a good postoperative quality of life, but also had three to four formed stools per day, a slightly increased incidence of fecal urgency and occasionally required antidiarrheal medication. There was a suggestion that postoperative problems were more severe in patients who had undergone an ileo-midrectal anastomosis (mid-rectal was defined as an anastomosis 10 cm proximal to the anal canal).¹³ These “manageable” results and low incidence of postoperative problems were contrasted with the need for more invasive, intensive lifetime surveillance in patients undergoing a more limited, segmental resection.

Life expectancy after an extensive resection was compared with that after a limited resection. The gain in life expectancy after a proctocolectomy with an IPAA compared with a segmental resection was 3.2 years if the initial operation was performed at age 27. With operative intervention at age 47, the gain was 1.3 years, and the gain was 0.3 year with operative intervention at age 67. The gain in life expectancy after a total abdominal colectomy with an ileorectal anastomosis compared with a segmental resection was 2.3 years if the initial operation was performed at age 27. With operative intervention at age 47, the gain was one year, and the gain was 0.3 year with operative intervention at age 67. It was noted that older patients had significantly more difficulty with postoperative bowel control and received very little benefit in additional life expectancy after either type of extended resection.¹³

The same study evaluated the differences in life expectancy after each type of operative intervention in patients with HNPCC when stratified by the Dukes classification of tumor stage at the time of diagnosis and treatment. The study found that the earlier the stage at which an MMR gene for colorectal cancer was detected and the younger the patient at the time of detection, the greater was the benefit in years of life expectancy gained using the more extensive operations. A proctocolectomy with an IPAA compared with a segmental colectomy or hemicolectomy yielded an average gain in life expectancy of 4.7 years in Dukes A tumors, 2.4 years in Dukes B tumors, and 9 months in Dukes C tumors. The gain was 3.4 years after a total abdominal colectomy with an ileorectal anastomosis in Dukes A lesions. These differences decreased drastically with advancing age to the point at which the type of operation made no difference in years of life expectancy at age 67, irrespective of the Dukes tumor stage. Stated another way, older age was associated with a negligible gain in life expectancy after a more extensive, radical operation, irrespective of tumor stage. (The data appeared to indicate that “older age” was between 50 and 60 years, although the authors stated only that it was “less than 60 years of age.”) The authors did point out that the results may have been influenced by a bias in the choice of operative treatment, as the study was performed retrospectively before the knowledge of the tumor stage.¹³

The authors underscored the statistically significant gain in years of life expectancy in relation to regular, intensive surveillance beginning at a young age, to detect tumors at an early stage.¹³

It is recommended that in younger patients with a known diagnosis of a Lynch I or Lynch II colorectal tumor, an extended resection should be performed. The type of extended resection is an individual decision balancing the expected increase in postoperative life expectancy and the postoperative long-term morbidity. A total abdominal colectomy with an ileorectal anastomosis and annual proctoscopic surveillance is a reasonable option in younger patients. As HNPCC tumors tend to occur in the proximal colon, leaving the rectum intact to obtain a better functional result achieves a reasonable balance between cure, prevention and morbidity.

In older patients, especially in those with abnormal sphincter function, there is minimal gain in life expectancy after a more radical resection compared with increased morbidity. A segmental resection and annual surveillance colonoscopy may be preferable.

In patients with a colorectal tumor who meet the Amsterdam-2 criteria or the Bethesda Guidelines and who have an MSI-H tumor or absent IHC protein staining, and no discoverable germline mutation (a non-informative test), a segmental resection with lifetime annual colonoscopic surveillance may be offered. The risk for developing colorectal cancer or extracolonic neoplasia is lower than in HNPCC, and the age at diagnosis of colon cancer is older than in HNPCC.⁷ Depending on the age of the patient and any other mitigating features, an extended resection with annual proctoscopy may be performed. Genetic counseling may assist in the decision-making process in these cases.¹⁴

Although the data are less clear with regard to a prophylactic resection in HNPCC-associated mutation carriers who do not have a colorectal malignancy, an extended resection remains the procedure of choice, because there is less remaining colorectal tissue at risk for metachronous disease. This is especially true in younger patients, but again, the patient must be aware of the increased morbidity accompanying an extended resection.

Rectal Cancer: Operative Options

In patients harboring a rectal cancer, a low anterior resection with sparing of the colon may be offered. Patients may have better bowel function after this but will require regular, lifetime surveillance of all remaining colonic tissue. However, the rate of development of a metachronous cancer in the remaining colon after a limited resection may be as high as 45%.^10,15 Alternatively, a proctocolectomy with an IPAA may be performed. The potential for developing a metachronous colon cancer using the limited resection would seem to favor performing the more extensive resection. Patient age, sphincter function, and genetic counseling may be the vital criteria used in decision making.

Prophylaxis for Women

Finally, in women with HNPCC who are undergoing a colon resection or other abdominal operations or who have completed childbearing, a prophylactic hysterectomy and bilateral salpingo-oophorectomy may be offered. This recommendation is emphasized for women with a specific family history of endometrial or ovarian cancer in addition to the MMR mutation.^9,16

New Knowledge, Improved Survival

HNPCC is associated with a 30% incidence of nodal metastases compared with an incidence as high as 65% in the more advanced stages of sporadic colorectal cancer.¹⁷ There is also a 9% incidence of peritumoral lymphocytic invasion in HNPCC tumors, signaling a possible enhanced immune response. When matched for age of onset and tumor stage, HNPCC colorectal cancers are associated with a significantly better survival rate than sporadic colorectal tumors.^18,19

Ultimately, treatment decisions should be discussed with the patient after consultations with all relevant specialists.

As new knowledge becomes available and light is shed on the genetic underpinnings of inherited colorectal cancers, the uncertainties in diagnosis and treatment will recede into the past history of our experience. Treatment and treatment algorithms will improve. But for now, a thorough understanding of the genetics of HNPCC will aid the physician in diagnosing and managing a complex problem in its early stages rather than later.

Parts 3 and 4 will examine familial adenomatous polyposis and other inheritable polyposis syndromes.

References

• Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110(4):1020-1027. Erratum in: Gastroenterology. 1996;111(5):1402.
• Chung D, Rustgi AK. The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications. Ann Intern Med. 2003;138(7):560-570.
• Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch Syndrome (hereditary non-polyposis cancer). J Med Genet. 2007:44(6):353-362.
• Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997;89(23):1758-1762.
• Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261-268.
• Reyes CM, Allen BA, Terdiman JP, Wilson LS. Comparison of selection strategies for genetic testing of patients with hereditary nonpolyposis colorectal carcinoma: effectiveness and cost-effectiveness. Cancer. 2002;95(9):1848-1856.
• Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293(16):1979-1985.
• Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348(10):919-932.
• Church J, Simmang C. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003;46(8):1001-1012.
• Lee JS, Petrelli NJ, Rodriguez-Bigas MA. Rectal cancer in hereditary nonpolyposis colorectal cancer. Am J Surg. 2001;181(3): 207-210.
• Rodriguez-Bigas MA, Vasen HF, Pekka-Mecklin J, et al. Rectal cancer risk in hereditary nonpolyposis colorectal cancer after abdominal colectomy. International Collaborative Group on HNPCC. Ann Surg. 1997;225(2):202-207.
• Natarajan N, Watson P, Silva-Lopez E, Lynch HT. Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis Colon Rectum. 2010;53(1):77-82.
• de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut. 2003;52(12):1752-1755.
• Church J. Prevention of metachronous colorectal cancer in patients with Lynch syndrome. Dis Colon Rectum. 2010;53(1):3-4.
• Guillem JG, Smith AJ, Calle JP, Ruo L. Gastrointestinal polyposis syndromes. Curr Probl Surg. 1999;36(4):217-323.
• Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecological cancers in the Lynch syndrome. N Engl J Med. 2006;354(3):261-269.
• Guillem JG, Puig-La Calle J Jr, Cellini C, et al. Varying features of early age-of-onset “sporadic” and hereditary nonpolyposis colorectal cancer patients. Dis Colon Rectum. 1999;42(1):36-42.
• Watson P, Lin KM, Rodriguez-Bigas MA, et al. Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer. 1998;83(2):259-266.
• Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology. 1996;110(3):682-687.

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HEREDITARY NONPOLYPOSIS COLORECTAL CANCER: GENETICS AND DIAGNOSIS

THE ALPHABET SOUP OF GENETICS AND DIAGNOSIS EXPLAINED

With a myriad of vexing abbreviations and obscure terminology, the genetics controlling the formation of colonic polyps and malignancies may be difficult to appreciate. Paradoxically, the physician, positioned at the beginning of the diagnostic effort, is often the person most hampered by a lack of basic understanding of this genetic alphabet soup. All that is required to overcome this obstacle is a refresher in basic genetics and a high index of clinical suspicion. As the science underlying the development of inherited colorectal cancer has become better understood, the clinician has become better equipped to stand at the forefront of the diagnostic and treatment effort.

Part I of this series will examine the roles of the pathologist and geneticist in diagnosing Hereditary Nonpolyposis Colorectal Cancer. Part II will discuss screening and treatment and the roles of the epidemiologist, the diagnosticians and the surgeon. In Parts III and IV, Familial Adenomatous Polyposis will be discussed.

SPORADIC, FAMILIAL AND INHERITED DISEASE

Of all colon cancers, eighty to ninety percent occur sporadically, with no known etiology. Ten to fifteen percent of patients have familial colorectal cancer, meaning that there are two or more colorectal malignancies found in a given family and that a specific causative gene has not been identified. Five percent of patients have an inherited or hereditary form of colon cancer and a causative genetic abnormality has been found to be associated with the malignancy.

Generally, inherited colorectal cancers are divided into two groups. The first group is composed of those malignancies arising in a background of epithelial polyposis or hamartomatous colonic polyps. Familial adenomatous polyposis is the most common syndrome in this group. The second group is represented by malignancies arising in grossly normal appearing mucosa with few or no visible underlying polyps. Hereditary nonpolyposis colorectal cancer is the most common syndrome in this group.

HEREDITARY NONPOLYPOSIS COLORECTAL CANCER

Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome accounts for four percent of all colorectal cancers. Originally characterized in 1895 as a familial clustering of colorectal and other types of cancer, and then re-described in 1971 by Henry Lynch, HNPCC is now defined molecularly as an inherited, cancer-predisposing syndrome secondary to a deleterious germline mutation in one of a group of DNA mismatch repair (MMR) genes.(1,2) MMR genes correct sequence errors in DNA that result from faulty replication. The MMR genes are part of a post-replication DNA repair system. This genetic machinery is as complex as the genetic replication machinery itself, underscoring the importance of the MMR system.

An estimated one hundred fifty thousand Americans may be carriers of the HNPCC mutation and have a ninety percent lifetime risk of developing some form of cancer. Up to eighty percent of carriers will develop colorectal cancer by age seventy years. Up to seventy percent of female carriers are at risk of developing endometrial cancer by age seventy. With germline mutation analysis, the aberrant genetic fingerprint is often detectable prior to the development of cancer. Unfortunately, our present day capabilities have not advanced to the point of being able to use this information to repair the faulty gene and prevent the development of disease in affected individuals. However, we do possess the ability to reduce cancer risk in selected patients by removing susceptible organs before malignant transformation occurs.(3)

UNDERSTANDING THE DISEASE: THE PATHOLOGIST

HNPCC, or Lynch syndrome, is divided into Lynch I and Lynch II. Muir-Torre Syndrome and Colorectal Cancer Type X are also members of the HNPCC group. Muir-Torre is not commonly seen in the clinical setting. These diseases are often discovered by the pathologist postoperatively upon finding certain pathological features during the examination of the resected surgical specimen.

In Lynch I, colorectal cancer is the most commonly occurring malignancy. The lifetime risk of developing a colorectal cancer in an individual with Lynch I syndrome is eighty percent. The average age at diagnosis is forty four years old, compared to age sixty four in the sporadic form of colon cancer. Multiple generations are usually affected. Most of the neoplasms are poorly differentiated and located proximal to the splenic flexure. Synchronous lesions occur in seven percent of cases compared with one percent in sporadic cases. Metachronous lesions are found in forty five percent of patients with HNPCC compared with five percent of those with sporadic colon cancer, signaling a possible mismatch repair defect. Colorectal cancer occurring in the absence of a visible polyp or polyposis is the final phenotypic expression of the MMR mutation. It is important to note that a polyp, whether visible or occult, is the precursor lesion of the colorectal cancer.

Lynch II describes the association of colorectal cancer with extracolonic malignancies. In women with Lynch II, there is a fifty to seventy percent lifetime risk of developing endometrial cancer, with the average age of diagnosis being forty six(4). Other malignancies associated with Lynch II are: ovarian cancer (three to thirteen percent), gastric cancer (two to thirteen percent), transitional cell carcinoma of the ureter and renal pelvis (one to twelve percent), small bowel cancer occurring most commonly in the duodenum and jejunum (four to seven percent), central nervous system tumors, most often glioblastomas (one to four percent), and hepatobiliary cancer (two percent)(5)

Muir-Torre Syndrome is a rare syndrome consisting of multiple benign and malignant neoplasms. It may be a variant of Lynch II. Sebaceous gland adenomas are the most common marker of the disease and are often found on the head. Keratoacanthomas, which may begin as a red nodule and progress to a shiny nodule with telangiectasia and a central crust, are located on the face and dorsum of the hands. Visceral carcinomas are frequent, occurring in one half of patients with Muir-Torre. The colonic neoplasms are the most frequent malignancies found in Muir-Torre syndrome and are usually located proximal to the splenic flexure. Genitourinary tumors are the second most common malignancy(6).

Familial Colorectal Cancer Type X is a disease in which those involved meet the clinical criteria of the nonpolyposis syndrome but do not have the MMR defect found in the nonpolyposis syndromes. More specifically, patients with Familial Colorectal Cancer Type X do not have a demonstrable mismatch repair mutation in one of the known MMR genes. The risk of developing colorectal cancer or extracolonic neoplasia is lower than in those patients with HNPCC, and the age of diagnosis of colon cancer is higher than in patients with Lynch Syndrome. Colonic malignancies are not predominantly right sided as in patients with Lynch Syndrome. Unlike patients with the Lynch II syndrome, these individuals do not seem to develop malignancies in other organ systems(7).

UNDERSTANDING THE GENETICS: THE GENETICIST

HNPCC is transmitted through germ cells in an autosomal dominant fashion and is highly penetrant. Germline cells are those cells passed down through generations. The commonly involved genes are MSH2, found in sixty percent of HNPCC mutations and MSH6, found in ten percent of HNPCC mutations. Both are located on chromosome two. MLH1, located on chromosome three is responsible for thirty percent of mutations. Numerous other genes account for rare cases of HNPCC. These genes normally produce proteins responsible for removing and repairing specific nucleotide sequences in DNA which may have become corrupt as a result of faulty replication. One copy of the mutant HNPCC gene is found in all cells and in all tissues of carriers. A second, normal copy of the gene from the unaffected parent is also present in all cells. Any event causing a mutation and inactivation of this second normal gene in colorectal epithelium or other susceptible epithelium causes a transcription silencing of an important part of the MMR genetic machinery. The mutation is considered to be a “second hit” as both genes coding for the production of mismatch repair proteins are now non-functional. Without mismatch repair, there is a rapid accumulation of somatic mutations and a neoplastic cascade leading to tumor development, which is the ultimate expression of the HNPCC phenotype.

The defect in mismatch repair genes also leads to mutations in “bystander” genes, known as microsatellites. Microsatellites are short, non-coding, tandemly repeated DNA sequences of one to six nucleotide bases located primarily on the telomere or centromere, but also located next to the coding region of MMR genes. These sequences are unique to each individual. They can be affected by a mutation termed microsatellite instability (MSI). MSI results from the erroneous insertion, deletion or mis-incorporation of bases during DNA replication or recombination, with failure of the mismatch repair system to correct these errors(8). In HNPCC, mutant microsatellites begin to accumulate and can be detected in the tumor tissue of ninety five percent of affected patients using fluorescent multiplex polymerase chain reaction-capillary electrophoresis. The tumor microsatellite nucleotide repeats are compared with the repeats found in normal tissue adjacent to the tumor tissue. The tumor is considered to be microsatellite unstable if the tumor repeats are different from the normal tissue repeats. MSI testing can be performed on fresh tissue or fixed paraffin blocks. In 1993, the genetics underlying mismatch repair were elucidated, allowing for MSI testing of tumor tissue in an attempt to diagnose HNPCC. (9,10,11,12) Depending on the number of abnormal nucleotide repeats found in the tumor tissue, results are reported as MSI-H (high), MSI-L (low) or MSI-S (stable).

An alternative detection technique consists of using antibodies to normal MMR gene proteins, combined with imunohistochemistry (IHC) fluorescent staining. IHC testing can be performed on fresh tissue or fixed paraffin blocks. Lack of staining is usually considered to be a positive test result, indicating loss of the normal protein product. This is due to the existence of a mutant, non-functioning mismatch repair gene. In 1996, monoclonal antibodies to mismatch repair gene proteins were discovered, allowing for this additional technique in the search for MMR mutations.(13,14)

Both MSI testing and IHC staining evaluate the phenotypic results of the HNPCC MMR gene mutation and are considered to be surrogate markers for HNPCC. (15,16,17) Cases of false positives results and rare false negative result exist and these must be considered as the clinician begins the evaluation. Higher detection sensitivities of up to ninety eight percent have been reported when using MSI testing in combination with IHC, as compared to using either test by itself. Tumor testing has a high sensitivity, and a lack of tumor microsatellite instability (MSI-S or MSI-L) or normal IHC staining effectively rules out the possibility of having classic Lynch I or Lynch II. No genetic mutation in a known MMR gene will be found on further testing. However, as these patients meet the clinical criteria for having an inherited colorectal cancer, they have been termed Familial Colorectal Cancer Type X, or “the other half of HNPCC”.(18,19)

Additionally, positive results (MSI-H) do not guarantee that a germline mutation will be found. An important and not uncommon example of a false positive test result which, if left undiscovered could lead to expensive and time consuming testing, is caused by hypermethylation and subsequent transcription silencing of MLH1. This is thought to be the etiology of fifteen percent of sporadic colorectal cancers. This is an epigenetic (non-mutational) change and means that although the underlying DNA morphology and sequence is normal, gene functioning is affected by a superimposed error, in this case, methylation of MLH1. MSI testing will be positive for microsatellite instability, but will not distinguish sporadic from inherited disease. The βRAF gene manufactures a βRAF protein which is involved in transmitting signals related to cell growth. A βRAF gene mutation is present in the majority of sporadic tumors with hypermethylation, but is not found in cases of HNPCC germline mutations. The combination of MSI testing, MLH1 hypermethylation testing and βRAF mutation analysis can help distinguish sporadic colorectal cancer from HNPCC and help to avoid otherwise unnecessary genetic testing and the resulting patient anxiety.

Germline analysis, with the discovery of a genetic mutation in one of the MMR genes is an important step in diagnosing HNPCC. It is performed on samples of whole blood. However, germline analysis is not widely available for all patients. Detection of the deleterious germline mutation has become the ultimate diagnostic criterion for HNPCC. The mutant gene is identified, as is the exact nucleotide mutation. This valuable information can be used in screening and in genetic counseling of family members. Patients identified as having a mutation in MSH2 or MLH1 comprise ninety percent of HNPCC patients. Therefore, germline testing directed toward these genes will yield the most obvious benefit. Finding a germline mutation in patients with MSI-H tumors or in tumors with absent IHC staining represents the ultimate diagnostic confirmation of HNPCC. However, up to fifty percent of clinically defined individuals with HNPCC do not display a mutation in one of the known MMR genes and are considered to have Familial Colorectal Cancer Type X.

To summarize the most common test results, in patients meeting the clinical criteria for having HNPCC (criteria to be discussed in part II), who have a colorectal cancer, which is MSI-S or MSI-L or shows normal IHC staining, classic Lynch Syndrome is effectively ruled out and the patient is considered to have Familial Colorectal Cancer Type X. If the tumor is found to be MSI-H, it may be a Lynch I or Lynch II tumor. Germline testing will confirm or rule out the diagnosis of HNPCC. If a germline mutation is not found in an MSI-H tumor, it may represent a case of sporadic colorectal cancer secondary to hypermethylation of MLH1. Further testing for this possibility may be performed by testing for a combination of a βRAF mutation and MLH1 hypermethylation using a test kit which can specifically evaluate this possibility.

Finally, there are many families with several members who have colorectal cancer but who do not demonstrate an underlying genetic basis for the disease. All available genetic test results are normal and non-informative. Clearly not every mutant gene involved in the production of a colon malignancy has been identified. Until such time as the genetic basis for colorectal cancer is completely delineated, clinicians will have to rely upon clinical guidelines to begin the screening process.

Part II will examine screening strategies and treatment recommendations for HNPCC.

REFERENCES

1. Classics in oncology, Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. By Aldred Scott Warthin, 1913. CA Cancer J Clin 1985, 35:348-359

2. Lynch HT, Krush AJ: Cancer Family “G” revisited: 1895-1970. Cancer 1971, 27:1505-1511

3. Benns, M.V. et al, The American Surgeon, June 2009.

4. Chung D., The hereditary nonpolyposis colorectal cancer. Ann Intern Med 2003; 138:560-570

5. Vasen HFA et al, Guidelines for the clinical management of Lynch Syndrome, J Med Genet. 2007:44:353-362

6. Schwartz RA et al, J Am Acad Dermatology 1995;33:90-104

7. Lindor N et al. Lower Cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293(16): 1979-1985

8. Iyer R., et al DNA mismatch repair: functions and mechanisms, Chem Rev 106(2): 302-323

9. Fishel R, et al. The Human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993, 75:1027-1038

10. Leach FS, et al. Mutations of MutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993. 75:1215-1225

11. Lindblom a. et al. Genetic mapping of a second locus predisposing to hereditary nonpolyposis colon cancer. Nat. Genet. 1993, 75:279-282

12. Ionov Y. et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993. 5:279-282

13. Salahshor S et al Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Invest 2001, 81:535-541

14. Soreide K: Molecular testing for microsatellite instability and DNA mismatch repair defects in hereditary and sporadic colorectal cancers-ready for prime time? Tomour Biol 2007, 28:290-300

15. Lindor NM, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002; 20: 1043–8. [PubMed]

16. Hampel H et al A. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005; 129: 415–21. [PubMed]

17. Mangold E et al Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 2005; 207: 385–95. [PubMed]

18. Lindor, N. Familial Colorectal Cancer Type X: The Other Half of Hereditary Nonpolyposis Colon Cancer Syndrome. Surgical Oncology Clinics of North America Vol 18, issue 4, 637-645

19. Aaltonen, L et al, Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR –stable tumors. Clin Cancer Res 2007;13(1) January 1, 2007

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Unusual Forms of the Disease.  Early symptoms.  Late Diagnosis.

ADENOCARCINOMA

Squamous cell cancer of the anal canal is rare and adenocarcinoma is rarer still, accounting for 10% of all anal cancers. The three types of anal adenocarcinoma are those arising in the anorectum, those arising in anal glands, and those arising in an anorectal fistula.

Occurring most proximally is the adenocarcinoma arising from the rectal type of anal mucosa. It appears similar to a rectal adenocarcinoma. The second type of adenocarcinoma arises from the base of the anal glands and may be an adenomatous type of cancer or a squamous variety depending upon its cellular origin. The third type arises from a chronic anorectal fistula and may be a well-differentiated mucinous adenocarcinoma.

It is useful to understand the anatomy and histology of the anal canal in order to appreciate the derivation of these tumors.

The anal canal is a small but complicated structure (Figure 1). It is 4 cm in length and begins at the anorectal ring, which is formed by the upper edge of the internal anal sphincter and the puborectalis muscle. The canal extends to the anal verge. Distal to this is the perianal skin. The perianal skin extends outward, onto the buttocks for 5 cm.

The histology of the anal canal is intricate and variable. The lining of the proximal canal is mucosal or endodermal, and is composed of a columnar epithelium. The columnar epithelium gradually transitions into a cutaneous or ectodermal squamous epithelium through the anal transition zone (ATZ). The ATZ is 1 cm in length and ends at the dentate line, which is located approximately 2 cm proximal to the anal verge. The dentate line is the remnant of the embryonic proctodeal membrane, or junction of the endoderm and ectoderm. Distal to the dentate line, the anal epithelium approximates that of skin except that it is non-keratinized and does not contain hair or glandular structures. This area is referred to as the anoderm. At the anal verge, the lining becomes that of true keratinized skin with hair, sebaceous glands and sweat glands.

The lining of the anal canal proximal to the dentate line is thrown into pleats or columns due to the narrowing size of the canal as it moves distally. The columns, 5 to 15 in number, are termed the columns of Morgagni. At the lower end of each column, and between each column is a small pocket, or anal crypt. These crypts connect to anal glands.

Anal glands begin at the crypt and extend outward. The ducts of the anal glands are lined by a squamous epithelium. This epithelium transitions into a columnar epithelium deep in the gland. Interspersed along the length of this epithelium are mucus-secreting cells or goblet cells. The glands are involved with the pathogenesis of anorectal abscesses, fistulous disease and with rarely occurring anal fistula malignancies.

The rectal type of adenocarcinoma looks like a distal colonic adenocarcinoma and usually is indistinguishable from a colorectal neoplasm. This is the most common type of anal canal adenocarcinoma.

The adenocarcinoma arising in a fistula is a well-differentiated cancer most commonly arising in patients with a chronic anal fistula or perianal disease.

Anal glandular adenocarcinomas commonly arise in the sixth to eighth decades of life.2, These tumors may present with signs and symptoms identical to other benign anorectal disorders. In a study of 21 patients by Jensen, patients complained of pain, leakage, bleeding, pruritus, prolapse or weight loss. Exams disclosed induration, an associated abscess or fistula, or a mass. An initial misdiagnosis was common. Patients experienced complaints and symptoms for 18 months prior to the correct diagnosis being made. Tumors of the anal canal averaged 5 cm in length and those of the perianal area averaged 10 cm in length. Sixty two patients presented with regional or distant metastases and 20 of 21 patients were dead within 18 months after treatment. Theses lesions often arise in an extramucosal location and there is no involvement of the mucosa. In the same series reported by Jensen, nine tumors were found in the ischioanal space, seven were found in the anal canal and the remaining five were seen in a fistula. With the variable nature of the glandular mucosa, the pathology of glandular cancer may be an adenocarcinoma or squamous cancer.

Because there are so few reported cases of anal adenocarcinoma, uniform treatment recommendations based on solid data are difficult to obtain. It is clear that treatment results are relatively poor and this disease seems to be much more aggressive than its anal squamous cell counterpart when matched for local recurrence rates and survival rates.

Treatment regimens have included wide local excision (WLE), abdominoperineal resection (APR), radiation, chemoradiation, and combined modality therapy, usually pre- or post-operative chemoradiation and an APR.

WLE may be possible in small tumors of the proximal anal canal. The tumors must be mobile, well-differentiated and should not invade the sphincters. These types of tumors are rare.

In a large multicenter study by Belkacemi,5 82 patients with anal canal adenocarcinoma were evaluated for treatment results. The three treatment groups consisted of radiotherapy with surgical extirpation, chemoradiation, or an APR. The five year survival and disease-free survival rates were best in the chemoradiation group. Five and ten year overall survival rates were 58% and 39% respectively. Disease-free rates at five and ten years were 54% and 20% respectively. Additionally the authors concluded that an APR should be reserved for salvage. The independent predictors of survival were T stage, N stage, histologic grade and mode of treatment.

Two other studies suggested that survival rates of 60% could be obtained with chemoradiation and surgery 2, In the study by Beal et al,2 the average radiation dose was 50.4 Gy. The chemotherapy was based upon the cell type and was most commonly 5-FU with leucovorin for treatment of adenocarcinoma. The authors stressed that their study, as well as other studies contained too few patients to confidently make definitive treatment recommendations. They suggested that APR with pre- or post-operative chemoradiation “achieves reasonable local control and survival.”

Chemoradiation with surgery as the primary mode of treatment seems to be the most common approach for adenocarcinoma of the anal canal.

MELANOMA

Anal melanoma is an ominous tumor. Fortunately, it is also a rare tumor. Fewer than 500 cases have been reported and it constitutes between 0.5% and 5% of all anal malignancies. Melanoma of the anal canal is the third most common site of occurrence after skin and ocular melanoma . Those with anal melanoma are often white females with an average age of 63 years old. The disease is rarely reported in the African-American or Asian populations. , , Women are twice as likely as men to have this lesion. Although the etiology is unknown, one report of 117 cases detailed a tripling of the incidence of the disease in males younger than 44 years of age in San Francisco when compared with other geographic locations (14.4 vs. 4.8 per 10 million population). In this study the male to female ratio was 1:1.72 with an average age of diagnosis of 57 years for males and 71 years of age for females. Males had a survival advantage over females at one and two years (62.8% vs. 51.4% at 1 year, and 40.6% vs. 27.7% at two years respectively. This new bimodal trend was noted and HIV was suggested as a risk factor.

The lesion may arise at any location in the anal canal.13, Bleeding is the usual patient complaint, followed by pain. Altered bowel habits and tenesmus are also reported. Weight loss is common. The most common presenting sign is an anal mass. Seventy five percent of patients have a mass greater than 1 cm in size, and the average diameter is 4 cm. Many patients have associated involved inguinal lymph nodes.

Anal melanoma is often confused with a thrombosed hemorrhoid. Larger lesions may be polypoid and ulcerated distinguishing the lesion from a thrombotic hemorrhoid. In one study, 71% of patients had “gross and/or histologic pigmentation,” while other studies have found these lesions to be amelanotic in 41% of cases.16, If melanin is seen on microscopic examination, the diagnosis is straightforward. In the amelanotic form, the presence of “malignant cells in clusters” helps to differentiate this lesion from an undifferentiated squamous cell carcinoma.19

38% of patients had either metastatic nodal involvement (perirectal, perianal and mesenteric nodes, followed by inguinal node disease) or distant metastases to the liver and lung. Between 38% and 62% of patients presented initially with metastatic disease to lymph nodes, and not uncommonly to distant sites as well. Submucosal spread is common.

Although there are conflicting issues in trying to choose a treatment modality and predict survival rates using various parameters, one point is clear; five year survival rates are dismal. Survival rates range between 0% and 29%.10,18, , , Up to 35% of patients have metastatic disease at the time of presentation, and one study showed that in patients whose tumors are thicker than 10 mm, cure is not possible.22

In a review of the Mayo Clinic experience, no single factor predicted survival. Factors evaluated were “gender, size of the lesion, presence of melanin, depth of penetration, positive perirectal lymph nodes and wide local excision versus APR.21 Interestingly, the Memorial Sloan-Kettering series found that the only long-term survivors were women.18

Available surgical options include wide local excision or abdominoperineal resection. In the Memorial Sloan-Kettering and Mayo clinic series, overall five year survival rates were 17% and 22% respectively and were unrelated to the type of surgical procedure used to extirpate the disease.18, 21 However, the Memorial Sloan-Kettering series of 85 patients suggested that five year, disease-free survival using an “APR was more favourable than that of patients who underwent local procedures only, although this was not statistically significant (27% vs 5%, APR vs local procedures respectively; p= 0.11)”18 This report concluded that an APR should be used in those patients with localized anorectal melanomas and no evidence of nodal disease. However, the Mayo clinic series of 50 patients,21 found five year survival, and recurrence rates to be the same after curative wide local excision or APR but concluded that “Wide local excision with a negative margin of at least 1 cm is suggested as the treatment of choice. APR should be reserved for tumor not amenable to local excision or for palliative treatment of large obstructive lesion (sic) until effective adjuvant therapies are available.”

One study examined tumor thickness, comparing anorectal melanoma to cutaneous melanoma in an attempt to formulate guidelines for treatment. The study recommended wide local excision with a 1 cm margin of normal tissue for tumors less than 1 mm in thickness, and wide local excision with a 2 cm margin of normal tissue in tumors between 1 and a 4 mm in thickness as long as the internal sphincter was tumor-free, and an APR for all other tumors.

Most authors note that with documented regional metastatic disease or distant metastases patients should be spared an APR and permanent colostomy, as long-term survival rates are almost non-existent. However, in those with bulky tumors, or in patients in whom the surgeon is unable to obtain 1 to 2 cm tumor-free margins with a wide local excision, or in patients with tumor involvement of the anal sphincters, or in those patients who would be rendered incontinent after a wide local excision, an APR may be the treatment of choice.4

Numerous immunologic and adjuvant chemotherapeutic treatments have been tried with little benefit in patients with anal melanoma.23 Radiation therapy is of unproven benefit as well. Local control, while possible with surgical treatment, is often useless, as distant metastatic disease is a major cause of death.23,

NEUROENDOCRINE CARCINOMAS:

Also called a small cell carcinoma or a large cell neuroendocrine tumor, or a Merkel cell carcinoma, this tumor is so named because it is derived from cells of both the endocrine system and the nervous system. Neuroendocrine cells are found in many organ systems and tissues, with the gastrointestinal tract harboring the largest volume of these cells. These tumors are rare, comprising less than 1% of all lower digestive tract cancers. Most neuroendocrine tumors are found in the rectum and cecum. , In a study from the Memorial-Sloan Kettering Cancer Center of 6,495 patients with colorectal cancer over a 23 year period, 6 neuroendocrine tumors, representing less than 0.1% of all colorectal malignancies, were found in the anal canal.

Colorectal neuroendocrine tumors are classified as either low-grade carcinoids or high-grade neuroendocrine carcinomas. The neuroendocrine lesions can be further subdivided into small cell carcinomas or large cell neuroendocrine carcinomas. All of these high-grade neuroendocrine tumors have at least 50% of the tumor demonstrating typical neuroendocrine characteristics. “These features include a densely cellular, solid growth pattern, with cells arranged in nests having minimal intercellular stroma.” There is no gland formation. There are features of necrosis and a mitotic rate “of greater than ten per high power” field on microscopy. 27 Based on cytological features, further subdivision into small cell carcinoma or large cell neuroendocrine carcinoma is possible, with the small cell form resembling the pulmonary form of small cell cancer. This division into small and large cell forms resembles the classification of pulmonary neuroendocrine tumors. The small cell carcinoma does not require immunohistochemical documentation and may be diagnosed solely by hematoxylin and eosin microscopy. The large cell variant does require immunohistochemical documentation, with the finding of at least 1 of 3 neuroendocrine markers chromgranin, synaptophysin and neuron-specific enolase) in at least 10% of the tumor cells.27

In the Memorial-Sloan Kettering study, 80% of all neuroendocrine tumors stained positive immunohistochemically for neuroendocrine markers and most presented at an advanced stage, although no mention was made as to the specific stage of presentation seen in anal lesions.27

Diagnosis involves a high index of suspicion in patients with any type of anorectal complaint. An obvious lesion removed surgically will then be submitted for the appropriate microscopic and immunohistochemical evaluation.

As these tumors are rare, no single series can reliably evaluate the different modes of available treatment and survival statistics. Patients have been treated with excision, radical extirpative procedures with or without adjuvant therapy, radiation alone or chemotherapy alone. Staging is important as up to 85% of extrapulmonary small cell tumors in one series presented with metastatic disease not amenable to surgical cure.27 Small cell variants with documented metastatic spread can be treated like pulmonary tumors, with cisplatin and etoposide. Other chemotherapeutic regimens including cycolphosphamide, doxorubicin and vicristine have been used in treatment programs. The success of chemotherapeutic treatment of anal lesions has not been verified.

Although not validated, it would make sense to treat patients with disease limited to the anal canal with extirpative surgery and/or chemoradiation, akin to the treatment for anal adenocarcinoma.

In the study by Bernick et al., looking at all treatment modalities in 36 patients who completed treatment and follow up, median survival was 10.5 months, with an overall disease-specific median survival of 16 months. Small cell carcinomas and large cell neuroendocrine carcinomas demonstrated similar survival curves. One-year, two-year and three-year survival rates were 46%, 26% and 13% respectively.

These are aggressive tumors and are difficult to treat. The best that can be said of them is that they are rare.

CITATIONS

• Basik, M., Rodriguez-Bigas, M. A., Penetrante, R., Petrelli, N. J., “Prognosis and Recurrence Patterns of Anal Adenocarcinoma.” The American Journal of Surgery 169(1995): 233-237.
• Beal, K. P., Wong, D., Guillem, J.G., et al. “Primary Adenocarcinoma of the Anus Treated with Combined Modality Therapy.” Diseases of the Colon and Rectum 46 (2003): 1320-1324.
• Fenger, C., Frisch, M., Marti, M. C., Parc, R., “Tumors of the Anal Canal”. Hamilton, S. R., Aaltonen, L. A., eds. WHO classification of tumors. Pathology and genetics of tumors of the digestive system. Lyon, France: International Agency for Research for Research on Cancer. (IARC), 2002:146-155
• Wolff, B. G., Fleshman, J. W., Beck, D. F., Pemberton, J. H., Wexner, S. D. “The ASCRS Textbook of Colon and Rectal Surgery” Pg. 494. Springer Science+Business Media, LLC, 2007
• Belkacemi, Y., Berger, C., Poortmans, P., et al., “Management of Primary Anal Canal Adenocarcinoma: A Large Retrospective Study from the Rare Cancer Network.” International Journal of Radiation Oncology Biology Physics 56(2003): 1274-1283.
• Jensen, S.L., Shokouh-Amiri, M.H., Hagen, K., Harling, H., Nielson, O. V., “Adenocarcinoma of the Anal Ducts: a Series of 21 Cases ” Diseases of the Colon and Rectum 31 (1988): 261-272.
• Hobbs, C. M., Lowry, M. A., Owen, D., Sobin, L. H., “Anal Gland Carcinoma.” Cancer 92 (2001): 2045-2049.
• Papagikos, M., Crane, C., Skibber, J., Janjan, N., Feig, B., Rodriguez-Bigas, M., Hung, A., Wolff, R., Delclos, M., Lin, E., “Chemoradiation for Adenocarcinoma of the Anus1.” International Journal of Radiation Oncology Biology Physics 55.3 (2003): 669-678.
• Klas, J. V., Rothenberger, D. A., Wong, W. D., Madoff, R. D., “Malignant Tumors of the Anal Canal: the Spectrum of Disease, Treatment and Outcomes.” Cancer 85 (1999): 1686-1693
• Malik, A, Hull, T. L., Floruta, C., “What Is the Best Surgical Treatment for Anorectal Melanoma?” International Journal of Colorectal Disease 19.2 (2004): 121-123
• Mason, J. K., Helwig, E. B., “Anorectal Melanoma.” Cancer 19.1 (1966): 39-50.
• Gervasoni, J. E., and Wanebo H. J., “Cancers of the Anal Canal and Anal Margin.” Cancer Investigation 21 (2003): 452-464.
• Billingsley, K., L. Stern, Lowy, A., Kahlenberg, M., Thomasjr, C., “Uncommon Anal Neoplasms.” Surgical Oncology Clinics of North America 13.2 (2004): 375-388.
• Chang, A. E., Karnell, L.H., Menck, H. R., “Base Report on Cutaneous and Noncutaneous Melanoma: a Summary of 84,836 Cases from the past Decade.” Cancer 83 (1998): 1664-1678
• Cagir, B; Whiteford, M. H., Topham, A., Rakinic, J., Fry, R. D., “Changing Epidemiology of Anorectal Melanoma” Diseases of the Colon & Rectum. 42(9):1203-1208.
• Ward, M. W. N., Romano, G., Nicholls, R. J., “The Surgical Treatment of Anorectal Malignant Melanoma.” British Journal of Surgery 73.1 (1986): 68-69
• Quan, S. H. “Malignant Melanoma of the Anorectum.” Seminars in Colon and Rectal Surgery 6 (1995): 166-168.
• Brady, M. S., Kavolius, M. D., Quan, S. H., “Anorectal Melanoma: A 64 Year Experience at Memorial Sloan-kettering Cancer Center.” Diseases of the Colon and Rectum 38 (1995): 146-151
• Chiu, Y. S.; Unni, K. K.; Beart, Robert W. Jr. “Malignant Melanoma of the Anorectum” Diseases of the Colon & Rectum. 23(2):122-124
• Cooper, P. H., Mills, S. E., Allen, M. S., Jr., “Malignant Melanoma of the Anus. Report of 12 Patients and Analysis of 255 Additional Patients.” Diseases of the Colon and Rectum 25 (1982): 693-703.
• Thibault, C., Sagar, P., Nivatvongs, S., Ilstrup, D. M., Wolff, B. G., “Anorectal Melanoma: An Incurable Disease?” Diseases of the Colon and Rectum 40 (1997): 661-668.
• Weyandt, G. H., et al. “Anorectal Melanoma: Surgical Management Guidelines According to Tumour Thickness.” British Journal of Cancer 89 (2003): 2019-2022
• Bullard, K. M., Tuttle, T. M., Rothenberger, D. A., “Surgical Therapy for Anorectal Melanoma.” Journal of the American College of Surgeons 196 (2003): 206-211.
• Roumen, R. “Anorectal Melanoma in The Netherlands: a Report of 63 Patients.” European Journal of Surgical Oncology 22 (1996): 598-601
• Saclarides, T. J., Szeluga, D., Staren, E. D., “Neuroendocrine Cancers of the Colon and Rectum; Results of a Ten Year Experience.” Diseases of the Colon and Rectum 37 (1994): 635-642.
• Hung, S. S. “Small Cell Carcinoma of the Colon. a Case Report and Literature Review.” Journal of Clinical Gastroenterology 11 (1989): 335-339.
• Bernick, P. E., Klimstra, D. S., Shia, J., et al. “Neuroendocrine Carcinomas of the Colon and Rectum.”Disease of the Colon and Rectum 47 (2004): 163-169
• Travis, W. D., Gal, A. A., Colby, T. V., “Reproducibility of Neuroendocrine Lung Tumor Calssification.”Human Pathology 29 (1998): 272-279.

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Anal Canal Squamous Cell Carcinoma. A Compelling Historical Vignette – Short, and to the Point

Part I of this series covered anal anatomy and anal intraepithelial neoplasia.  Part II covered perianal cancers and their treatment. Part III will examine squamous cancers of the anal canal. Part IV will look at unusual cancers of the anal canal.

Neoplasms of the anal canal may behave differently than those of the perianal region and therefore should be evaluated separately.

ANAL INTRAEPITHELIAL NEOPLASIA (AIN): A MALIGNANT PRECURSOR?

Research has focused on data pointing to the human papilloma virus (HPV) in combination with other risk factors as the etiology of many anal cancers. This may be similar to the HPV causation of cervical cancer.

HPV is a double stranded DNA virus which infects the stratified epithelium of skin or mucus membranes. At least 20 of the more than 200 known HPV genotypes infect the anogenital area. HPV-6 and 11 are associated with anal condyloma (warts) and low grade anal intraepithelial neoplasia (AIN). These rarely become malignant. Genotypes 16, 18, 31, 33 and 35 are associated with high grade AIN (also called Bowen’s disease, carcinoma in situ or CIS, or AIN III) as well as with invasive cancers of the anus and cervix.

Anal intraepithelial neoplasia can be found in the anal canal as well as in the perianal region and there is evidence that it not only behaves in a more aggressive fashion in the anal canal but that it may be a true precursor to anal carcinoma ( ). The upper anal canal transitional epithelium is composed of a columnar epithelium with an overlay of non-keratinized squamous metaplasia. Metaplastic non-keratinized tissue may be unusually susceptible to infection with HPV, leading to disease. HPV-16 and 18 are commonly found in anal canal carcinomas, especially proximal to the dentate line. In fact, these upper canal cancers are rarely found without HPV-16 or 18. HPV DNA is almost never found in normal anal canal tissue. It is uncommon to find HPV-16 or 18 DNA in the modified skin of the lower anal canal, with its keratinized mucosa, and HPV is rarely found in non-squamous cell anal cancers such as adenocarcinoma.(2, 3, 4)

An abnormal anal Pap smear showing atypical squamous cells may lead to further investigation looking for AIN or a carcinoma. A simple exam under anesthesia with acetic acid staining or Lugol’s staining may reveal abnormal tissue for biopsy. Suspicious areas for targeted biopsy appear white when stained with acetic acid. AIN III appears as a tan area of anal mucosa when stained with Lugol’s solution (Figure 1). Anal canal colposcopy in conjunction with aceto-whitening to highlight potential abnormal mucosal areas for biopsy may be used by those with the necessary technical experience, to more closely evaluate the anal canal. High resolution anoscopy with anal mapping, whereby a grid system is mapped onto the anal area to record precise biopsy locations looking for pathologically diagnosed occult lesions in need of treatment may be used, although its use is less common now than in the past. The rationale behind diagnosing and treating AIN, especially AIN III or Bowen’s disease, is that in so doing, the physician may possibly halt the development of an anal canal cancer. However, it is not proven that AIN I transitions through AIN II and AIN III to an invasive squamous cancer.

Treatment of AIN I, II and III is more completely covered in part I of this series. It appears as if treatment is shifting toward topical therapy with imiquimod, topical 5-FU, or targeted electrofulgeration, while reserving surgical extirpation for patients with persistent symptomatic disease or invasive carcinoma. As always, physicians should be aware of the possibility of malignant disease in other organs.

SQUAMOUS CELL CARCINOMA. MANY NAMES. MANY FACES

Squamous cell carcinoma (SCC) of the anal canal is a tumor that has been given many names such as cloacogenic carcinoma, basaloid carcinoma, transitional cell carcinoma, and keratinizing or nonkeratinizing large-cell carcinoma.

Ideally, the diagnosis of squamous cell carcinoma of the anus should be made early in the clinical course of the disease. However, patient or physician delay is not uncommon and the initial presentation often may be one of late stage disease. Symptoms of this treatable disease may have been present for months to years before a correct diagnosis is suspected. Bleeding occurs in 50% of patients (5,6,7). Other symptoms include anal pain, pruritus, discharge or a mass. Advanced tumors may present with a change in bowel habits, incontinence, an anovaginal fistula or pelvic pain, and may represent a tumor with sphincter involvement, signifying later stage disease. Because of the variable presentation of disease, an incorrect initial diagnosis is common and one third of patients may be incorrectly diagnosed as having benign disease (6,8 )

STRAIGHTFORWARD DIAGNOSIS…IF THE PHYSICIAN THINKS OF IT.

Diagnosis is usually straightforward when a patient presents with symptoms and the physician includes SCC in the differential diagnosis of an otherwise benign set of symptoms. A history of an HPV or HIV infection, cervical neoplasia or immunosuppresion should alert the physician. A digital exam will reveal a mass which may or may not be fixed. The size of the mass as well as its exact location should be noted. Attention must be given to the inguinal region as this area is a common site of metastatic disease when the primary tumor is located distal to the dentate line. In women, a pelvic examination should be performed looking for tumor invasion into the vagina. An HIV test should be performed in high-risk patients. Highly active antiretroviral therapy (HAART) should be started in patients with newly diagnosed HIV. Those patients with CD4 counts less than 200 will often require modifications to the treatment protocol ( 9).

A colon evaluation may be performed, especially for those over age 50, and an endoanal or endorectal ultrasound may be helpful in evaluating the depth of tumor invasion as well as possible nodal disease. If an abnormality is found on chest x-ray examination, CT scanning of the chest will aid in searching for metastatic disease. An abdominal and pelvic CT will be useful in searching for metastatic disease and in evaluating the inguinal regions and the pelvis. However, the sensitivity of pelvic imaging is not high ( 10). It is impacted by both the limits of the technology and the inability of the technology to discriminate between malignant and benign lymph nodes. As 44% of metastatic lymph nodes may be less than 5 mm in size, CT scanning might not be sensitive enough to accurately predict nodal involvement (11 ). FDG-PET scanning, which looks at the fluorine-18 fluorodeoxyglucose (FDG) metabolic uptake of tissue, may have promise in identifying metastatic disease, especially when FDG-PET scanning is combined with CT scanning (PET/CT). FDG-PET scanning is dependent on tissue metabolic activity and not dependent on nodal size. Confirmation of the usefulness of this modality will have to await trials of PET scanning with confirmatory histopathological proof of nodal involvement in nodes identified by PET scanning. A fine needle aspiration, core biopsy or an open biopsy should be performed on suspicious inguinal disease to differentiate reactive nodal hyperplasia from carcinoma which requires treatment.

Finally, a confirmatory biopsy through an anosocpe or proctoscope is diagnostic. However, an open surgical biopsy may be preferable for enhanced visualization, a more thorough anal canal inspection and patient comfort. The relationship of the lesion to the dentate line should be documented.

INVOLVED LYMPH NODES. TOO COMMON.

Depending on the anatomical location of the tumor, various lymph node regions may harbor metastatic disease (Figure 2). The TNM system is used to stage the tumor and is a relatively accurate predictor of prognosis. (Table).

Tumors located proximal to the dentate line may spread along the superior rectal vascular and nodal pathway to the inferior mesenteric nodes. When located on the dentate line, the tumor may also spread laterally along the internal pudendal, hypogastric or obturator nodes. If the tumor is located below the dentate line, the inguinal nodes are the commonest site of spread. Of course these patterns of spread are variable and a thorough nodal evaluation should be performed.

The rate of lymphatic spread directly correlates with the size of the tumor. The larger the tumor, the more frequent is nodal metastatic disease. Nodal metastases may also be related to the depth of invasion and the histologic grade of the tumor, although this relationship is not as certain. Nodal disease is found in up to 20% of patients at the time of diagnosis and may become apparent later in up to 25% of patients (12). These variables impact treatment recommendations.

With respect to tumor size or T-stage, in tumors less than 2 cm in size (T1), nodal spread is rare as compared to those malignancies larger than 2 cm (T2 orT3), in which spread may be encountered in up to 35% of cases (13 ).

With respect to depth of invasion, with smooth muscle tumor involvement, affected nodes may be found in 30% of patients and in 60% in those with tumor spread beyond the external sphincter. In one study of 172 patients, only 17 were found to have tumor confined to only the epithelium or subepithelial connective tissue (12).

At the time of diagnosis, 53% of patients had only local disease, whereas 38% had regional disease and 9% showed evidence of distant metastatic disease (14 ). Clearly, early diagnosis might help to discover small, superficial tumors and possibly improve survival statistics.

TREATMENT – FROM YESTERDAY TO TODAY

Traditionally, an abdominoperineal resection (APR) was the treatment of choice, but was associated with local recurrence rates as high as 45%, and 5 year survival rates as low as 40% (10, 13, 15-19 ) The presence of lymph node involvement at the time of initial diagnosis worsened survival rates even further. With the finding that wide local excision in highly selected cases yielded five year survival rates of 100%, and with the introduction of a curative chemoradiation protocol, APR as a primary treatment modality was abandoned except for its present-day use in those patients unable or unwilling to undergo chemoradiation. APR may also be used in patients with persistent or recurrent disease after chemoradiation, or in those patients presenting with bulky tumors or with incontinence and extensive sphincter involvement. The procedure can be performed in an open fashion or laparoscopically by those surgeons with experience in the laparoscopic technique.

Anal squamous cell cancers are quite radiosensitive, and radiation therapy with a curative intent has been used since the end of World War I as the primary mode of treatment. The radiation was administered as external beam or brachytherapy. An increasing dose of radiation was found to be associated with an improved tumor response, but doses as high as 55 Gy had to be administered (20,21 ). Local control and cure rates were high, but these came at the price of increased morbidity secondary to the radiation. Additionally, with T3 and T4 lesions, or in patients with N1 disease, cure rates were seen to diminish to 50% (20,22 ). Major morbidity was found to include anal necrosis or stenosis, fecal incontinence, small bowel obstruction, iliac artery stenosis, urethral stenosis, cystitis, diarrhea or anorectal ulcerations (23 ). With the loss of normal functioning of the anal canal, a colostomy was needed in up to 12% of patients. The occurrence rate of other major morbidities was found to be dose-dependent (22,24 ). The only independent predictor of the need for a colostomy was found to be the size of the primary tumor (25). As such, radiation therapy alone as a primary treatment modality is offered rarely unless the patient is too ill for surgical therapy, refuses surgical treatment or is unable to receive chemoradiation.

FROM YESTERDAY TO TODAY- HOW DID WE GET HERE?

A TREATMENT MILESTONE: THE NIGRO PROTOCOL- A VIGNETTE

Searching for a method to improve the survival statistics associated with an abdominoperineal resection for SCC, Norman Nigro, in 1972, began administering preoperative chemoradiation. Doctor Nigro noted “There are causes for the low cure rates even beyond the biologic characteristics of the neoplasm itself. The anatomic features of the anal canal are such as to promote early spread of malignant cells. The area has both a profuse blood supply and an abundant lymphatic drainage system which leads in all directions. At the same time, there is a serious limitation in the amount of tissue around the anal canal which can be removed. Lymphatic involvement occurs early to areas like the deep pelvic nodes, which are always difficult and sometimes impossible to remove.” He continued, “It appears to us that surgical excision is not likely to be adequate treatment for many patients with cancer of the anal canal.” (26 )

The results of a three patient experiment were presented in a lecture to the American Proctologic Society in 1973. This three page report was published in 1974 in Diseases of the Colon and Rectum (26). In anticipation of the performance of a curative abdominoperineal resection for squamous cell cancer of the anal canal, three patients were given preoperative chemoradiation. Six weeks after the completion of the month-long regimen, two of the patients underwent the planned operation. One of the three patients refused operative intervention after the initial chemoradiation. All three patients were tumor-free between six and fifteen months after the completion of treatment.

The treatment protocol began with 30 Gy of preoperative perineal, pelvic and inguinal nodal irradiation over 15 days. A five day course of 5-FU was given as a continuous infusion beginning on day 1 (25mg/kg). Mitomycin C (MMC) was given as a bolus on day 1 only (0.5mg/kg). The chemotherapy was given during an inpatient hospitalization. An APR was performed 6 weeks following this treatment and the two surgical specimens were studied. Neither specimen contained any tumor.

A follow up “pilot study” on ten additional patients was published in 1977 (27 ). This report was 2 pages in length. The chemotherapeutic regimen had been modified slightly. Nine patients underwent post treatment APR.

Six patients, all of whom had tumors less than 4 cm in diameter, had no residual tumor in the resected specimens after an APR. One patient with a 4 cm lesion refused an operation and was disease-free at 18 months post-treatment. Overall, 7 patients with tumors 4 cm or less in size remained tumor-free at 2 to 53 months postoperatively. The three patients with either persistent tumor or metastatic disease had cancers which were originally between 6 and 8 cm in size. Of note, Doctor Nigro noted that “The tissues were not grossly altered, bleeding was not excessive, and dissection presented no technical difficulty. Healing of all tissues, including the perineal wounds, was normal.”

It was at this time that it was suggested that an abdominoperineal resection might not be necessary in those patients whose tumors were smaller than 4 cm and who showed no residual tumor in the resected scar after the completion of chemoradiation. Thus began the era of “less is more” for treatment of squamous cell carcinoma of the anal canal.

In 1984, Doctor Nigro presented his four page follow up on 104 patients (28 ). Eighty two patients were alive and disease-free at between 2 years and 11 years post-treatment (22 having undergone APR, and 60 having undergone only chemoradiation.) Of note, 7 patients underwent a delayed APR for recurrent disease after initially having been found to be disease-free following chemoradiation and normal post-treatment biopsies showing no residual tumor. Four of these were alive and without disease after salvage APR (“two for three years and two for four years”). The conclusions were simple: “This experience with chemoradiation therapy for squamous cell cancer of the anal canal has convinced us that it is as effective as abdominoperineal resection of the rectum in the majority of patients.”

All of this was presented over 12 years in three articles and occupied a total journal space of only 9 pages.

PRESENT DAY TREATMENT PROTOCOLS:

Chemoradiation has been found to be superior to operation alone or radiation alone, with respect to colostomy-free rates, local failure rates and cancer-specific survival rates.(29-31). During the years following Nigro’s introduction of chemoradiation for anal cancer, changes have been made to the chemotherapeutic regimens and variations in the treatment protocols have been studied. The Nigro protocol however, remains the model for treatment.

Importantly, before beginning treatment, patients with anal canal cancer, must be evaluated appropriately for other malignancies. Even though radiotherapy has not been found to be associated with an excess of new, radiation-induced cancers (32 ), a pretreatment baseline evaluation should be performed.

TREATMENT CHOICES.

CARCINOMA IN SITU AND T1 LESIONS.

Chemoradiation is widely accepted to be the initial treatment choice for T1 lesions. Results equal those after wide local excision. The administration of prophylactic inguinal radiation is not standard in T1 disease. Arguments against prophylactic inguinal radiation include the development of lymphedema and the onset of debilitating anorectal dysfunction, albeit at a rare rate of occurrence. However, the rate of severe morbidity associated with inguinal radiation is minimal and recurrence rates seem to be higher in those patients who have not undergone prophylactic inguinal irradiation. Many centers do administer prophylactic inguinal radiation.

As in treatment for squamous cell cancers of the perianal skin, wide local excision in selected cases can achieve a cure while preserving anorectal functioning. In a highly selected, small group of patients, survival rates have been found to approach 100% (13, 17, 18). The key to success seems to be in patient selection. The tumors should be mobile, less than 2 cm in size, well differentiated and demonstrate invasion no deeper than the submucosa. If local excision fails and there is persistent disease or a local recurrence, salvage chemoradiation or APR may be curative.

T2, T3, T4 LESIONS

In those patients requiring anything other than wide local excision, chemoradiation with 5-FU with MMC is currently the initial treatment modality. Treatment regimens differ, but most authors accept that a standard treatment includes 40 Gy to 54 Gy administered to the perineum and inguinal nodal basins over twenty five days in those with T2 lesions. In patients with T3 and T4 tumors, pelvic irradiation is added.

Chemotherapy includes cycles of 5-FU during weeks 1 and 5 and a single dose of MMC on day 1. Many centers repeat MMC on day 29. With T3 and T4 tumors, radiation boosts can be given to a total of 55 Gy. 70 Gy can be used to treat with radiation alone in those patients unable to undergo chemotherapy.

RADIATION THERAPY AND CHEMOTHERAPY: TOXIC CURES

After receiving radiation therapy, relatively normal anorectal functioning is preserved in up to 90% of patients. However, with radiation doses greater than 40 Gy, the rate of complications increases as well. The complications may be systemic, such as dermatitis, mucositis, fatigue or bone marrow suppression. Death is rare. There may be associated anorectal irritability with tenesmus, proctitis, diarrhea, bleeding, urgency and incontinence. Most of these symptoms can be controlled with medication, but a proximal ostomy may become necessary. Far from causing further disability, an ostomy may be a welcome relief from symptoms caused by disease treatment (24). Pelvic complications include urethral stenosis, cystitis, small bowel obstruction and arterial stenosis.

Hematologic toxicity, specifically anemia, neutropenia and thrombocytopenia, may occur in up to 64% of patients receiving MMC, but the use of MMC has been found to further decrease colostomy rates, increase colostomy-free rates and increase disease-free survival rates. However, overall survival rates at 4 years have been shown to be no different with or without MMC (33 ).

Suggestions have been made that cisplatin might be substituted for MMC in an attempt to decrease hematologic toxicity. Cisplatin, although less toxic than MMC, is also myelosuppressive, with pancytopenia occurring in 25% to 30% of patients. This is more pronounced in those receiving high doses of cisplatin (greater than 50mg/m2). Patients may also experience hemolytic anemia. Results of trials have not substantiated a survival benefit and there is a statistically significant higher colostomy rate when using cisplatin in place of MMC (19% versus 10% respectively). There were more study-related deaths in the cisplatin group, although it was not implied that cisplatin was the cause of death. As expected, there was less severe acute hematologic toxicity in the cisplatin group compared with the MMC group (61% vs. 42% respectively) (34, 35). Cisplatin has not replaced MMC in the standard chemoradiation protocol for squamous cell carcinoma of the anus.

Capecitabine (Xeloda,® Roche) is an oral chemotherapeutic agent which is enzymatically converted to 5-FU in tumor tissue. If it proves efficacious, capecitabine might be substituted for 5-FU so as to avoid prolonged intravenous infusion.

RESULTS OF TREATMENT-THE STATISTICS: SIZE MATTERS

Over the years since Norman Nigro’s seminal work, numerous studies have shown that on average, with varying doses of radiation and various chemotherapeutic protocols, complete responses occur in up to 87% of cases, local control occurs in up to 86% and five year survival rates are between 66 and 92% ( ). When stratified by T-stage, without lymph node metastatic disease, T1 tumors show a long-term survival rate of 93%. In T2 disease, long-term survival is 84%. Survival drops to 60% in T3 disease and to 37% in T4 disease (with or without involved lymph nodes) ( ). Tumors larger than 5cm are more problematic, with 50% requiring a salvage APR. However, if patients with these larger tumors are disease-free at the conclusion of the initial chemoradiation, only 25% will require a salvage APR (36).

THE INGUINAL LYMPH NODE QUESTION:

TREATING UNINVOLVED NODES AT DIAGNOSIS: WAIT OR DON’T WAIT?

In the absence of involved inguinal nodes at the time of initial diagnosis in T1 lesions, it is not clear as to whether prophylactic inguinal radiation has a place in the standard treatment of newly diagnosed SCC. Two common approaches include a wait-and-see approach and a prophylactic irradiation strategy. In one study of 24 patients without inguinal lymph nodes at the time of diagnosis, two developed nodal involvement, one in an irradiated inguinal field and one in a non-irradiated field (38). Three studies showed the late nodal recurrence rate to be between 15% and 25% when inguinal fields were not routinely included in the radiation treatment (13, 39, 40).

WAIT?

The rationale underlying the wait-and-see approach is that up to 90% of patients will need no therapy to the inguinal region. This would avoid the potential morbidity associated with inguinal radiation. However 10% to 15% will develop metachronous disease, but this can be controlled in 50% of those so affected (22 41, 42, 43). Acute toxicity, sometimes leading to mortality can also occur, albeit rarely, in 2% of cases (30, 33). This seems to occur in elderly or frail patients.

DON’T WAIT!

Prophylactic bilateral radiation of initially uninvolved inguinal regions is associated with the appearance of inguinal disease in less than 5% of patients so treated. (24, 30, 33) In an effort to reduce the volume of radiation and associated complications, some institutions will irradiate only one inguinal and iliac nodal region if the tumor is clearly located on the homolateral side of the anal canal. Standard doses of 45-55 Gy are used (13, 22, 43). Several institutions use a lower dose of radiation when combining treatment with chemotherapy (24, 33, ). This approach lowers the risk and morbidity of radiation toxicity while also controlling the disease. Iliac recurrences are difficult to control and prophylactic radiation may circumvent the development of iliac disease. (45 )

Presently, most protocols do include prophylactic inguinal irradiation (46 )

Prophylactic inguinal dissection does not increase 5 year survival and carries a high morbidity rate. It is not used routinely (6, 7).

SYNCHRONOUS INGUINAL NODES:

Synchronous inguinal lymph node involvement is reported in 10% to 25% of cases. (6, 10, 13, 18, 45) The rate of inguinal metastases increases as the tumor size increases. The overall survival in patients with synchronous inguinal node disease is 48% (30% to 60%). Large nodes (greater than 2 cm in size) in larger tumors (T3 or T4) decrease the survival rate even further, to approximately 30%.

There is not one standard protocol for treating synchronous inguinal node disease and various centers use inguinal radiation alone, chemoradiation or selective groin dissection with follow-up radiation or chemoradiation. The most common approach for treating synchronous nodal disease is chemoradiation. Local control rates are reported as high as 90% (24, 47). Radiation alone results in inferior local control rates of 65% (38). A radical groin dissection is rarely successful in extending survival and is associated with morbid complications (10).

Complications occur with radiation and are not insignificant (45). While higher doses of radiation help to eradicate disease, (21) the complication rate begins to rise. Split course radiation may help to minimize complications (24) but may be associated with a decrease in survival rates (32).

RESULTS OF SYNCHRONOUS NODE TREATMENT: THE STATISTICS:

In patients treated with chemoradiation, those with synchronous nodal disease had an overall five year survival of 54% compared with 74% in patients without synchronous disease. Those with synchronous nodes larger than 2 cm or those with T3 or T4 tumors also had poor survival rates of 30% (45).

METACHRONOUS NODES:

Metachronous nodes are reported to occur in 5% to 25% of cases (6, 10). These nodes usually appear within six months of initial treatment. In one study looking at the treatment of synchronous and metachronous inguinal node metastases, it was stressed that pathologic confirmation was obtained prior to the recommended treatment of limited groin dissection with removal of all macroscopic disease followed by irradiation when the surgical wound had healed. The average time to recurrence after initial treatment was 16 months. The risk of recurrence was higher in T3 and T4 primary lesions. Again it was observed that in patients with tumors clearly located on either side of the anal canal, the metachronous nodal recurrence was in the ipsilateral inguinal region.(45)

RESULTS OF METACHRONOUS NODE TREATMENT: THE STATISTICS:

In this same study, 8% of 270 patients were found to have metachronous nodal involvement. Using inguinal dissection followed by irradiation, local control of the inguinal region was obtained in 68% but the 5 year survival rate was only 41%.(45) Others have recommend only chemoradiation for metachronous nodal disease (10). Five year survival in patients with metachronous nodal disease is approximately 62% when treated with chemoradiation and this appears to be the treatment of choice for metachronous nodal disease. Adding a surgical lymphadenectomy may be useful if chemoradiation fails to eradicate the disease. (10)

HIV-POSITIVE PATIENTS:

As squamous cell carcinoma of the anal canal is associated with anoreceptive intercourse, it is useful to look at disease treatment in HIV-positive patients.

In those with CD-4 counts as low as 105 cells/ml, especially in those who are not taking highly active antiretroviral therapy (HAART), local excision of superficial lesions is associated with excellent results. Patients tend to succumb to HIV rather than anal disease (45 ).

Currently, in HIV-positive patients with invasive anal cancer and CD4 levels greater than 200/cc, treatment is similar to that in uninfected patients. In those with lower CD4 counts, treatment remains individualized. Cisplatin has been substituted for MMC and prophylactic inguinal irradiation has been omitted in an effort to reduce toxicity in this group of immunocompromised patients.(49) Highly active antiretroviral therapy is important, especially during treatment for squamous cell cancers of the anus. Studies have shown that in patients with all stages of anal disease and with widely differing CD-4 counts, chemoradiation can be given with low toxicity. Most patients can receive the total planned dose of radiation, but the chemotherapy doses may need to be reduced in 66% of patients and one half may experience non-fatal hematologic or skin toxicity unrelated to the CD-4 counts. Opportunistic infections are rare. Three year survival rates are high in HIV-positive patients treated with HAART (48,50 ).

TREATMENT FAILURE: PERSISTENT OR RECURRENT DISEASE

Up to 35% of patients may have persistent disease at the conclusion of chemoradiation or recurrent disease more than 6 months post-treatment. When failure occurs in the form of recurrent disease, the disease may appear in the pelvis, regional nodes or in the anal area. Attempts should be made to distinguish a bona fide recurrence from radiation-induced reactive disease. PET scanning may help in this regard.

Treatment for failed chemoradiation with a pelvic recurrence or with locally recurrent disease, is with a salvage APR with or without a radiation boost (24). There is a significant rate of wound healing problems which might require coverage with flaps or grafts. The original T-stage is not predictive of survival after salvage attempts, but it appears that node positivity does correlate with mortality rates (25, 32, 51 ). Overall, results of salvage APR show widely discrepant survival rates in the literature. However, this should not preclude salvage therapy. APR is contraindicated if there is sidewall fixation precluding curative resection with clear margins (52 ). Adjacent organ involvement is not a contraindication to APR as long as tumor-free margins can be obtained (52).

TREATMENT RESULTS IN PERSISTENT OR RECURRENT DISEASE: THE STATISTICS:

After salvage attempts, five year survival ranges between 24% and 58% (51, 52, ). If the local recurrence is mobile, median survival is 40 months (51). Nodal disease at salvage is associated with an 11% five year survival. (52). Those with pelvic side wall fixation after initial treatment, experience an average 8 month survival, with no patient surviving beyond two years (51).

DISTANT METASTASES: OMINOUS

Distant metastases occur in 10% to 17% of patients (30, 31), and are commonly found in the liver, lung, bone and subcutaneous tissue. Twenty percent of patients with recurrent disease die from distant metastases (54 ). Studies are underway looking at different combinations of drugs with or without irradiation in the treatment of metastatic disease. When the metastatic disease is isolated and the primary focus of disease has been controlled, metastatic resection may play a role in salvage.

FOLLOW UP: DON’T STOP!

Follow up examinations should be performed six to twelve weeks after the conclusion of treatment. Regular exams should be conducted every three to six months for several years as there may be a late recurrence. Examination should include a visual inspection of the operative site, the inguinal region and any other body part of concern to the patient. A digital anorectal exam should be performed and if there is a suspicion of persistent or recurrent disease, an open biopsy under sedation should be done. Anoscopy is useful in obtaining a visual inspection of the anorectum. Although no longer used commonly, post-treatment scar excision may be performed in an effort to find and treat any persistent disease.

SUMMARY OF TREATMENT OPTIONS:

In patients with T1 lesions measuring less than 2 cm in greatest dimension and without sphincter involvement, either local excision or chemoradiation are acceptable modes of treatment. Chemoradiation is the more common form of primary treatment. The chemotherapeutic agents are 5-FU and Mitomycin C. Higher doses of radiation enhance survival, but this may come at the cost of an increased morbidity. There should be no treatment breaks if possible.

Synchronous lymph node involvement is rare in T1 lesions. However, it is common to irradiate at least the ipsilateral inguinal field if the lesion is clearly unilateral, or both inguinal fields for less clearly defined laterality. Histopathologic confirmation of apparently involved nodes should be obtained prior to treatment.

In T2, T3 and T4 lesions, treatment is with chemoradiation. Using radiation, the perineal and inguinal fields are irradiated in T2 lesions, as the rate of synchronous nodal involvement increases in these lesions. Pelvic irradiation is added for T3 and T4 lesions.

In those patients developing biopsy-proven metachronous inguinal nodes, chemoradiation may be administrated and a surgical lymphadenectomy may be performed for resistant disease.

With persistent or recurrent disease, a salvage abdominoperineal resection is performed. Invasion into other pelvic organs (T4) is not a contraindication to resection for cure. However, an APR for salvage should not be performed in patients with pelvic disease if tumor-free margins cannot be obtained.

In patients with recurrence after surgical salvage or in any patients with distant metastases, chemotherapy may have a role to play in treatment. Various chemotherapeutic protocols are available.

In the HIV-positive patient, treatment is as for all other patients, if the CD4 count is greater than 200 cells/cc. HAART therapy should be given concomitantly (unless contraindicated). For those with lower CD4 counts, treatment is individualized with close monitoring for toxicity.

Although squamous cell malignancies are the most common anal and perianal tumors, there is a final group of anal canal tumors which must be considered in any differential diagnosis of a common set of symptoms. This group of rare tumors will be reviewed in the final part of this series. The best that can be said of them is that they are rare.

CITATIONS

• Feuger, C. “Intraepithelial Neoplasia in the Anal Canal and Perianal Area.” Current Topics in Pathology 81 (1990): 91-102.
• Shroyer, K. R., Kim, J. G., Manos, M.M., Greer, C. E., Pearlman, N.W. and Franklin, W. A. “Papilloma Virus Found in Anorectal Squamous Carcinoma, Not in Colon Adenocarcinoma.” Archives of Surgery 127 (1992): 741-744.
• Palmer, J. G., Scholfield, J. H. and Coates, P. J.. “Anal Cancer and Human Papilloma Viruses.”Diseases of the Colon and Rectum 32 (1989): 1016-1022.
• Fisch, M., Glimelius, B. and Van Den Brule, A. J.. “Sexually Transmitted Infection as a Cause of Anal Cancer.” New England Journal of Medicine 337 (1997): 1350-1358.
• Beahrs, Oliver H., Wilson, S. M., “Carcinoma of the Anus.” Annals of Surgery 1984. (1976): 422-428.
• Stearns, M. W., and Quan, S. H. Q., “Epidermoid Carcinoma of the Anorectum.” Surgery Gynecology and Obstetrics 131 (1970): 953-957.
• Welch, J. P., and Malt, R. A., “Appraisal of the Treatment of Carcinoma of the Anus and Anal Canal.” Surgery Gynecology and Obstetrics 145 (1997): 837-844.
• Jensen, S. L., Hagen, K., Shokouh-Amiri, M. H., Nelson, O. V., “Does an Erroneous Diagnosis of Squamous-cell Carcinoma of the Anal Canal and Anal Margin at First Physician Visit Influence Prognosis?” Diseases of the Colon and Rectum 30 (1987): 345-351.
• Hoffman, R., Welton, M. I., Klencke, B., Weinberg, V., Krieg, R., “The Significance of Pretreatment of CD4 Count on the Outcome and Treatment Tolerance of HIV-positive patients with Anal Cancer.” Int J Radiat Oncol Bio Phys 44 (199): 127-131
• Fuchshuber, P. R., Rodriguez-Biagas, M., Buffat, L., Peorelli, N. J., “Anal Canal and Perianal Epidermoid Cancers. Collective Review.” Journal of the American College of Surgeons 185 (1997): 494-505
• Wade, D. S., Herrera, I., Castillo, N. B., Petrelli, J., “Metastases to the Lymph Nodes in Epidermoid Carcinoma of the Anal Canal Studied by a Clearing Technique.” Surgery Gynecology and Obstetrics 169 (1989): 238-242.
• Cummings, B. J., “Treatment of Primary Epidermoid Carcinoma of the Anal Canal.” Int J. Colorectal Dis 2 (1987): 238-242
• Boman, B. M., Moertel, C. G., O’Connell, M. J., et al. “Carcinoma of the Anal Canal: A Clinical and Pathological Study of 188 Cases.” Cancer 54 (1984): 114-125.
• Maggard, M., Beanes, S. R.,Ko, C. Y.. “Anal Canal Cancer: A Population Based Reappraisal.” Diseases of the Colon and Rectum 46 (2003) 1517-1524.
• Jensen, S. L., Hagen, K., Harling, H., Shokouh-Amiri, M.H., Nielson, O. V., “Long term Prognosis after Radical Treatment for Squamous-cell Carcinoma of the Anal Canal and Anal Margin.” Diseases of the Colon and Rectum 31 (1988): 273-278.
• Gordon, P. “Current status- perianal and anal canal neoplasms” Diseases of the Colon and Rectum 33 (1990): 799-808
• Schraut, W. H., Wang, C. H., Dawson,P. J., Block, G. E., “Depth of Invasion, Location, and Size of Cancer of the Anus Dictate Operative Treatment.” Cancer 51 (1983): 1291-296.
• Pintor, M. P., Northover, J. M., Nicholls, R. J., “Squamous Cell Carcinoma of the Anus at One Hospital from 1948 to 1984.” British Journal of Surgery 76.8 (1989): 806-810.
• Ryan, D. P., and Mayer. R. J., “Anal Carcinoma: Histology, Staging, Epidemiology, Treatment.” Current Opinions in Oncology 12 (2000): 345-354.
• Hughes, L. L., Rich, T. A., Delclos, L., Ajani, J. A., Martin, R. G., “Radiotherapy for Anal Cancer: Experience from 1987-1989.” Int J Radiat Oncol Biol Phys 17 (1989): 1153-1160
• Constantinou, E. C., Daly, T. A., Fung, L., Willett, J. A.,Kaufman, D. S., DeLaney, T. F., “Time-dose Considerations in the Treatment of Anal Cancer.” Int J Radiat Oncol Biol Phys 39 (1997): 651-657
• Toubal, E., Schlienger, M, Buffat, L., et al. “Epidermoid Carcinoma of the Anal Canal. Results of Curative-intent Radiation Therapy in a Series of 305 Epidermoid Carcinomas.” Cancer 73 (1994): 1569-1579.
• Wolff, B. G., Fleshman, J. W., Beck, D. F., Pemberton, J. H., Wexner, S. D. “The ASCRS Textbook of Colon and Rectal Surgery” Pg. 494. Springer Science+Business Media, LLC, 2007
• Cummings, B. J., Keane,T., J., O’Sullivan, B., Wong, C. S., Catton, C. N., “Epidermoid Anal Cancer: Treatment by Radiation Alone or by Radiation and 5-fluoruracil with and without Mitomycin C.” Int J Radiat Oncol Biol Phys 21 (1991): 1115-1125.
• Nguyen, W. D. Mitchell, K. M.; Beck, D. E., Risk Factors Associated With Requiring a Stoma for the Management of Anal Cancer. Diseases of the Colon & Rectum. 47(2004):843-846,
• Nigro, Norman D., Vaitkevicius, V. K., Considine, B., “Combined Therapy for Cancer of the Anal Canal: A Preliminary Report.” Diseases of the Colon & Rectum 17 (1974): 354-356.
• Buroker, T. R., Nigro, N., Bradley, G., Pelok, L., Chomchai, C., Considine, B., Vaitkevicius., V. K., “Combined Therapy for Cancer of the Anal Canal: A Follow-up Report.”Diseases of the Colon & Rectum 20 (1977): 677-678
• Nigro, N. D. “An Evaluation of Combined Therapy for Squamous Cell Cancer of the Anal Canal.” Diseases of the Colon and Rectum 27 (1984): 763-66.
• Sato, H., Koh, P., Koon, B., , David, C. C., “Management of Anal Canal Cancer.” Diseases of the Colon & Rectum. 48(6):1301-1315.
• UKCCCR. Epidermoid Anal Cancer: Results From The UKCCCR Randomized Trial of Radiotherapy Alone Versus Radiotherapy, 5-Fluorouracil, and Mitomycin C. UKCCCR Anal Cancer Trial Working Party. UK Coordinating Committee on Cancer Research. Lancet 1996;348:1049-1054.
• Bartelink, H., Roelofsen, F., Eschwege, F., Rougier, P.,Bosset, J. F., Gonzalez, D. G., Peiffert, D.,Van Glabbeke, M., Pierart, M., “Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups” Journal of Clinical Oncology, (15) 2040-2049,
• Myerson, R. J., Kong, F., Birnbaum, E. H., “Radiation Therapy for Epidermoid Carcinoma of the Anal Canal, Clinical and Treatment Factors Associated with Outcome.” Radiother Oncol. (61):201 15-22
• Flam, M., John, M., Pajak, T.F., et al., “Role of Mitomycin in Combination with Fluoruracil and Radiotherapy, and of Salvage Chemoradiation in the Definitive Nonsurgical Treatment of Epidermoid Carcinoma of the Anal Canal: Results of a Phase III Randomized Intergroup Study.” Journal of Clinical Oncology. (14) 1996 2527-2539
• Glynne-Jones, R, Mawdsley, S., “Anal Cancer: The End of the Road for Neoadjuvant Chemoradiotherapy?” Journal of Clinical Oncology, (26) 2008: 3669-3671
• Ajani, J. A, Winter, K. A, Gunderson, L. L, Pedersen, J, Benson, A. B 3rd, Thomas, C. R. Jr, Mayer, R. J., Haddock, M. G., Rich, T. A., Willett, C., “Fluorouracil, Mitomycin, and Radiotherapy vs Fluorouracil, Cisplatin, and Radiotherapy for Carcinoma of the Anal Canal: A Randomized Controlled Trial.” JAMA. (299) 2008:1914-1921
• Eng, C., Abbruzzese, J., Minsky, B., D., “Chemotherapy and Radiation of Anal Canal Cancer: the First Approach.” Surgical Oncology Clinics of North America 13. (2004): 309-320.
• Myerson, R. J. “Carcinoma of the Anal Canal.” Radiother Oncol 16 (2001): 131-134
• Cummings, B. J., Thomas, G. M., Keane, T. J., Harwood, A. R., Rider, W. D., “Primary Radiation Therapy in the Treatment of Anal Canal Carcinoma.” Diseases of the Colon & Rectum 25 (1982): 778-782
• Papillon, J.; Montbarbon, J. F., “Epidermoid carcinoma of the anal canal: A series of 276 cases”. Diseases of the Colon & Rectum. 30 (1987):324-333
• Stearns, M. W., Urmacher, C., Sternborg, S. E., Woodruff, J., Attiyeh, F.F. “Cancer of the Anal Canal.” Current Problems in Cancer 4 (1980): 1-44.
• Schlienger, M., Krzisch, C., Pene, F., Marin, J. L., Gindrey, V. B., Mauban, S., et al. “Epidermoid Carcinoma of the Anal Canal. Treatment Results and Prognostic Variables in a Series of 242 Cases.” Int J Radiat Oncol Biol Phys 17 (1989): 1141-1151
• Allal, A, Laurencet, F. M., Reymond, M. A., Kurtz, J. M., Marti, M. C., “Effectiveness of Surgical Salvage Therapy for Patients with Locally Uncontrolled Anal Carcinoma after Sphincter Conserving Treatment.” Cancer 86 (1999): 405-409.
• Gerard, J. P., and et al. “Treatment of Anal Carcinoma with High Dose Radiation Therapy and Concomitant Fluoruracil-Cisplatinum. Long Term Results in 95 Patients.” Radiother Oncol 46 (1998): 256.
• Myerson, R. J., Shapiro, S. J., Lacey, D., Lopez, M., Birnbaum, E., Fleshman, J., Fry, R., Kodner, I. “Carcinoma of the Anal Canal.” American Journal of Clinical Oncology 18 (1995): 32-39.
• Gerard, J. P., Chapet, O., Samiei, F., et al. “Management of Inguinal Lymph Node Metastases in Patients with Carcinoma of the Anal Canal: Experience in a Series of 270 Patients Treated in Lyon and Review of the Literature.” Cancer 92 (2001): 77-84.
• Blumetti, J., Bastawrous, A., L., “Epidermoid Cancers of the Anal Canal: Current Treatment”. Clinical Colon and Rectal Surgery 22 (2009) 77-83.
• Sischy, B. “The Use of Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus and Marginally Resectable Carcinoma of the Rectum.” Int J Rad Oncol Biol Phys 11 (1985): 1587-1593.
• Place, R. J., Gregory, S. G., Huber, P.J.,Simmang, C. l.., “Outcome Analysis of HIV-Positive Patients with Anal Squamous Cell Carcinoma.” Diseases of the Colon and Rectum 44 (2001): 506-512.
• Berry, J. M., Polefsky, J. M., Welton, M. L., “Anal Cancer and its Precursors in HIV-Positive Patients: Perspectives and Management.” Surgical Oncology Clinics of North America 13 (2004): 355-373.
• Oehler-Janne, C. F., Huguet, S. Provencher, B. Seifert, L. Negretti, M. O., Riener, M., Bonet, A. S., Allal, A., Ciernik, I. F., “HIV-Specific Differences in Outcome of Squamous Cell Carcinoma of the Anal Canal: A Multicentric Cohort Study of HIV-Positive Patients Receiving Highly Active Antiretroviral Therapy.” Journal of Clinical Oncology 26 (2008): 2550-2557.
• Ellenhorn, J. D., Enker, W. E., Quan, S. H. Q., “Salvage Abdominoperineal Resection following Combined Chemotherapy and Radiotherapy for Epidermoid Carcinoma of the Anus.” Annals of Surgical Oncology 1 (1994): 105-110.
• Akbari, R. P., Paty, P. B., Guillem, J. G., et Al. “Oncologic Outcomes of Salvage Surgery for Epidermoid Carcinoma of the Anus Initially Managed with Combined Modality Therapy.” Diseases of the Colon and Rectum 47 (2004): 1136-1144
• Van Der Wal, B. C., et al., “Rresults of Abdominoperineal Resections for Recurrent Anal Carcinoma Following Combined Chemoradiationtherapy.” Journal of Gastrointestinal Surgery 5 (2001): 383-387
• Gupta, N., Longo, W. E., Vernara, A. M., Wade, T. P., Johnson, F. E., “Treatment of Recurrent Epidermoid Carcinoma of the Anal Canal.” Seminars in Colon and Rectal Surgery 6 (1995): 160-165.

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PERIANAL CANCERS – MULTIMODALITY TREATMENT

The anal canal and perianal region are subject to a diverse group of diseases. The anatomy of this region was covered in part I of this series and malignant precursors were discussed. Part II will examine perianal cancers. Part III will examine squamous cancers of the anal canal. Part IV will look at unusual cancers of the anal canal.

PERIANAL SQUAMOUS CELL CARCINOMA

Squamous cell carcinomas of the perianal area are five times more rare than their anal canal counterparts. They are similar to other skin-based squamous cell cancers. They may be located anywhere on the perianal skin, which begins at the anal verge and extends up to five cm outward. Males and females are almost equally affected with an average age at presentation of between sixty and seventy years.  Symptoms may be similar to those of other benign perianal conditions, often lulling the patient or physician into false sense of complacency. Misdiagnosis is common and one third of patients are incorrectly diagnosed at their initial visit to a physician. A late stage presentation with a large tumor is not uncommon even though a mass, bleeding, pain, discharge or pruritus should have alerted the patient or physician to a problem at a much earlier time.1 Even large perianal squamous cancers are often diagnosed twenty four months after the first appearance of symptoms. However, diagnostic delay does not seem to worsen the prognosis,3 underscoring the slow growing nature of these tumors. When delay is associated with nodal involvement, cure rates are poor.

These tumors are commonly keratinized and well differentiated, similar to typical skin cancers. Lymphatic spread to the inguinal and femoral nodes may occur, but usually only in larger lesions. (Figure 1). Further spread occurs via the iliac nodal system.

As was discussed in Part I of this series, certain genotypes of HPV are strongly associated with anal canal squamous cancers, especially those cancers proximal to the dentate line where the mucosa is commonly non-keratinized. In these cancers, HPV is thought to play a prominent role in causation. However, perianal squamous cancers are located in keratinized skin and less often have associated HPV. The etiology of perianal squamous cell cancers may be different from those found in the anal canal.

WHAT DO THEY LOOK LIKE AND HOW ARE THEY DIAGNOSED?

Not all perianal skin lesions are malignant. Symptoms of a short duration, symmetrical rashes and local irritations that resolve with topical therapy are usually secondary to a benign condition. Once the condition has resolved, patients should be followed to ensure that resolution has been maintained. However, persistent or recurrent symptoms call for further attention and biopsy.

When clinical suspicion prompts investigation, diagnosis is usually straightforward. A visual examination may be telling. The tumor appears as a central ulcer with rolled, everted edges (Figure 2). It may be small, less than 1 cm in size, or may be large, obstructing the anal opening. A digital exam will yield information about the lesion, its size and the possible presence of tumor fixation to underlying structures. Any non-healing ulceration should be considered malignant and biopsied. Although a biopsy can be performed in the office setting, patient comfort and diagnostic precision are enhanced when patients are examined under anesthesia. It is important to differentiate anal canal lesions from perianal lesions as prognosis and treatment programs may differ. The location of the tumor relative to the anal verge should be noted at the time of biopsy. A pelvic exam should be performed in women to search for vaginal invasion or associated genital lesions. Patients must be examined for involved lymph nodes, with careful evaluation of the inguinal nodal system. Suspicious nodes may be evaluated with a fine needle aspiration. A chest X-ray should be performed looking for metastatic disease. Chest CT scanning can be performed if the chest X-ray is worrisome for the spread of disease. Although perianal squamous carcinoma is not specifically associated with other colon cancers, a colon evaluation should be performed in patients who would otherwise have an examination under the present screening guidelines.

CT scanning or MRI evaluation of the abdomen and pelvis are recommended to search for liver involvement and possible nodal disease. A caveat: scanning may be unreliable when evaluating nodal systems, due to the limitations of the technology when examining small lymph nodes, or the inability of the technology to differentiate nodes with metastatic disease from nodes with reactive hyperplasia. FDG-PET scanning, which looks at the fluorine-18 fluorodeoxyglucose (FDG) metabolic uptake of tissue, may have promise in identifying metastatic disease, especially when FDG-PET scanning is combined with CT scanning (PET/CT). Endoanal ultrasound, while useful in evaluating fistulous disease and rectal malignancies, has an ill-defined role in the evaluation of perianal cancers. It may be useful in evaluating potential sphincter involvement by a locally invasive lesion.

TNM. THE 2010 AJCC STAGING SYSTEM.

The American Joint Committee on Cancer TNM staging system for anal cancers is used for staging the disease. (Table)

The T-stage of an anal cancer refers to the size of the lesion in its greatest dimension. T1 tumors are 2 cm or less in size. T2 tumors are greater than 2 cm but less than 5 cm in size. T3 lesions measure greater than 5 cm in size, and T4 tumors are of any size with invasion into adjacent extradermal tissues such as cartilage, skeletal muscle or bone. With respect to nodal status, the TNM system recognizes the absence or presence of regional nodes, with N0 representing the absence of involved nodes, and N1 representing the presence of involved nodes. The system is similar with respect to metastatic disease, with M1 referencing the presence of distant metastatic disease.

The two most important factors affecting survival and predicting prognosis are the diameter of the lesion and the absence or presence of involved lymph nodes. These both are reflected in the TNM system. Survival rates worsen significantly as the tumor diameter increases. In the 1992 study by Papillon, 17.5% of patients presented with T1 lesions and had 100% survival. 66.6% of patients presented with T2 lesions and had a survival rate of 61%, and 15.8% of patients presented with T3 lesions, with a survival rate of 12.5%2.

The incidence of nodal involvement also increases with increasing tumor size. With nodal metastases, survival rates again decrease. In the same study, 26% of patients had inguinal nodal metastases at the time of presentation. Nodal metastases were never seen with primary tumors less than 2 cm in size (T1). In T2 tumors between 2 and 5 cm in size, nodes were involved in 23% of cases, and in tumors greater than 5 cm in size (T3), nodes were involved in 67% of cases.2 Other important tumor factors potentially affecting survival are the depth of the tumor, specifically the possible presence of sphincter involvement, the degree of tumor differentiation, and the location of the primary tumor.

Although controversy exists regarding certain treatment aspects, it is well accepted that later stage disease is associated with a poor response to operative intervention, and is treated best with radiation or chemoradiation.2, , Again, tumor size and nodal status are instrumental in determining the disease stage.

TREATMENT OPTIONS:

Historically, wide local excision or abdominoperineal resection (APR) were used to treat perianal cancers. Failure rates were found to be high except in a small, select group of patients with early lesions. Present day treatment options have evolved considerably and are tailored to the specifics of the individual stage of the disease.

Currently, available options for eradicating disease are radiation therapy, with or without chemotherapy, or surgical excision in select cases. While radiation therapy, with or without chemotherapy is the commonest form of treatment, surgical excision is appropriate and effective in a small group of perianal cancers. The use of APR for initial tumor treatment is now of historical interest as local recurrence rates were found to range between 27% to 47% and five year survival rates ranged from 40% to 70%6, APR is reserved for those with patients with persistent or recurrent disease. APR may also be used in those infrequent patients with sphincter involvement and incontinence, in those with particularly bulky disease, or in those who have failed initial non-surgical treatment.

CARCINOMA IN SITU OR T1 DISEASE: T1 N0

Treatment commonly depends on the experience and judgment of the treating physician(s).

Cure rates approach 100% using wide local excision (WLE) when treating carcinoma in situ or T1 lesions. Lesions must not involve the anal sphincter to a substantial degree, and should be excisable with a 1 cm margin of normal tissue. 1, , The surgical option is an attractive one as radiation therapy is not without associated morbidity, including anal skin irritation, variable degrees of incontinence, proctitis and bleeding. Chemotherapy is associated with well-known systemic side effects.

There are patients who cannot or will not undergo surgical extirpation. Or, it may not be possible to obtain the necessary 1 cm margin of normal tissue around the tumor without disfigurement or dysfunction. Radiation therapy is the treatment of choice in these situations.

Radiation treatment of anal cancers has been used since the close of WW I. , The success of this modality was offset by the severe complications suffered as a result of the irradiation. The surgical option then became the preferred mode of treatment of anal cancers. Radiation therapy experienced a resurgence in use as better equipment and administration techniques became available. Its use in treating anal canal cancers increased in the1970’s. The renewed use of radiation in the treatment of perianal cancers followed shortly thereafter.

Chemoradiation of anal canal tumors was introduced by Norman Nigro in 1972. Subsequent to this, many physicians began using chemoradiation to treat perianal squamous cancers as well. Although not completely substantiated, it appears that chemoradiation is superior in many aspects when compared with radiation alone in the treatment of perianal squamous carcinomas. Five year survival rates approach 100%, similar to those rates seen with surgical extirpation. 2, 6, , The chemotherapeutic drugs used in treatment are 5-FU, a well known pyrimidine analogue whose metabolites are cytotoxic when incorporated into DNA and RNA, and Mitomycin C (MMC). MMC is an alkylating agent which binds to DNA and inhibits DNA synthesis. It is a radiosensitizer which is thought to target radiation-resistant hypoxic cells, rendering them more vulnerable to the effects of the radiation.

INGUINAL NODAL PROPHYLAXIS IN EARLY LESIONS:

For the most part, superficial T1 tumors do not spread to the inguinal nodal basins. Persistent disease after treatment or recurrent disease is also rare. T1 lesions are almost never associated with lymph node disease,2 allowing for the following conclusions: First, prophylactic surgical lymphadenectomy, a procedure associated with potential and significant morbidity in the form of lymphedema, is not needed or recommended in conjunction with wide local excision, unless the disease is associated with biopsy proven nodal involvement, and even then, the disease may be treated with inguinal radiation rather than operative excision. Biopsies should be performed to differentiate lymph node metastases from nodal reactive hyperplasia. Second, routine prophylactic inguinal node irradiation, also associated with the potential for morbidity in the form of lymphedema, is not needed or recommended in conjunction with curative perineal radiation or chemoradiation unless the disease is associated with biopsy proven nodal metastases.1, 8, 9 It should be noted that the treatment of clinically uninvolved inguinal regions is not standardized between institutions and many clinicians do administer prophylactic radiation to these areas.

LARGER LESIONS: T2, T3, T4 and N1

Treatment of early T2 lesions may be by wide local excision or radiation therapy.9 Radiation is administered through perineal portals. However many institutions add inguinal irradiation as even small T2 lesions may be associated with inguinal disease.2 The definition of an “early” T2 lesion is subjective and there is a risk of missed, untreated inguinal lymph nodes with only wide local excision of early T2 tumors. Radiation of the perineal and inguinal fields as the initial mode of treatment may be the more prudent alternative.

Larger T2 cancers and T3 and T4 cancers are usually treated with chemoradiation. Operative intervention is reserved for salvage of persistent or recurrent disease, for patients with large, bulky tumors, or for those patients unable or unwilling to undergo chemoradiation. With these more ominous tumors, prognosis worsens as survival rates decrease.

INGUINAL NODAL PROPHYLAXIS IN LARGER LESIONS:

While the incidence of lymph node involvement for T1 tumors approaches 0%, the incidence of nodal disease rises to 23% in T2 lesions and 67% in T3 lesions,2 necessitating the addition of nodal irradiation. Both the perineal and inguinal fields are treated in T2 disease.2, 7 With the larger T3 and T4 lesions, pelvic irradiation is added.2, 9, ,

Local control rates are variable with radiation therapy alone. The literature reports widely differing results and often is not clear as to how patients are stratified, as many studies report results of treatment mixing patients receiving radiation alone with patients receiving chemoradiation. Local control rates range between 60% to 100% for T2 lesions and 37% to 100% in T3 lesions.2, 7, 15, 16, 18 Fifty percent of irradiated patients with persistent tumor after treatment may be salvaged with further operative treatment or a radiation boost, thus raising the overall success rates of treatment.10

The overall 5 year survival rates range between 40% and 100% with survival rates decreasing with increasing tumor size (T-stage) or with the presence of nodal disease (N1).6, 9 Again, caution must be used when comparing treatment results based on differing treatment modalities.

There is data showing that chemoradiation is superior to radiation alone with respect to local control rates.16 Additional data comes from a study comparing radiation alone versus chemoradiation in the treatment of squamous cell cancers of the anal canal and anal margin. In this UKCCCR study, chemoradiation was found to be superior to radiation alone in local control rates. However, there was no improvement in overall survival. The authors noted that adding chemotherapy to the radiation treatment “increased immediate morbidity but did not add materially to long-term problems” and suggested that adding 5-FU and Mitomycin C to radiation therapy should be the standard treatment protocol for perianal cancers.

Long-term follow up is necessary in these patients as recurrences can occur as late as 11 years after the initial treatment. Patients must be educated as to the warning signs of a recurrence. Symptoms of recurrence are indolent and patients may complain of seemingly benign perineal discomfort, a lump, bleeding or soiling.

While post-treatment scar excision looking for persistent disease is not uncommonly performed for anal canal cancers, post-treatment scar excision may also be performed for post-treatment perianal cancers if the scar looks atypical or suspicious for persistent or recurrent disease.

Patients with persistent disease who were originally treated with radiation or chemoradiation may be salvaged with wide local excision or an APR with a 50% salvage rate. Patients with recurrence after a disease-free interval also may be treated with attempted surgical salvage.19

CHEMORADIATION. A TOXIC CURE.

With radiation doses greater than 40 Gy, the complication rate increases. Complications may be systemic, such as dermatitis, mucositis, diarrhea, fatigue or bone marrow depression. Death is rare. Local complications include cystitis, small bowel obstruction and iliac artery stenosis. Anorectal function is commonly preserved in up to 90% of patients, but there may be associated anorectal irritability with tenesmus, proctitis, diarrhea, bleeding, urgency and incontinence. Most of these can be controlled with medication, but a proximal ostomy may become necessary. Far from causing further disability, an ostomy may be a welcome relief from symptoms caused by disease treatment.

Anemia, neutropenia or thrombocytopenia may occur in up to 64% of patients receiving MMC. This is more pronounced in those receiving high doses of MMC (greater than 50mg/m2).

In a phase II trial evaluating chemoradiation in perianal squamous cancers, oral capecitabine was substituted for 5-FU. This decreased infusion needs and decreased hospital stays. Toxicity was found to be minimal and the regimen was well tolerated. Local control rates were found to be 70%.

SUMMARY OF INITIAL TREATMENT OPTIONS IN CARCINOMA IN SITU OR T1 LESIONS:

In patients with carcinoma in situ or T1 lesions, treatment may be initiated with either operative excision or chemoradiation. To be eligible for the surgical approach, the lesion must not involve the anal sphincter to a substantial degree, and a one cm margin of normal tissue should be obtained. In the case where the anal sphincter is involved with disease, treatment with chemoradiation is associated with less anal dysfunction. Inguinal nodal basins need not be irradiated unless associated with biopsy-proven metastatic disease, or unless metachronous disease develops. However, many clinicians do routinely administer prophylactic radiation to clinically normal inguinal regions.

SUMMARY OF INITIAL TREATMENT OPTIONS IN T2, T3 AND T4 LESIONS:

In patients with T2, T3 and T4 lesions, chemoradiation is the primary mode of treatment. Radiation is directed at the perineal and inguinal fields in T2 lesions. Radiation is directed toward the perineal, inguinal and pelvic basins in T3 and T4 tumors.

Persistent or recurrent disease is treated with surgical salvage.

A FINAL NOTE REGARDING TREATMENT

Active research is ongoing in an effort to further improve survival rates and decrease toxicity rates associated with treatment. For now, physicians should rely upon one of the known treatment regimens administered by those with experience in this area. Long-term close follow-up is critically important.

PAGET’S DISEASE

Perianal Paget’s disease is thought to be a neoplasm arising from the apocrine glands of the perianal skin. Unlike its mammary counterpart, perianal Paget’s disease may begin as a benign condition in the apocrine glands, and later transform into an invasive adenocarcinoma, spreading into the epidermis. Another theory holds that the disease begins as an intraepithelial adenocarcinoma with a lengthy preinvasive phase, which subsequently spreads to the deeper dermis.17,

Paget’s disease is exceedingly rare, with less than 200 reported cases. It affects people in the seventh decade of life and affects men and women equally.

Pruritus is a common presenting symptom, enlarging the differential diagnosis greatly. Other presenting symptoms include an erythematous perianal skin rash with eczema, oozing or scaling, weight loss, inguinal adenopathy or constipation. The diagnosis is often delayed because of the tumor’s similarity to many other benign anal skin conditions and because of physician unfamiliarity with the disease. The presenting lesion may be circumferential and extend proximally to the dentate line (Figure 3). The average duration of symptoms prior to diagnosis is 3 years. Anal Paget’s disease may present in up to 40% of cases with an associated invasive adenocarcinoma.23 25

A thorough anorectal examination must be performed looking for an associated carcinoma requiring more extensive treatment. A full colon evaluation and a search for visceral carcinomatosis are conducted. Visceral spread occurs in up to 50% of cases 22 24 Common sites of spread include the GI tract, prostate, neck and nasopharynx.23 25 26 27

A biopsy of the affected area will confirm the diagnosis. H and E staining will differentiate Paget’s disease from the similar appearing AIN and will show large, rounded cells, a large peripheral nucleus and abundant cytoplasm (Figure 4). Staining with CK7 and CK20 will differentiate Paget’s disease from anorectal adenocarcinoma.

TREATMENT OPTONS FOR PAGET’S DISEASE:

For patients who do not have an invasive cancer, a wide local excision is the treatment of choice. Small lesions are excised and left open, or closed primarily, while large defects are covered with a rotational flap, advancement flap or split thickness skin graft. Pre-operatively, dermatologic punch biopsies can be used to plan wide local excision margins. Once the excision is completed, intra-operative frozen sections are obtained to ensure adequate excisional margins.22 Positive margins require further excision or a return to the operating room for re-excision if intraoperative frozen sections were not utilized.24 The intraoperative biopsies must be taken 1 cm from the obvious edges of the tumor and in all four perineal quadrants, and must include both the outer skin margins and inner, anal canal margins to the dentate line (Figure 5) . If the margins are found to be clear on frozen section, a skin graft is utilized to cover the excision site.

With a non-invasive tumor, survival may approach 100%.29

Patients must be followed over a long period of time looking for local recurrence or invasive disease amenable to retreatment. Recurrence rates are reported ranging from 37% to 100%23 28 29 and most recurrences can be treated with wide excision. The development of invasive disease is associated with a poor prognosis.

Patients initially presenting with invasive disease may be candidates for an APR with an added inguinal lymphadenectomy if documented nodal disease is present. However, at the time of presentation, these patients have a 25% incidence of metastatic spread and all patients who die of anal Paget’s disease have an invasive component.23 This does not rule out aggressive treatment of patients with invasive disease, nor does it mean that all patients with invasive disease require an APR. In one study, 12 patients had invasive disease and yet only 2 patients died of the disease. In this same study however, 4 of five patients who had invasive disease and who underwent an APR were free of disease. Clearly, judgment is required.23

At present, the role of chemoradiation or perineal radiation therapy is unclear. However, chemoradiation may have a role in those patients unwilling or unable to undergo surgical excision.23

BASAL CELL CARCINOMA

Even rarer is the perianal basal cell carcinoma. Occurring in the seventh and eight decades of life, more commonly in men than women, the lesion looks like other cutaneous basal cell cancers with raised, rolled edges and a central ulceration. They rarely metastasize. The etiology of basal cell carcinoma is unknown. They do not contain HPV. Up to one-third have a history of a basal cell cancer at another bodily location. Lesions are usually smaller than 2 cm. They may also present as papules, plaques, nodules or ulcers. They are superficial and mobile making wide excision straightforward. As they are of a low invasive potential, treatment is gratifying. However, recurrence is not uncommon and a re-excision is the mainstay of treatment. APR or radiotherapy may be used for large lesions with anal canal extension, although this situation occurs rarely. In several series, no patient died of the disease after treatment. Five year survival with adequate excision or re-excision if necessary is 100%.

VERRUCOUS CARCINOMA

Associated with HPV-6 and 11, verrucous carcinoma or Buschke-Lowenstein tumor is a huge, soft, fleshy cauliflower-like cancer that is painful and slow growing (Figure 6). It affects men almost three times more often then women in the fifth decade of life. Symptoms include pain, abscesses, pruritus, bleeding, a malodorous smell and altered bowel habits. Located on the perianal skin or in the distal anal canal or rectum, these lesions are relentless in their growth. Although benign when viewed under the microscope, they must be considered malignant in their behavior, with the potential for local erosion, invasion into the ischioanal fossa and perirectal tissue. CT scanning will define the extent of invasion. Microscopically, verrucous carcinoma looks like condyloma acuminata. It does not metastasize21 33

Wide local excision is the treatment of choice, with APR performed in unusual cases of late-stage disease with sphincter invasion. Radical excision may be necessary in order to achieve a cure. Reports of radiotherapy, imiquimod treatment and CO2 laser treatment are available, but wide excision with postoperative vigilance looking for recurrences is the mainstay of therapy.

Moving in the proximal direction, the next review will focus on squamous cell carcinoma of the anal canal.

Citations

• Beahrs, Oliver H., Wilson, S. M., “Carcinoma of the Anus.” Annals of Surgery 1984. (1976): 422-428.
• Papillon, J., Chassard, J. L., “Respective Roles of Radiotherapy and Surgery in the Management of Epidermoid Carcinoma of the Anal Margin.” Diseases of the Colon and Rectum 35 (1992): 422-429.
• Jensen, S. L., Hagen, K., Shokouh-Amiri, M. H., Nielson, O. V., “Does an Erroneous Diagnosis of Squamous-cell Carcinoma of the Anal Canal and Anal Margin at First Physician Visit Influence Prognosis?” Diseases of the Colon and Rectum 30 (1987): 345-351.
• Moller, C., Saksella, E., “Cancer of the Anus and Anal Canal.” Acta Chir Scand 136 (1970): 340-348.
• “Cancer Staging Manual.” (2009): American Joint Committee on Cancer. Seventh Edition.
• Fuchshuber, P. R., Rodriguez-Biagas, M., Buffat, L., Peorelli, N. J., “Anal Canal and Perianal Epidermoid Cancers. Collective Review.” Journal of the American College of Surgeons 185 (1997): 494-505.
• Touboul, E. “Epidermoid Carcinoma of the Anal Margin: 17 Cases Treated with Curative-intent Radiation Therapy.” Radiotherapy and Oncology 34.3 (1995): 195-202.
• Schraut, Wolfgang H., Wang, C. H., Dawson, P. J., Block. G. E., “Depth of Invasion, Location, and Size of Cancer of the Anus Dictate Operative Treatment.” Cancer 51.7 (1983): 1291-1296.
• Newlin, H.E., Zlotecki, R. A., Morris, C. G., Hochwald, S. N., Riggs, C. E., Mendenhall, W. M., Journal of Surgical Oncology, 2004;86:55-62
• . S. L., Hagen, K., Harling, H., Shokouh-Amiri, M.H., Nielson, O. V., “Long term Prognosis after Radical Treatment for Squamous-cell Carcinoma of the Anal Canal and Anal Margin.” Diseases of the Colon and Rectum 31 (1988): 273-278.
• Gordon-Watson, C. “The Radium Treatment of Malignant Disease of the Rectum and Anus.” Proc R Soc Med 28 (1935): 53-59.
• Gabriel, W. B. “Squamous-Cell Carcinoma of Anus and Anal Canal: Analysis of 55 Cases.” Proc R Soc Med 34 (1941): 139-57.
• Nigro, N. D., Vaitevigus, M. D., Considine, B., “Combined Therapy for Cancer of the Anal Canal: a Preliminary Report.” Diseases of the Colon and Rectum 13; 1974: 354-356.
• Cummings, B. J. “Editorial.” Oncology 10 (1996): 1853-1854.
• Peiffert, D., Bey, P., Pernot, M., “Conservative Treatment by Irradiation of Epidermoid Carcinomas of the Anal Margin.” J Radiat Oncol Biol Phys 39 (1997): 57-66.
• Cummings, B. J., Keane, T. J., Hawkins, N. V., O’Sullivan, B., “Treatment of Perianal Carcinoma by Radiation (RT) or Radiation plus Chemotherapy (rtct).” International Journal of Radiation Oncology and Biological Physics 12 (1986): 170-173.
• Skibber, J., Rodriguez-Bigas, M., Gordon, P., “Surgical Considerations in Anal Cancer.” Surgical Oncology Clinics of North America 13 (2004): 321-338.
• Mendenhall, W. M., Zlotecki, R. A., Vauthey, J. N., Copeland, E. M., “Squamous Cell Carcinoma of the Anal Margin.” Oncology 10 (1996): 1843-1854
• UKCCCR. Epidermoid Anal Cancer: Results From The UKCCCR Randomized Trial of Radiotherapy Alone Versus Radiotherapy, 5-Fluorouracil, and Mitomycin C. UKCCCR Anal Cancer Trial Working Party. UK Coordinating Committee on Cancer Research. Lancet 1996;348:1049-1054.
• Glynne-Jones, R., H. Meadows, S. Wan, et al. “National Cancer Research Institute Anal Subgroup and Colorectal Clinical Oncology Group EXTRA- a Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer.” Int J Radiat Oncol Biol Phys 72(1) (2008): 119-126.
• Gordon, Philip H., and Nivatvongs, Santhat. “Perianal Neoplasms.” Principles and Practice of Surgery for the Colon, Rectum, and Anus”. Page 376.New York: Informa Healthcare, 2007.
• Billingsley, K. G., Stern, L. E., Lowy, A. M., Kalenberg, and Thomas, C. R.., “Uncommon Anal Canal Neoplasms”. Surg Oncol Clin North America 13 (2004): 375-88
• McCarter, M. D., Quan, S. H., Busam, K., Paty, P. P., Wong, D., and Guillem, J. G., “Long-term Outcome of Perianal Paget’s Disease.” Diseases of the Colon and Rectum 46 (2003): 612-616.
• Beck, D. E. “Paget’s Disease and Bowen’s Disease of the Anus.” Seminars in Colon and Rectal Surgery 6 (1995): 143-149.
• Jensen, S. L., Sjolin, K. E., Shokouh-Amiri, M. H., Hagen, K., Harling, H. “Paget’s Disease of the Anal Margin.” British Journal of Surgery 75 (1988): 1089-1092.
• Berardi, R. S., Lee, S., Chen H. P, “Perianal Extramammary Paget’s Disease.” Surgery Gynecology and Obstetrics 167 (1988): 359-66.
• Tulchinsky, H., Zmora, O., Brazowski, E., Goldman, G., Rabau, M., “Extramammary Paget’s Disease of the Perianal Region.” Colorectal Disease 6 (2004): 206-09.
• Sarmiento, J. M., Wolff, B. G., Burgart, L. J., Frizelle, F. A., Ilstrup, D. M.,. “Paget’s Disease of the Perianal Region: An Aggressive Disease?” Diseases of the Colon and Rectum 40 (1997): 1187-194.
• Beck, D. E., Fazio, V. W., Paget’s disease. Diseases of the Colon and Rectum 1987; 30: 263-266
• Brown, R. “Radiotherapy for Perianal Paget’s Disease.” Clinical Oncology 14 (2002): 272-284.
• Gibson, G. E., and Ahmed, I.., “Perianal and Genital Basal Cell Carcinoma: a Clinicopathologic Review of 51 Cases.” Journal of the Academy of Dermatology 45 (2001): 68-71.
• Nielsen, O. V., Jensen, S. L., “Basal Cell Carcinoma of the Anus-a Clinical Study of 34 Cases.” British Journal of Surgery 68 (1981): 856-57.
• Wolff, B. G., Fleshman, J. W., Beck, D. F., Pemberton, J. H., Wexner, S. D. “The ASCRS Textbook of Colon and Rectal Surgery” . Springer Science+Business Media, LLC, 2007
• Patterson, C. A., Young-Fadok, T. M., Dozois, R. R., “Basal Cell Carcinoma of the Perianal Region: 20-Year Experience.” Diseases of the Colon and Rectum 42 (1999): 1200-1202.

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MALIGNANT PRECURSORS?

Anal neoplasms are a rare, diverse group of lesions. Each manifests a different behavior. With the recent publicity surrounding anal cancer, attention has focused on screening, early diagnosis and treatment.

The incidence of anal carcinomas has been increasing slowly, with 3,500 cases reported in the United States in 2001, and 5,260 cases reported in 2009 . 85% per cent of cases arise in the anal canal. The remainder arise from the perianal skin. Patients present from age 25 to 75, with 95% older than age 45. In anal canal cancers, there is a marked female to male preponderance of 5:1. However, in locales with a large number of high-risk males, the ratio approaches 1:1. In contrast to anal canal cancers, perianal cancers are found almost equally in men and women.

Homosexual males have up to a 30 times higher risk of developing an anal squamous cell cancer than the general male population, with HIV-positive men seeming to be at particularly high risk.

ANAL ANATOMY. THE FIRST STEP IN UNDERSTANDING DISEASE.

It is useful to consider the anatomic site of origin when evaluating anal cancers, as tumors arising from differing locations in the anal canal may have different histogenetic origins, may behave differently and may be treated differently.

To best approach the diagnosis and staging of anal tumors, the anal canal first must be defined (Figure 1). The anal canal is small and complex, with differing areas of histology, differing lymph node drainage patterns, an intricate musculature and a complex neural innervation. The canal begins at the upper aspect of the anorectal ring, which is defined by the upper borders of the internal anal sphincter and the puborectalis muscles.  The proximal canal contains a columnar epithelium. The mucosa gradually changes to a non-keratinized stratified squamous epithelium as it passes through the 1 cm long anal transition zone above the dentate line. The canal continues distally to the anal verge and then to the mucocutaneous junction, which is that area of change from non-keratinized stratified squamous mucosa to a keratinized squamous epithelium of the epidermis, with hair bearing skin appendages and sebaceous or apocrine sweat glands.

The dentate line, so named because of its edged, tooth-like appearance, is located 1 to 2 cm proximal to the anal verge and is the transition between columnar mucosa and squamous mucosa. It is the remnant of the border between the embryological endoderm and ectoderm. The dentate line is often used as a point of reference when describing the location of anal disease.

Generally, the area proximal to the dentate line, the first centimeter of which is termed the anal transitional zone, has a lymphatic basin which drains into the superior rectal lymphatics and then to the inferior mesenteric nodes. Additionally, lateral drainage occurs through the middle and inferior lymphatics and the ischioanal fossa into the internal iliac nodes. Distal to the dentate line, drainage is primarily to the inguinal nodes. However, secondary drainage may also extend superiorly to the internal iliac nodes. The perianal skin begins at the anal verge and extends for five centimeters outward onto the buttocks. It drains exclusively to the inguinal nodes. Knowledge of the lymphatic drainage is important in guiding therapy of anal cancers so as to ensure that the appropriate nodal basins are included in the treatment.

GENETICS AND GENETIC EPIDEMIOLOGY. THE NEXT STEP IN UNDERSTANDING.

There exist many associations between anal cancer and a variety of possible causes such as smoking, the coexistence of sexually transmitted diseases, a history of cervical, vulvar or vaginal carcinoma, the use of solid-organ post-transplant immunosuppressive medications and various environmental factors. Anoreceptive intercourse is considered to be a risk factor in disease development and there is a suggestion that anoreceptive intercourse beginning at an early age is the specific high risk factor in the promotion of disease. However, most people with anal squamous cell cancers deny anoreceptive intercourse, leading to the idea that other modes of risk transmission may be operative.

HPV: THE CULPRIT? THE DATA.

Research has focused on data pointing to the human papilloma virus (HPV) in combination with other risk factors as the etiology of many anal cancers (Figure 2). This may be similar to HPV causation in cervical cancer.

HPV is a double stranded DNA virus which infects stratified epithelium of skin or mucus membranes. At least 20 of the more than 200 HPV genotypes infect the anogenital area. Types 6 and 11 are associated with anal condyloma (warts) and low grade anal intraepithelial neoplasia (AIN). These rarely become malignant (Figure 3). Genotypes 16, 18, 31, 33 and 35 are associated with high grade AIN (also called Bowen’s disease, carcinoma in situ or CIS, or AIN III) as well as with invasive cancers of the anus and cervix.

Interestingly, the more benign genotypes 6 and 11 are found as episomes. Episomes are pieces of genetic material existing separate from chromosomal DNA. HPV-6 and 11 are rarely associated with malignancies and this may be because of their lack of integration into the host chromosomal DNA. However, HPV-16 and 18 are integrated into the host DNA and as such, may promote a neoplastic cascade that ends in malignancy.

The upper anal canal transitional epithelium is composed of a columnar epithelium with an overlay of non-keratinized squamous metaplasia. Metaplastic non-keratinized tissue may be unusually susceptible to infection with HPV, leading to disease.9 HPV-16 and 18 are commonly found in anal canal carcinomas, especially proximal to the dentate line. In fact, these upper canal cancers are rarely found without HPV-16 or 18. It is uncommon to find HPV-16 or 18 DNA in the modified skin of the lower anal canal, with its keratinized mucosa. HPV DNA is almost never found in normal, non-malignant anal tissue, and is rarely found in non-squamous cell anal cancers such as adenocarcinoma.

Anal cancer pathogenesis may include a combination of an HPV infection in an immunocompromised host, in susceptible tissue, compounded by other, as of yet unknown environmental factors. Further bolstering the idea that a faulty immune system is a necessary precondition in anal squamous cell malignancies, it has been noted that immunocompromised transplant patients and those with post-chemotherapy carcinoma have a higher frequency of HPV infections with a greater progression to anal squamous cell carcinoma. Also, up to 50% of HIV-positive patients harbor detectable levels of HPV DNA, and an immunocompromised state may promote disease in combination with a persistent HPV infection in the anal canal.2

SCREENING. AN ALPHABET SOUP OF ACRONYMS.

Those at higher risk should be screened every one to three years with an anal Papanicolou (Pap) smear. Screening rationale is similar to that in screening women for cervical cancer. Abnormal cells found on an anal Papanicolou (Pap) smear should prompt further investigation using anal biopsies to identify intraepithelial neoplasia.

Men with a history of homosexual or bisexual activity and/or anal receptive intercourse, HIV-positive men and women irrespective of an anal intercourse history and women with cervical or vulvar lesion or carcinoma should be evaluated with physical exams and anal Pap smears. A special brush is used to obtain cells from the lower anal canal and anal verge (Figure 4). The specimen is fixed and then evaluated for the presence of abnormal cells. With 95% accuracy, certain abnormal results should prompt a closer evaluation using anoscopy and biopsies of areas targeted by acetic acid staining. Borrowing a page from the Bethesda gynecological grading system, anal Pap smears are graded as follows:

• Normal
• Atypical squamous cells of undetermined significance (ASCUS)
• Low grade squamous intraepithelial lesion (LGSIL or LSIL)
• High grade squamous intraepithelial lesion (HGSIL or HSIL)

It is not established whether or not patients with anal ASCUS or LSIL require further evaluation. By analogy to cervical Pap evaluation, many physicians do pursue findings of ASCUS or LSIL. However, it is not clear that this part of the evaluation algorithm is truly similar to anal cytological evaluation. Some physicians do move forward with further evaluation, and some do not. At any rate, in HIV-positive patients with normal anal Pap smears, repeat exams are performed every 12 months. In HIV-negative patients, exams are repeated every two or three years. The examinations are painless, highly accurate and inexpensive.

In those with HSIL, or in those patients with normal Pap smears but in whom the physician has a high level of suspicion that disease may exist, further inquiry with biopsies is initiated looking for AIN or occult malignancies.

Biopsy proven anal intraepithelial neoplasia is graded as AIN I, II or III. With AIN III, in situ carcinoma is seen microscopically. There are multinucleated giant cells, the so-called bowenoid cells seen, with some vacuolization, giving a “halo” effect. AIN III is a worrisome finding.

PERIANAL PREMALIGNANT DISEASE: MANY NAMES. MANY TREATMENTS.

Evaluating and treating all forms of AIN may lead to over-treatment. Treating only selected patients such as those with AIN III may lead to under-treatment and a failure to prevent an ominous progression of the disease. Longitudinal studies will be illuminating.

The recommendations for evaluating and treating AIN I and AIN II are not uniform.

AIN I or II may be observed and re-evaluated every three to six months. These may regress spontaneously.

Some practitioners do treat AIN I however, with the rationale that treating AIN I prevents the further spread of disease, reduces the symptoms associated with AIN I and reduces the extent of disease to the point that topical therapy remains possible.

The purported rationale for treating AIN II and AIN III is to prevent cancer. Again the natural history of the disease is not known, and the progression to an anal malignancy is not a given.

Erring on the side of caution, consideration must be given to eradicating AIN III.

High grade AIN (AIN III) is an intraepithelial squamous cell carcinoma or carcinoma in situ and is the same disease as the older moniker, Bowen’s disease. The term Bowen’s disease should be used only in an historical context. AIN III is strongly associated with the presence of HPV-16 and 18 and is considered to be a pre-malignant condition that has not yet undergone malignant transformation. Observations show a low incidence of malignant transformation of AIN III in patients who are immunocompetent . Definitive proof that AIN III progresses to anal cancer is lacking however, and the natural history of perianal AIN is not firmly established. Studies suggest that up to 28% of patients with AIN III have a synchronous invasive squamous cell carcinoma at the time of diagnosis of AIN III.16 Perianal AIN may be associated with malignancies in other organs.

WHAT DOES AIN LOOK LIKE?

Crusted plaques with erythema or scales and occasional pigmentation are typical of AIN. Areas of ulceration may signal carcinomatous changes. Circumferential disease is common. Lesions may be accompanied by itching, burning or bleeding and a definitive diagnosis is made by biopsy. The disease may involve the anoderm just above the anal verge, the anal verge itself, the perianal skin or the vulva. Disease borders are notoriously indistinct. Intraoperative localization is aided by using an operating microscope, acetic acid or Lugol’s solution (Figure 5). Areas to be biopsied appear white when exposed to acetic acid. AIN III lesions appear yellow or tan when stained with Lugol’s solution. Diagnosis may also be made incidentally by finding AIN in hemorrhoidectomy specimens.

MANY CURES. WHICH IS BEST?

There is ample literature supporting a watch-and-wait posture with AIN III. With this approach, patients are followed with regular exams rather than being treated. Any change in symptoms or the appearance of new lesions would prompt further investigation.

However, after evaluating the available data, many physicians have chosen to aggressively treat AIN III. Either way, vigilance is mandatory.

TOPICAL THERAPY

Several modes of treatment are available to treat AIN III. Imiquimod (Aldara, 3M Pharmaceuticals, St. Paul, Minnesota), an immune response modifier, was originally approved as a treatment for genital warts. It had been used for other benign and malignant skin disorders as well. Imiquimod increases the local production of interferon. It is applied as a 5% cream, three times weekly at night for up to three months. It is left in place for 8 hours per treatment. While safe, Imiquimod may cause local itching, pain or burning or constitutional reactions such as headache, myalgia or GI symptoms. A two or three week rest period may be necessary as the local reaction may be significant. While promising as a treatment, further studies are necessary to determine if it will become the first line treatment for AIN III.

Topical 5% 5-FU is a well known antineoplastic agent. When applied to anal disease, it has been shown to be highly effective in treating and eradicating AIN III. In a prospective study conducted over a six year period, a 16 week course of topical 5-FU treatment was given for patients whose disease was greater than one half the circumference of the anal canal. Patients with lesser involvement of the canal underwent surgical excision. One year after treatment, all patients underwent anal mapping and biopsies. Eight of eleven patients underwent topical treatment, three underwent surgical excision. All but one (who was HIV-positive) were free of disease at the conclusion of therapy. All patients were followed yearly for between 12 and 74 months and there were no recurrences. No long-term side effects or morbidity were reported. Topical 5-FU is commonly used as the first line of defense in treating perianal carcinoma in situ.

OPERATIVE INTERVENTION

Both cautery ablation and surgical excision are readily available to experienced surgeons. Ablation has the advantage of causing less long term damage to the perianal area. Ablation does not allow for tissue diagnosis, and more extensive disease or carcinoma may be overlooked. Ablation should be combined with biopsies. The location of each biopsied area should be noted in detail so as to be able to treat any newly disclosed disease. When combined with acetic acid visualization, targeted ablation can be performed with a low incidence of non-healing wounds or stricture. With extensive or circumferential disease, treatment should be performed in stages to avoid stricture development. A caveat: AIN III may involve hair follicles, sweat glands, and sebaceous glands. During cautery ablation, occult disease in these structures may be overlooked and subsequently untreated. Of note, ablation is curative in almost all HIV-negative patients, whereas HIV-positive patients have a recurrence rate close to 100%. Close follow up is mandatory.15

High resolution anoscopy with guided biopsies has shown promise in improving targeted treatment. However, this technique requires specialized training and may not be available in all operating rooms.

Although it would seem logical that wide local excision (WLE) would be the treatment of choice for extensive disease, this may not be the case. However, most surgeons seem to favor this approach. Excision margins may be difficult to define and normal appearing skin may harbor HPV, especially genotypes 16 and 18. Diseased areas treated with wide local excision have a high recurrence rate, even with the use of disclosing agents and mapping. Normal appearing mucosa may harbor microscopic disease, leading to recurrence.21 WLE is associated with anal stricture, ectropion and incontinence, occasionally necessitating an ostomy. As an adequate excision might need to include the anoderm up to the dentate line, V-Y island flaps may be needed. Obviously, the surgeon must be experienced in the anatomy and operative treatment of the anal and perianal areas.

AIN IN A HEMORRHOIDECTOMY SPECIMEN.

In the special case where disease is found in a hemorrhoidectomy specimen, treatment recommendations vary from a return to the operating room after sufficient healing, for a wide local excision with frozen section evaluation of the specimen margins, to topical therapy or watchful waiting. The more radical surgical approach is associated with high recurrence rates and the potential for anal stenosis and continence difficulties .

WHAT TO DO?

AIN evaluation and treatment guidelines are continuing to evolve as new data and research are published.

It appears as if treatment for high-grade disease is shifting away from routine surgical extirpation24 toward either watchful waiting or topical therapy with imiquimod or 5-FU. Targeted electrofulgeration in patients discovered to have AIN III is also a possible initial treatment option.16 Surgical extirpation may be reserved for patients with persistent untreatable symptomatic disease or invasive carcinoma. Long term follow-up is a necessity. As always, physicians should be aware of the possibility of coexisting anal malignant disease or malignant disease in other organs.

Physicians treating AIN should vigilantly follow patient’s clinical complaints and physical examinations, and remain cognizant of the ever-changing treatment recommendations.

VACCINATION. PREVENTION IS ALWAYS BEST.

In women, two vaccines are available to prevent cervical HPV infection in those who have not yet been exposed to the disease. It is hoped that immunization between the ages of 9 and 26 will reduce the incidence of cervical neoplasia. What about male vaccination?

Gardasil® (Whitehouse Station, New Jersey), a quadrivalent recombinant vaccine, has the advantage of proven effectiveness against HPV-6 and 11, the viruses associated with anal condyloma, as well as HPV-16 and 18, the genotypes thought to cause AIN and anal cancer. Gardasil contains recombinant virus-like particles that look like HPV virions but lack the viral DNA. They cannot induce cancer, but do promote an antibody response, and thus protect against infection with the four HPV types represented in the vaccine. It now has been approved for use in boys and men as well as in women. Its efficacy appears promising.

Vaccination will not prevent disease in those already exposed to one of the genotypes of HPV. However, it may prevent disease caused by another one of the three remaining genotypes. Vaccination will not cause regression of established disease. Finally, vaccination will not prevent disease caused by any of the more than 16 other genotypes that infect the anogential region. Rather than offering vaccination to only high-risk groups, universal immunization may be offered prior to the beginning of sexual experience, as HPV is a sexually acquired pathogen with a ubiquitous presence. Universal vaccination recommendations have not yet been formulated.

With progression to the malignant stage, perianal cancers become more ominous and treatments become more radical. These issues will be the subject of the next review.

CITATIONS

• “Detailed Guide: Anal Cancer What Are the Key Statistics About Anal Cancer?” American Cancer Society.
• Deans, G. T., McAlee, J. A., Spence, R. J. “Malignant Anal Tumors.” British Journal of Surgery 81 (1994): 501-508
• “Tumors of the Anal Canal.” WHO Classification of Tumors. Pathology and Genetics of Tumors of the Digestive System. (2002): 146-155. IARC – INTERNATIONAL AGENCY FOR RESEARCH ON CANCER.
• Maggard, M., Beanes, S. R., Ko, C. Y. “Anal Canal Cancer: A Population-Based Appraisal.” Diseases of the Colon and Rectum 46 (2003): 1517-1524.
• Nivatvongs, S., Stern, H. S. and Fryd, D.S. “The Length of the Anal Canal.” Diseases of the Colon and Rectum 24 (1982): 600-601.
• Milligan, E. T. and Morgan, C. N.. “Surgical Anatomy of the Anal Canal: with Special Reference to Anorectal Fistulae.” Lancet 2 (1934): 1150-1156.
• Fenger, C. “The Anal Transition Zone.” Acta Pathol Microbiol Immunol Scand 85. Suppl 289 (1987): 1-42.
• Morson, B. C., Dawson, I. P. “Gastrointestinal Pathology.” Gastrointestinal Pathology (1972): 603-606.
• Shroyer, K. R., Kim, J. G., Manos, M.M., Greer, C. E., Pearlman, N.W. and Franklin, W. A. “Papilloma Virus Found in Anorectal Squamous Carcinoma, Not in Colon Adenocarcinoma.” Archives of Surgery 127 (1992): 741-744.
• Palmer, J. G., Scholfield, J. H. and Coates, P. J.. “Anal Cancer and Human Papilloma Viruses.”Diseases of the Colon and Rectum 32 (1989): 1016-1022.
• Fisch, M., Glimelius, B., Van Den Brule, A. J.. “Sexually Transmitted Infection as a Cause of Anal Cancer.” New England Journal of Medicine 337 (1997): 1350-1358.
• Welton, M. L. “Etiology of Human Papilloma Virus Infections and the Development of Anal Squamous Intraepithelial Lesions.” Seminars in Colon and Rectal Surgery 15 (2004): 193-195.
• Mullerat, J., Northover, J. “Human Papilloma Virus and Anal Neoplastic Lesions in the Immunocompromised (transplant) Patient.” Seminars in Colon and Rectal Surgery 15 (2004): 215-217.
• Solomon, D. “The Bethesda System: Terminology for Reporting Results of Cervical Cytology.” Journal of The American Medical Association 287. (2002): 2114-2119.
• Chang, G. J., Welton, M. L., “Anal Neoplasia.” Seminars in Colon and Rectal Surgery 14 (2003): 111-118.
• Brown, S. R., Skinner, P., Tidy, J., Smith, J. H., Sharp,F. and Hosie, K. B., “Outcome after Surgical Resection for High-grade Anal Intraepithelial Neoplasia (Bowen’s Disease).” British Journal of Surgery 86 (1999): 1063-1066.
• Scholefield, J. H., Castle, M.T., N. F.,Watson, S. “Malignant Transformation of High-grade Anal Intraepithelial Neoplasia.” British Journal of Surgery 92 (2005): 1133-1136.
• Abbasakoor, F., Boulos, P. B., “Anal Intraepithelial Neoplasia.” British Journal of Surgery 92 3 (2005): 277-290.
• Machesa, P., Fazio, V. W., Oliart, S., Goldblum, J.R., Lavery, I. C., “Perianal Bowen’s Disease: A Clinico-pathological Study of 47 Patients.” Diseases of the Colon and Rectum 40 (1997): 1286-1293.
• Sarmiento, J. M., Wolff, B. G., Burgart, L. J., Frizelle, F. A., Ilstrup. D. M., “Perianal Bowen’s Disease. Associated Tumors, Human Papilloma Virus, Surgery and Other Controversies.” Diseases of the Colon and Rectum 40 (1997): 912-918.
• Gordon, Philip H., and Nivatvongs, Santhat. “Perianal Neoplasms.” Principles and Practice of Surgery for the Colon, Rectum, and Anus. New York: Informa Healthcare, 2007.
• Chen, K., Shumack. S., “Treatment of Bowen’s Disease Using a Cycle of Imiquimod 5% Cream.” Clin Experimental Dermatology 28.Suppl (2003): 10-12.
• Graham, B. D., Jetmore, A. B.,Foote, J.E., and Arnold, L. K., “Topical 5-Fluorouracil in the Management of Extensive Anal Bowen’s Disease: a Preferred Approach.” Dis Colon Rectum 48 (2005): 444-450.
• Skinner, P. P., Ogunbiyi, O. A.,Scholefield, J. H., Starts, J.F., Smith, J. H. F., Sharp, F., Rogers, K., “Skin Appendage Involvement in Anal Intraepithelial Neoplasia.” British Journal of Surgery 84 (1997): 675-678.
• Cleary, R. K., Schaldenbrand, J. D., Fowler, J. J., Schuler, J. M., Lampman, R. M.. “The Treatment Options for Perianal Bowen’s Disease: Survey of American Society of Colon and Rectal Surgeons Members.” American Journal of Surgery 66 (2000): 686-688.
• Scholfield, J. H. “Anal Intraepithelial Neoplasia.” British Journal of Surgery. 86 (1999):1364.
• Stanberry, L. R. “A Human Papilloma Virus Type 16 Vaccine.” New England Journal of Medicine 348 (2003): 1404.

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The Good News? These are Rare Lesions.

PERIANAL TUMORS:

“Most of these rare anal tumors are aggressive tumors and are difficult to treat. The best that can be said of them is that they are rare.”

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Paget’s Disease Perianal Paget’s disease is thought to be a neoplasm arising from the apocrine glands of the perianal skin. Unlike its mammary counterpart, perianal Paget’s disease may begin as a benign condition in the apocrine glands, and later transform into an invasive adenocarcinoma, spreading into the epidermis. Another theory holds that the disease begins as an intraepithelial adenocarcinoma with a lengthy preinvasive phase, which subsequently spreads to the deeper dermis.

Anal Paget’s disease is exceedingly rare, with less than 200 reported cases. It affects people in the seventh decade of life and affects men and women equally.

Pruritus is a common presenting symptom. Other presenting symptoms include an erythematous perianal skin rash with eczema, oozing or scaling, weight loss, inguinal adenopathy or constipation. The diagnosis is often delayed because of the tumor’s similarity to many other benign anal skin conditions and because of physician unfamiliarity with the disease. The presenting lesion may be circumferential and extend proximally to the dentate line. The average duration of symptoms prior to diagnosis is 3 years. Anal Paget’s disease may present in up to 40% of cases with an associated invasive adenocarcinoma.

A thorough anorectal examination must be performed looking for an associated carcinoma requiring more extensive treatment. A full colon evaluation and a search for visceral carcinomatosis should be conducted. Visceral spread occurs in up to 50% of cases. Common sites of spread include the GI tract, prostate, neck and nasopharynx.

A biopsy of the affected area will confirm the diagnosis.

TREATMENT OPTONS: For patients who do not have an invasive cancer, a wide local excision is the treatment of choice. With a non-invasive tumor, survival may approach 100%.

Patients initially presenting with invasive disease may be candidates for an abdominoperineal resection (APR), with an added inguinal lymphadenectomy if documented nodal disease is present.

Recurrence rates are reported ranging from 37% to 100% and most recurrences can be treated with repeat wide excision.

Basal Cell Carcinoma Even rarer is the perianal basal cell carcinoma. Occurring in the seventh and eight decades of life, more commonly in men than women, the lesion looks like other cutaneous basal cell cancers with raised, rolled edges and a central ulceration. They rarely metastasize. Up to one-third have a history of a basal cell cancer at another bodily location. Lesions are usually smaller than 2 cm. They may also present as papules, plaques, nodules or ulcers.

TREATMENT OPTONS: They are superficial and mobile making wide excision straightforward. As they are of a low invasive potential, treatment is gratifying. Five year survival with adequate excision or re-excision for recurrences is 100%.

Verrucous Carcinoma Associated with HPV-6 and 11, verrucous carcinoma or Buschke-Lowenstein tumor is a large, soft, fleshy cauliflower-like cancer that is painful and slow growing. It affects men almost three times more often then women in the fifth decade of life. Symptoms include pain, abscesses, pruritus, bleeding, a malodorous smell and altered bowel habits. Located on the perianal skin or in the distal anal canal or rectum, these lesions are relentless in their growth. Although benign when viewed under the microscope, they must be considered malignant in their behavior, with the potential for local erosion or invasion into the ischioanal fossa and perirectal tissue. CT scanning will define the extent of invasion. Microscopically, verrucous carcinoma looks like condyloma acuminata. It does not metastasize.

TREATMENT OPTONS: Wide local excision is the treatment of choice, with APR performed in unusual cases of late-stage disease with sphincter invasion. Radical excision may be necessary in order to achieve a cure. Chemotherapy has been shown to be of little benefit in treating these lesions.

ANAL CANAL TUMORS:

Adenocarcinoma Anal adenocarcinoma accounts for 10% of all anal cancers. The three types of anal adenocarcinomas are those arising in the anorectum, those arising in anal glands, and those arising in an anorectal fistula.

Because there are so few reported cases of anal adenocarcinoma, uniform treatment recommendations based on solid data are difficult to obtain. It is clear that treatment results are relatively poor and this disease seems to be much more aggressive than its anal squamous cell counterpart when matched for local recurrence rates and survival rates.

TREATMENT OPTONS: Treatment regimens have included wide local excision (WLE), abdominoperineal resection, radiation, chemoradiation, and combined modality therapy, usually pre- or post-operative chemoradiation and an abdominoperineal resection. The five year survival and disease-free survival rates have been found to be best in the chemoradiation group, with five and ten year overall survival rates of 58% and 39% respectively.

Melanoma Anal melanoma is an ominous tumor. Fortunately, it is also a rare tumor. Fewer than 500 cases have been reported and it constitutes between 0.5% and 5% of all anal malignancies. Melanoma of the anal canal is the third most common site of occurrence after skin and ocular melanoma. Those with anal melanoma are often white females with an average age of 63 years old. The disease is rarely reported in the African-American or Asian populations. Women are twice as likely as men to have this lesion.

The lesion may arise at any location in the anal canal. Bleeding is the usual patient complaint, followed by pain. Altered bowel habits and tenesmus are also reported. Weight loss is common. The most common presenting sign is an anal mass. Seventy five percent of patients have a mass greater than 1 cm in size, and the average diameter is 4 cm. Many patients have associated involved inguinal lymph nodes.

Anal melanoma is often confused with a thrombosed hemorrhoid. Larger lesions may be polypoid and ulcerated distinguishing the lesion from a thrombotic hemorrhoid. In one study, 71% of patients had “gross and/or histologic pigmentation,” while other studies have found these lesions to be amelanotic in 41% of cases.

Between 38% and 62% of patients presented initially with metastatic disease to lymph nodes, and not uncommonly to distant sites such as liver and lung.

In a review of the Mayo Clinic experience, no single factor predicted survival. Factors evaluated were “gender, size of the lesion, presence of melanin, depth of penetration, positive perirectal lymph nodes and wide local excision versus APR”. Interestingly, the Memorial Sloan-Kettering series found that the only long-term survivors were women.

TREATMENT OPTONS: Although there are conflicting issues in trying to choose a treatment modality and predict survival rates using various parameters, one point is clear; five year survival rates are dismal. Survival rates range between 0% and 29%. One study showed that in patients whose tumors are thicker than 10 mm, cure is not possible.

Using wide local excision or abdominoperineal resection, overall five year survival rates have been found to be 17% and 22% respectively. Most authors note that patients with documented regional metastatic disease or distant metastases should be spared an APR and permanent colostomy, as long-term survival rates are almost non-existent. However, in those with bulky tumors, or in patients in whom the surgeon is unable to obtain 1 to 2 cm tumor-free margins with a wide local excision, or in patients with tumor involvement of the anal sphincters, or in those patients who would be rendered incontinent after a wide local excision, an APR may be the treatment of choice.

Numerous immunologic and adjuvant chemotherapeutic treatments have been tried with little benefit in patients with anal melanoma. Radiation therapy is of unproven benefit as well. Local control, while possible with surgical treatment, is often useless, as distant metastatic disease is a major cause of death.

Neuroendocrine Carcinomas Also called a small cell carcinoma or a large cell neuroendocrine tumor, or a Merkel cell carcinoma, this tumor is so named because it is derived from cells of both the endocrine system and the nervous system. Neuroendocrine cells are found in many organ systems and tissues, with the gastrointestinal tract harboring the largest volume of these cells. These tumors are rare, comprising less than 1% of all lower digestive tract cancers. Most neuroendocrine tumors are found in the rectum and cecum.

Colorectal neuroendocrine tumors are classified as either low-grade carcinoids or high-grade neuroendocrine carcinomas. The neuroendocrine lesions can be further subdivided into small cell carcinomas or large cell neuroendocrine carcinomas.

Diagnosis involves a high index of suspicion in patients with any type of anorectal complaint. An obvious lesion removed surgically will then be submitted for the appropriate microscopic and immunohistochemical evaluation.

TREATMENT OPTONS: As these tumors are rare, no single series can reliably evaluate the different modes of available treatment and survival statistics. Patients have been treated with excision, radical extirpative procedures with or without adjuvant therapy, radiation alone or chemotherapy alone.

Although not validated, it would make sense to treat patients with disease limited to the anal canal with extirpative surgery and/or chemoradiation, akin to the treatment for anal adenocarcinoma.

Most of these rare anal tumors are aggressive tumors and are difficult to treat. The best that can be said of them is that they are rare.

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