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Background
The vast majority of carcinomas arising within the anal canal are squamous cell carcinomas. These carcinomas are associated with both Human Papilloma virus infection as well as AIDS. Until recently, the prognosis was dismal. Now with a combination of radiation therapy, chemotherapy, and surgery, excellent chances of survival have been achieved. Recently, anal-rectal cytology has proven to be an effective screen for high risk patient populations. Prior to multi-agent chemotherapy for AIDS patients, most patients who were at risk for anal carcinoma, died of AIDS and its associated complications. Now with prolonged survival of AIDS patients, the precursor lesions of anal intraepithelial neoplasia can progress to anal carcinoma. This leads to a new sense of urgency in screening these high risk populations.
OUTLINE
PATHOGENESIS CHARACTERIZATION Correlation between mRNA levels of IL-6 and TNF alpha and progression rate in anal squamous epithelial lesions from HIV-positive men.
Arany I, Muldrow M, Tyring SK.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
Anticancer Res 2001 Jan-Feb;21(1A):425-8 Abstract quote
BACKGROUND: The incidence of anal high-grade intraepithelial lesions (HSILs) and progression of anal low-grade intraepithelial lesions (LSILs) to HSIL are high in HIV-positive men. Endogenous cytokines might support the pathogenesis of this progression.
MATERIALS AND METHODS: Accordingly, we determined mRNA levels of IL-6 and TNF alpha and their receptors together with viral genes (HIV-gag and HPV E7) in biopsies of anal condylomas, LSILs and HSILs from HIV-positive individuals by a semiquantitative RT-PCR method.
RESULTS: We found that HSIL significantly differs in expression of these genes from LSIL and condylomas, and the latter two lesions were virtually undistinguishable from each other. A correlation between cytokine levels and HIV as well as HPV E7 transcripts suggests that changes might be associated with each other.
CONCLUSIONS: These findings reveal important molecular events associated with progression of anal intraepithelial lesions (ASILs) in HIV-infected men
Detection of genetic changes in anal intraepithelial neoplasia (AIN) of HIV-positive and HIV-negative men.
Haga T, Kim SH, Jensen RH, Darragh T, Palefsky JM.
Department of Laboratory Medicine, University of California San Francisco, 94143, USA.
J Acquir Immune Defic Syndr 2001 Mar 1;26(3):256-62 Abstract quote
Compared with HIV-negative individuals, HIV-positive individuals have a higher prevalence of anogenital human papillomavirus (HPV) infection, as well as a higher incidence of HPV-associated anal cancer. Little is currently known of chromosomal changes occurring in anal intraepithelial neoplasia (AIN), the probable precursor to anal cancer.
Genetic changes in AIN were characterized by comparative genomic hybridization (CGH) in a study of samples obtained from 19 HIV-positive and 11 HIV-negative men. The proportion with genetic changes significantly increased with the severity of the histopathologic grade with none diagnosed as (0%) AIN 1; 5 of 17 (29%) as AIN 2; and 5 of 9 (56%) AIN 3 showing genetic changes (p = .02). This correlation was also found in study subjects who had multiple biopsies with different grades of pathology concurrently or serially over time. The most common regional DNA copy number change was gain mapped to chromosome arm 3q (12% of AIN 2 and 33% of AIN 3).
This alteration was previously reported to be commonest alteration in cervical cancer, which suggests a common molecular pathway for these two HPV-associated anogenital neoplasias.
p16
Hum Pathol. 2006 May;37(5):513-9. Abstract quote
Recent studies have revealed that cervical cancers associated with high-risk human papillomavirus (HPV) showed overexpression of the p16 protein, a cyclin-dependent kinase inhibitor.
The expression of this cell cycle regulator in lesions of the anogenital region in association with HPV physical status (episomal or integrated) has not been studied at the present time. In this report, immunohistochemical analysis of p16 and HPV detection by in situ hybridization were performed on 110 formalin-fixed and paraffin-embedded samples of anogenital lesions.
The results showed strong diffuse p16 staining in all integrated high-risk HPV-positive lesions, whereas most episomal HPV-positive lesions or HPV-negative lesions showed no p16 immunostaining. However, there were a few HPV-negative lesions or lesions with episomal HPV harboring p16 overexpression. On the other hand, some lesions were p16 negative while showing the presence of high-risk HPV in its episomal form.
In conclusion, screening for p16 overexpression in cutaneomucous lesions of the anogenital region allowed good discrimination between HPV-integrated lesions and lesions harboring episomal HPV or no HPV. But p16 overexpression was not always predictive of the presence of high-risk HPV; moreover, absence of p16 immunostaining observed in some high-risk HPV lesions suggested that limiting the screening to p16 would exclude some patients harboring high-risk HPV from any follow-up.
CHARACTERIZATION RADIOLOGIC Anal carcinoma: prognostic value of endorectal ultrasound (ERUS). Results of a prospective multicenter study.
Giovannini M, Bardou VJ, Barclay R, Palazzo L, Roseau G, Helbert T, Burtin P, Bouche O, Pujol B, Favre O.
Oncology and Endoscopic Unit, Paoli-Calmettes Institute, Marseilles, France.
Endoscopy 2001 Mar;33(3):231-6 Abstract quote
BACKGROUND AND STUDY AIMS: The classification of anal carcinoma is based on the clinical examination and the estimation of the tumor height (Union Internationale Contre le Cancer (UICC) 1987 Classification). This classification has a direct therapeutic application since tumors which are designated T1 and T2 are generally treated by radiotherapy whereas T3, T4 or N+ lesions are treated by concomitant radiation and chemotherapy. The aim of this prospective multicenter study was to evaluate endorectal ultrasound (ERUS) and to define an ERUS-based classification.
PATIENTS AND METHODS: Between January 1994 and May 1997, 146 patients (42 men and 104 women; mean age, 63) from eight different centers were studied prospectively. The ERUS classification incorporates disease of the anal canal and the perirectal lymph nodes, thus: usT1 describes involvement of the mucosa and submucosa with sparing of the internal sphincter; usT2, involvement of the internal sphincter with sparing of the external sphincter; usT3, involvement of the external sphincter; usT4, involvement of a pelvic organ; N0 describes no suspicious perirectal lymph nodes, and N+, perirectal lymph nodes fulfilling endosonographic criteria for malignancy (e.g. round, hypoechoic). Tumors classified as UICC T1-T2 (<4cm) N0 were treated by radiotherapy alone, whereas lesions with a UICC classification of T2 (> 4 cm), T3-T4, N0-N1-2-3 received combined radiochemotherapy.
RESULTS: Data concerning the treatment and follow-up were available for 115/146 patients (78.7%). We compared the prognostic importance of the two classification schemes for treatment response and the rate of local relapse (chi-squared test). A significantly greater proportion of T1-T2N0 lesions classified by ERUS had a complete response to treatment than those classified by conventional UICC staging (94.5% vs. 80%, respectively; P = 0.008). The ERUS T and N stage were significant predictors of relapse (P=0.001 and P=0.03, respectively) whereas the corresponding clinical (UICC) stages were not (P = 0.4 and P = 0.5, respectively). Using a Cox model, usT stage was the only significant predictive factor for patient survival.
CONCLUSION: This muticenter prospective study demonstrated the superiority of ERUS-based staging over traditional clinical staging in the prediction of important outcomes such as local tumor recurrence and patient survival.
LABORATORY MARKERS
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL Anal carcinoma: a 15-year retrospective analysis.
Olofinlade O, Adeonigbagbe O, Gualtieri N, Gingold B, Berlin I, Sayeed R, Robilotti J.
Dept. of Medicine, St Vincent's Hospital, New York, NY 10011, USA.
Scand J Gastroenterol 2000 Nov;35(11):1194-9 Abstract quote
BACKGROUND: Using a 15-year experience in two teaching hospitals to illustrate the clinicopathologic, treatment and survival characteristics of cloacogenic and squamous cell carcinoma of the anus.
METHOD: A retrospective analysis over a 15-year period from St Vincent's Hospital (SVH) and the Catholic Medical Center (CMC) in New York City. The patients in the study all had a diagnosis of either squamous or cloacogenic cell carcinoma of the anus.
RESULTS: Cloacogenic and squamous cell carcinoma accounted for 2.5% of all large bowel cancers. In the population sample, 28/92 (30.4%) were of the cloacogenic type and 64/92 (69.6%) were of the squamous cell type. The male-to-female ratio was 1:1.5 in those with cloacogenic cancer and 1.8:1 in those with squamous cell carcinoma. The mean age of presentation was 57 +/- 2.8 years for the squamous cell carcinoma patients and 66.3 +/- 3.4 years in those with cloacogenic carcinoma (P < 0.02); 3/28 (10.7%) of patients with cloacogenic cancer were human immune deficiency virus (HIV) positive while 15/64 (23.4%) of the squamous cell cancer patients were HIV positive. The most common clinical presentation in both groups were rectal bleeding, pain, constipation and the presence of an anal mass. Of patients with squamous cell cancer 25% had evidence of infection with the human papilloma virus (HPV) while none of those with cloacogenic cancer had evidence of HPV infection (P < 0.0005). The treatment modality and survival were similar in both histologic groups. The most important factors that affect survival in both groups are female sex and stage of disease.
CONCLUSION: Cloacogenic and squamous cell carcinoma account for only a small proportion of large bowel cancers. The squamous cell type is the more common type and presents at a younger age in both sexes. The squamous cell type is also more common in males and is associated with human papilloma and HIV infection. Treatment modality and survival is, however, similar in both histologic variants of anal cancer.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL Vast majority are squamous cell carcinomas ROLE OF ANAL CYTOLOGY J AIDS and Hum Retrovir 1997;14:415-42
Anal cytology has been shown to be a sensitive test for the identification of cytologic abnormalities.
Sensitivity Specificity HIV+ 81% 63% HIV- 50% 92% VARIANTS ADENOCARCINOMA Adenocarcinoma of the anal ducts. A series of 21 cases.
Jensen SL, Shokouh-Amiri MH, Hagen K, Harling H, Nielsen OV.
Department of Surgical Gastroenterology C, Rigshospitalet, University of Copenhagen, Denmark.
Dis Colon Rectum 1988 Apr;31(4):268-72 Abstract quote
The records of 21 patients treated for adenocarcinoma of the anal ducts between 1943 and 1982 were reviewed.
The patients were followed until death or current status in April 1987. The median follow-up period was eight months (range, 3 to 144 months). Fifteen patients had an erroneous diagnosis made at first physician visit resulting in a median doctor's delay of 14 months (range, 3 to 24 months) before correct treatment was carried out. Nine of the tumors were localized perianally (ischiorectal space), seven anally, and five in a fistula-in-ano. Tumors localized anally were significantly smaller and had a significantly shorter history than perianally or fistula-in-ano localized tumors (P less than .05 for each localization). Three patients with anal tumors had their diagnosis made accidentally by routine histologic examination of an excised hemorrhoid. First examination revealed distant metastases in 13 patients and follow-up examination revealed regional or distant metastases in seven patients.
Modes of treatment were wide local excision (N = 3), abdominoperineal resection (N = 3), colostomy (N = 9), and radiotherapy (N = 2). Twenty of the 21 patients died within 18 months due to the cancer. One long-term survivor was observed; the patient was alive 12 years after local excision of the tumor without evidence of recurrent disease. The crude five- and 10-year survival was only 4.8 percent.
Adenocarcinoma of the anal glands. Results of a survey.
Abel ME, Chiu YS, Russell TR, Volpe PA.
California Pacific Medical Center, San Francisco
Dis Colon Rectum 1993 Apr;36(4):383-7 Abstract quote
Anal gland adenocarcinoma is rare, with information concerning this lesion communicated mostly as case reports. Cases seen by authors, combined with a survey of the membership of The American Society of Colon and Rectal Surgeons, allowed 52 cases with sufficient data for analysis.
It became clear from the survey that most colorectal surgeons have not treated this malignancy. Predominant symptoms are anal pain (58 percent), rectal bleeding (40 percent), and the presence of perianal mass (37 percent). Fifty-four percent of patients present with a fistula, the incidence of fistula being significantly higher in males. Metastases, which may be inguinal, pelvic, or hepatic, are present at diagnosis in 13.5 percent of patients. Three-fourths of patients are eventually treated by abdomino-perineal resection (APR). Twelve percent of the patients in this series had an APR after a failed local excision.
The conclusions from this study are: 1) if local excision is attempted, it must be complete, and the patient must be followed closely for many years, and 2) APR is needed in most patients for local control, with the role of subsequent radiation therapy and/or chemotherapy not yet defined.
Prognosis and recurrence patterns of anal adenocarcinoma.
Basik M, Rodriguez-Bigas MA, Penetrante R, Petrelli NJ.
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.
Am J Surg 1995 Feb;169(2):233-7 Abstract quote
BACKGROUND: Anal adenocarcinomas are rare cancers, constituting fewer than 10% of all anal cancers. This is a retrospective review of 10 patients with anal adenocarcinoma.
PATIENTS AND METHODS: Seven men and 3 women with a median age of 59 years (range 38 to 82) participated in the study. Using the 1976 World Health Organization classification, 4 patients had the rectal type of cancer, 2 had the anal duct type, and 1 had the anorectal fistula type. The 3 remaining patients had unclassifiable tumors with solely extramucosal disease. Seven patients underwent abdominoperineal resection, 1 had a radical vulvectomy and proctectomy, and 2 had local excision.
RESULTS: The median survival was 29 months (range 5 to 249). Seven patients developed a recurrence at the following sites: 2 perineal, 5 inguinal, and 5 distant metastases. Five patients died from their disease a median of 28 months after surgery, and 2 patients died of unrelated causes. Three patients are alive at a median of 54 months; 2 of these patients are free of disease and 1 has a perineal recurrence.
CONCLUSION: Anal adenocarcinomas were found to be a rare, heterogeneous group of tumors with a poor prognosis despite radical surgery.
Primary adenocarcinoma of the anus: a retrospective analysis.
Joon DL, Chao MW, Ngan SY, Joon ML, Guiney MJ.
Department of Radiation Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Int J Radiat Oncol Biol Phys 1999 Dec 1;45(5):1199-205 Abstract quote
PURPOSE: To report the clinical features and outcome of patients with primary adenocarcinoma of the anus following radiotherapy with or without chemotherapy.
METHODS AND MATERIALS: A retrospective analysis was performed on 15 patients referred to Peter MacCallum Cancer Institute between 1981 to 1998 with primary adenocarcinoma of the anus. The median follow-up was 7.5 years. Six patients underwent treatment with curative intent-either chemoradiation or radiotherapy alone. Surgery was mainly limited to either incisional or excisional biopsy. The remaining nine patients were treated with palliative intent because of advanced age, advanced disease, or poor medical status. The biological equivalent doses were calculated for all patients and correlated with time to progression.
RESULTS: None of the curative group had relapsed after a median follow-up of 6.6 years. All except one were alive and well. No patient developed any serious long-term toxicity and all patients avoided colostomy. All patients managed with palliative intent died with persistent locoregional disease with a median survival of 0.8 year.
CONCLUSION: Primary adenocarcinoma of the anus is a very rare disease that precludes a rigorous analysis. This study demonstrates that radiation and in particular chemoradiation are effective therapies consistent with other recent series and analogous to squamous cell carcinomas of the anus. It also emphasizes the poor prognosis of patients treated with palliative intent.
Anal duct carcinoma: case report and review of the literature.
Perkowski PE, Sorrells DL, Evans JT, Nopajaroonsri C, Johnson LW.
Department of Surgery, Louisiana State University Health Science Center, Shreveport, USA.
Am Surg 2000 Dec;66(12):1149-52 Abstract quote
This report details the clinical course of two patients with true anal duct carcinoma.
The incidence of this malignancy is low. The tissues of origination are the glands of the anal duct. The features that differentiate this tumor from the usual rectal carcinoma are prominent ductal structures, abundant mucin production with organized mucinous pools, and infiltration into the perirectal soft tissue. The clinical management of anal duct carcinoma remains a surgical challenge. The extent of surgical resection must be radical because of the infiltrative nature of the tumor. This report describes treatment of two patients with anal duct carcinoma. The first patient was a black woman with no previous history of rectal disease. Her operative procedure was an abdominoperineal resection with posterior vaginectomy. Nine months after initial surgery a local recurrence was resected. The second patient was a white man with a previous history of hemorrhoidectomy and anal fissure. He underwent an abdominoperineal resection but had positive dermal skin margins on permanent sections despite wide perirectal soft tissue resection. A secondary resection with confirmed clear margins of the skin was performed 2 weeks postoperatively. O
ne management aspect of anal duct carcinoma that needs emphasis is the need for wide local excision of the perirectal soft tissues.
VARIANTS Incidence and natural history of dysplasia of the anal transitional zone after ileal pouch-anal anastomosis: results of a five-year to ten-year follow-up.
O'Riordain MG, Fazio VW, Lavery IC, Remzi F, Fabbri N, Meneu J, Goldblum J, Petras RE.
Department of Colorectal Surgery, Cleveland Clinic Foundation, Ohio 44195, USA.
Dis Colon Rectum 2000 Dec;43(12):1660-5 Abstract quote
PURPOSE: Preservation of the anal transitional zone during ileal pouch-anal anastomosis is still controversial because of the risk of dysplasia and the theoretical risk of associated cancer. Without long-term follow-up data, the natural history and optimal treatment of anal transitional zone dysplasia are unknown. The aim of this study was to determine the long-term risk of dysplasia in the anal transitional zone and to evaluate the outcome of a conservative management policy for anal transitional zone dysplasia.
METHODS: Two hundred ten patients undergoing anal transitional zone-sparing ileal pouch-anal anastomosis for ulcerative or indeterminate colitis between 1987 and 1992 and who were studied with serial anal transitional zone biopsies for at least five years postoperatively were included. Median follow up was 77 (range, 60-124) months.
RESULTS: Anal transitional zone dysplasia developed in seven patients 4 to 51 (median, 11) months postoperatively. There was no association with gender, age, preoperative disease duration or extent of colitis, but the risk of anal transitional zone dysplasia was significantly increased in patients with prior cancer or dysplasia in the colon or rectum. Dysplasia was high grade in one and low grade in six. Two patients each with low-grade dysplasia detected on three separate occasions underwent mucosectomy 29 and 38 months after detection of low-grade dysplasia, but no cancer was found. The five other patients with dysplasia on one or two occasions were treated expectantly and were apparently dysplasia-free for a median of 72 (range, 48-100) months.
CONCLUSIONS: Anal transitional zone dysplasia after ileal pouch-anal anastomosis is infrequent, is most common in the first two to three years postoperatively and may apparently disappear on repeated biopsy. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone after five to ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, anal transitional zone excision with neoileal pouch-anal anastomosis is recommended.
Anal carcinoma arising from condyloma acuminata.
Byars RW, Poole GV, Barber WH.
Department of Surgery, University of Mississippi Medical Center, Jackson 39216-4505, USA
Am Surg 2001 May;67(5):469-72 Abstract quote
Condyloma acuminata is a common anorectal condition that frequently requires surgical evaluation and treatment. We have noted an increased incidence of anal carcinoma in patients with condyloma acuminata. The purpose of this study is to review the incidence of malignant transformation of condyloma in our recent experience.
We conducted a 5-year retrospective review of patients with condyloma acuminata treated at a university medical center that serves as a major referral center for the state.
From May 1994 through May 1999 257 patients were treated for anal condyloma. During the same time period 74 patients were diagnosed with squamous cell carcinoma of the anus; nine of these patients also had condyloma acuminata (12.2% of patients with anal carcinoma). All nine were immunosuppressed by illness and/or medication. The extent of carcinoma at diagnosis ranged from stage 0 (carcinoma in situ) to stage IVb. Overall 3.5 per cent of patients with condyloma acuminata also had squamous cell carcinoma of the anus. One patient with stage IVb disease died shortly after initial evaluation. Two patients with advanced disease required extensive surgical intervention and had complex postoperative courses.
Malignant transformation of condyloma acuminata may be increasing in incidence. This disease progression can be insidious and may be fatal. Screening of high-risk patients might be of value, and more aggressive early management of condyloma may prevent the development of malignancy.
BASALOID
- Basaloid Squamous Carcinoma of the Anal Canal With an Adenoid Cystic Pattern: Histologic and Immunohistochemical Reappraisal of an Unusual Variant.
Chetty R, Serra S, Hsieh E.
From the *Department of Pathology, University Health Network; and daggerSunnybrook and Women's College Health Sciences Center, University of Toronto, Toronto, Ontario, Canada.
Am J Surg Pathol. 2005 Dec;29(12):1668-1672. Abstract quote
Two cases of a distinctive variety of basaloid squamous carcinoma (BSC) of the anal canal are described. Both occurred in female patients who presented with bleeding per rectum.
Histologic evaluation of the tumors showed lobules and aggregates of medium-sized basaloid cells with distinctive peripheral palisading and focal areas of central, comedo-necrosis. Accompanying dysplasia of the overlying squamous mucosa was absent. However, the microscopic pattern was dominated by the presence of eosinophilic, hyaline, paucicellular basement membrane-like material around and within tumor nests.
This appearance together with microcystic spaces simulated that of an adenoid cystic carcinoma. Immunohistochemistry of the tumors revealed the following profile: CK7, CK5/CK6, 34betaE12 positive, CK14 focally positive but CK20 negative. The following were all negative: EMA, CEA, smooth muscle and muscle-specific actin, calponin, and S-100. The tumor cells exhibited diffuse nuclear positivity with p63. The eosinophilic basement membrane hyaline material was positive for collagen type IV and also for laminin. BSC of the anal canal with an adenoid cystic pattern is an infrequently encountered and reported variant, although it is seen more often in the aerodigestive tract. There may be an increased propensity for BSC with an adenoid cystic pattern to metastasize to the liver, but the number of cases encountered are too small to be definitive.
The histologic differential diagnosis is true salivary gland-type adenoid cystic carcinoma and basal cell adenocarcinoma. Immunohistochemistry and awareness of this unusual pattern of BSC will facilitate the correct diagnosis being reached.
SPECIAL STAINS/
IMMUNOPEROXIDASEEPIDERMAL GROWTH FACTOR RECEPTOR
Lyly H. Lê, MD, CM, etal.
Most anal canal carcinomas (ACCs) are squamous cell carcinomas (SCCs). SCCs in other tumor sites strongly express epidermal growth factor receptors (EGFRs), the inhibition of which might result in favorable changes in tumor growth. A review of the published scientific literature reveals no information regarding the expression of EGFR in ACCs.
Therefore, we obtained archived pathology samples from ACC biopsies and examined the frequency and level of expression of EGFR and other cell surface and cell cycle markers. The 21 samples studied universally and strongly expressed EGFR and were negative for HER-2.
Clinical studies of EGFR inhibitors in advanced ACC are warranted.p16
Am J Surg Pathol. 2006 Jul;30(7):795-801. Abstract quote
P16 is a tumor suppressor gene product, shown to be overexpressed in most cervical carcinomas and dysplasias associated with high-risk human papilloma virus (HPV) infection. HPV is also associated with anal squamous dysplasias and carcinomas. Significant interobserver and intraobserver variation exists in the interpretation of biopsies for anal intraepithelial neoplasia (AIN).
This study was undertaken to assess the potential role of p16 and Ki67 immunohistochemical expression in refining the diagnosis and grading of AIN.One-hundred and four anal biopsies from 74 patients were retrieved from the surgical pathology files of the department. After discrepancies were resolved and concurrence was achieved by at least 2 of 3 reviewing pathologists, the diagnoses were as follows: 37 negative, 12 condylomas without overt dysplasia, 14 AIN I, 25 AIN II, and 16 AIN III. p16 and Ki67 expression was evaluated by ABC immunoperoxidase staining whereas the presence of the high-risk subtypes of HPV virus was determined by in situ hybridization on a subset of the biopsies. Results were reviewed by 2 pathologists and positive and negative staining was correlated with H&E diagnoses. Nuclear and/or nuclear and cytoplasmic staining was considered as positive for p16 when present in >10% of squamous cells.
Two patterns of positive p16 staining were observed: (1) "spotty" in which positive cells were scattered throughout the lesion and (2) "band" in which >90% of contiguous cells in the lesion stained positive. A band-like pattern of p16 immunoreactivity was seen in 21.4% AIN I, 80% AIN II, and 87.5% AIN III cases. None of the condylomas and only 1 of the negative cases showed a band of p16 positive staining. Spotty p16 immunoreactivity was observed in 8.1% negative, 8.3% condyloma, 14.3% AIN I, 12.0% AIN II, and 12.5% AIN III cases. More than 50% of nuclei stained positive for Ki67 in 28.6% AIN I, 48.0% AIN II, and 75.0% AIN III cases but in none of the negative or condyloma cases. On the basis of these results, a band-like pattern of p16 staining and Ki67 positivity in >50% of the squamous cell nuclei were strongly associated with high-grade AIN. Conversely, absence of a p16 band of positivity coupled with Ki67 positivity in <50% of nuclei was frequently associated with benign lesions. Band like p16 staining also correlated strongly with the presence of high-risk HPV. Most AIN I lesions stained similar to the nondysplastic cases. A small subset of biopsies studied did not conform to the pattern described above: 4 of 14 (28.6%) AIN I lesions showed a band-like pattern of p16 staining and/or >50% Ki67 positive nuclei. Two of these cases were positive for high-risk HPV DNA. 4 of 25 (16.0%) AIN II lesions comprising 9.8% of the 41 high-grade AINs (AIN II and III) showed spotty p16 positivity and <50% Ki67 positive nuclei. One was positive for high-risk HPV DNA.
We conclude that when used together and evaluated in conjunction with H&E stained sections, p16 and Ki67 immunoexpression is a useful adjunct in the diagnosis and grading of AIN.
p63
The University of Michigan Medical Center, Ann Arbor, MI.
Anal canal carcinomas account for between 1% and 2% of all gastrointestinal carcinomas in the United States. By far, the most common carcinoma in this site is squamous cell carcinoma, but the differential diagnosis typically includes poorly differentiated adenocarcinoma and well-differentiated neuroendocrine carcinoma or carcinoid tumor.
Because the first diagnostic specimen received in the pathology laboratory is usually a small, sometimes suboptimal biopsy, the distinction of these types of carcinoma can be difficult. However, accurate diagnosis is imperative, because the treatment differs between squamous carcinoma (chemoradiation) and the other types of carcinoma (surgical therapy). The p63 protein has been previously shown to be involved in epithelial proliferation and differentiation, and is known to be related to squamous carcinomas in many sites.
Therefore, we undertook to ascertain its usefulness in the diagnosis of squamous carcinomas in the anal canal. We retrieved 24 anal squamous carcinomas, 68 colorectal adenocarcinomas (including a tissue microarray), and 32 colorectal neuroendocrine carcinomas from the archives at the University of Michigan, and immunostained them for the p63 antigen.
As a result, this immunohistochemical stain had a specificity of 98% and a positive predictive value of 92% for squamous cell carcinoma once invasive carcinoma had been established. It also stained the dysplastic epithelial cells in adjacent areas of anal intraepithelial neoplasia.
We report that the p63 immunostain is a highly specific and useful tool in the diagnosis of carcinomas of the anal canal.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS J AIDS and Hum Retrovir 1998;17:314-419
In general, risk factors include:
HIV infection
Decreasing CD4 counts
Infection with multiple HPV typesJ AIDS 1999;21:S42-48
At least 75% of those with anal HSIL do not regress while receiving HAART for AIDSConservative treatment by irradiation of epidermoid cancers of the anal canal: prognostic factors of tumoral control and complications.
Peiffert D, Bey P, Pernot M, Guillemin F, Luporsi E, Hoffstetter S, Aletti P, Boissel P, Bigard MA, Dartois D, Baylac F.
Radiotherapy Department, Centre Alexis Vautrin, Nancy, France.
Int J Radiat Oncol Biol Phys 1997 Jan 15;37(2):313-24 Abstract quote
We analyzed in a retrospective series of patients treated by conservative irradiation for an epidermoid cancer of the anal canal (ECAC) the prognostic factors of locoregional control (LRC), survival, late severe complications (LSC), and sphincter conservation (SC).
METHODS AND MATERIALS: From 1976 until 1994, 118 patients presenting with an ECAC were conservatively treated (mean age, 65 years). According to the 1987 International Union Against Cancer (TNM) classification, they were: 19 T1, 70 T2, 22 T3, 7 T4, 94 N0, and 24 N1-3. The treatment started with external beam irradiation (EBI) (36 Gy in 3 weeks or 45 Gy in 5 weeks). Concomitant chemotherapy (5-fluorouracil and mitomycin C) was delivered to 31 patients. Two months later, a boost of 20 Gy was delivered by interstitial 192Ir brachytherapy to 101 patients and EBI in 5. Twelve other patients had an abdominoperineal resection (APR). The mean follow-up was 6 years.
RESULTS: At 5 years the overall survival was 60%, and specific survival (SS) was 75%; it was 94% for T1, 79% for T2, 53% for T3, and 19% for T4. In multivariate analysis, tumor size (> or = 4 cm), node involvement, and no response to the EBI were factors of poor prognosis for SS. Thirty-two locoregional recurrences occurred of which 21 were local recurrences in the 106 patients treated by a conservative schedule. Only tumor size and response to the EBI were prognostic factors on multivariate analysis for local and LRC. A total of 17 patients presented with LSC (Grade 3, 16 patients; and Grade 4, 1 patient), which was treated by APR in 4 patients and colostomy in 11 (of which 7 were definitive). The only significant prognostic factor for LSC in the multivariate analysis was the total extrapolated response dose of irradiation. The definitive rate of SC after conservative treatment in cured patients was 100% for T1, 82% for T2, 58% for T3, and 100% for T4. Since 1989, improvements of the technique have allowed reduction of the LSC in maintaining the same local control.
CONCLUSION: The results of this series are similar to those of the literature. The confirmation of pretherapeutic prognostic factors related to response to the treatment should allow us to adapt the therapeutic intensity for each case to obtain better tumor control, with as few sequelae as possible, to yield a better rate of SC.
Reduced expression of p21WAF1 is an indicator of malignant behaviour in anal carcinomas.
Holm R, Skovlund E, Skomedal H, Florenes VA, Tanum G.
Department of Pathology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.
Histopathology 2001 Jul;39(1):43-9 Abstract quote
AIMS: p21 and p27 protein expression were examined in a comparatively large series of patients with squamous cell carcinoma of the anal canal and compared with clinical and histopathological data (tumour stage, nodal status and differentiation).
METHODS AND RESULTS: We analysed the expression of p21 and p27 protein in 94 anal carcinomas by immunohistochemistry. Nuclear p21 and p27 staining were detected in 71% (67/94) and 75% (71/94) of the cases, respectively. There was no significant association between p27 staining and tumour stage, nodal status or overall survival. We observed that negative p21 immunoreactivity was significantly associated with poorly differentiated anal carcinomas. Furthermore, a shorter overall survival for patients with no p21 protein expression was seen.
CONCLUSIONS: Our data indicate that p21 levels, but not p27 expression, may be a useful predictor of survival in patients with anal carcinomas.
Expression of Ki-67 can assist in predicting recurrences of low-grade anal intraepithelial neoplasia in AIDS.
Calore EE, Nadal SR, Manzione CR, Cavaliere MJ, de Almeida LV, Villa LL.
Pathology Section, Emilio Ribas Infectology Institute, Sao Paulo, SP, Brazil.
Dis Colon Rectum 2001 Apr;44(4):534-7 Abstract quote
PURPOSE: The incidence of anogenital squamous-cell carcinoma was observed to have increased since the beginning of the human immunodeficiency virus infection epidemic among male homosexuals, both with acquired immunodeficiency syndrome and without acquired immunodeficiency syndrome. It seems that immunosuppression is the most important risk factor for the progression of anogenital lesions, recurrences of anal condyloma, and development of anal carcinoma, in particular in acquired immunodeficiency syndrome. High-grade anal intraepithelial neoplasia was predominantly observed in the human immunodeficiency virus-positive men. We have also observed a high rate of recurrences of anal lesions in cases of high-grade anal intraepithelial neoplasia. However, there are many cases of recurrences of low-grade anal intraepithelial neoplasia that cannot be predicted by routine histologic studies. By using immunohistochemical methods, we studied the expression of Ki-67 in epithelial cells of low-grade anal intraepithelial neoplasia of patients with acquired immunodeficiency syndrome to try to predict recurrence of these lesions.
METHODS: Anal biopsies of 38 patients were studied retrospectively. Of these patients, 14 had no recurrences (Group 1), and 24 patients had recurrence of the anal lesions before one year of follow-up (Group 2).
RESULTS: The median percentage of Ki-67-positive cells in Group 1 was 6.3 +/- 7.03 and in Group 2 was 24.1 +/- 16.72. The difference between Groups 1 and 2 was statistically significant (P < 0.001).
CONCLUSIONS: Our results showed a high correlation between the percentage of Ki-67-positive cells and recurrences. We concluded that Ki-67 counting in low-grade anal intraepithelial neoplasia can aid in predicting recurrences and therefore aid in the follow-up of these patients.
RECURRENCE Patterns of recurrence in squamous cell carcinoma of the anal canal.
Luna-Perez P, Fernandez A, Labastida S, Lira-Puerto V, Vazquez-Curiel JA, Herrera L.
Hospital de Oncologia, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, D.F.
Arch Med Res 1995 Autumn;26(3):213-9 Abstract quote
The objective of the study was to identify the patterns of recurrence in patients with squamous cell carcinoma of the anal canal (SCCAC) vs. the size of the primary tumor and its further possible impact on its treatment outcome.
We reviewed 78 patients treated between 1975 to 1991. They were classified according to to the AJC/UICC classification. From 1975 to 1985, 16 patients were treated with radical surgery (RS). From 1985 to 1991, 43 patients were treated with radiotherapy (RT) at doses of 45 Gy/4-5 weeks, to the pelvis and a boost of 15-30 Gy to the perineum. Since 1989, in 19 selected patients, 5-FU and mitomycin-C have been added to the RT schedule (C-RT). There were 55 females and 23 males.
The overall recurrence rate was 62%. In T1 tumors, no recurrences occurred. The local recurrence (LR) according to treatment approach and T were: radical surgery: T2, 50%; T3, 71%; T4, 100%. Radiation therapy: T2, 25%; T3, 41%; T4, 66%. Chemoradiation therapy: T2, 12%; T3, 40%; T4, 50%. Regional recurrences were in RS: T2, 16%; T3, 28%; T4, 100%. RT: T2, 0%; T3, 16%; T4, 33%. C-RT: T2, 0%; T3, 20%; T4, 25%. Distant recurrences were in RS: T2 and T3, 0%; T4, 66%. In RT: T2, 0%; T3, 8%; T4, 33%. In C-RT: T2, 0%; T3, 8%; T4, 50%. In T1 patients, no recurrences were observed. In T2 tumors the recurrence pattern was local. In T3 tumors it was locoregional and to the groin area. In T4 tumors it was locoregional and distant.(
Patterns of recurrence in anal canal carcinoma.
Faynsod M, Vargas HI, Tolmos J, Udani VM, Dave S, Arnell T, Stabile BE, Stamos MJ.
Department of Surgery, Harbor-UCLA Medical Center, Box 25, 1000 W Carson St, Torrance, CA 90509, USA.
Arch Surg 2000 Sep;135(9):1090-3 Abstract quote
HYPOTHESIS: The initial modality of treatment of anal canal carcinoma (ACC) influences the pattern of recurrence of disease.
DESIGN: A retrospective analysis comparing patterns of recurrence in patients with ACC undergoing either surgery or chemoradiotherapy as their initial therapeutic intervention. Anal margin cancers and adenocarcinomas were excluded.
SETTING: A university-affiliated urban medical center.
PATIENTS: Eighty-one patients were given a diagnosis of ACC between February 1, 1952, and December 31, 1998. Fifty-one (63%) of the patients initially underwent surgery: abdominoperineal resection in 38 patients (75%) and local excision in 13 patients (25%). Chemoradiotherapy was the initial therapeutic intervention in 30 patients (37%).
MAIN OUTCOME MEASURES: The patterns of recurrence (local vs distant disease) and survival were compared between the group that underwent palliative surgery (hereafter referred to as the surgical group) and the group that received chemoradiotherapy (hereafter referred to as the chemoradiotherapy group).
RESULTS: The mean follow-up was 40 months. Local recurrence occurred in 7 patients (14%) in the surgical group vs 7 patients (23%) in the chemoradiotherapy group (P =.46). Using Kaplan-Meier actuarial analysis, local recurrence rates for the surgical and chemoradiotherapy groups at 1 year were 0% and 6%, respectively (P =.32), and at 5 years were 17% and 36%, respectively (P =.02). The average (+/-SD) time to local recurrence in the surgical group was 23 +/- 0.7 months and for the chemoradiotherapy group 16 +/- 2.9 months (P =.27). Five (71%) of the 7 patients with local recurrences in the chemoradiotherapy group underwent salvage abdominoperineal resection with 100% disease-free survival at a mean follow-up of 35 months. When patients presenting with metastatic disease were excluded, distant recurrences developed in 7 patients (16%) in the surgical group and 2 (7%) in the chemoradiotherapy group (P =.31). Actuarial 5-year distant recurrence rates for the surgical and chemoradiotherapy groups were 26% and 19%, respectively (P =.65). Five-year survival was 42% in the surgical group and 74% in the chemoradiotherapy group (P =.01).
CONCLUSION: There was a higher rate of local recurrence in patients with ACC treated with chemoradiotherapy vs surgical resection as the initial therapeutic intervention. However, when this occurred, abdominoperineal resection was effective salvage therapy and was associated with a 100% disease-free survival at 3 years. Therefore, chemoradiotherapy is justified as the initial treatment for ACC and has an overall 5-year survival that is significantly higher than that attained with initial surgical treatment.
Sacropelvic resection for recurrent anorectal cancer. A multidisciplinary approach.
Weber KL, Nelson H, Gunderson LL, Sim FH.
University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Orthop 2000 Mar;(372):231-40 Abstract quote
A multimodal approach including preoperative external beam radiation, surgical resection, and intraoperative electron radiation was used in 23 patients with locally advanced anal or recurrent rectal cancers involving the sacrum.
\The proximal extent of complete sacral resection was S2 in three patients, S3 in 12 patients, S4 in two patients, and S5 in one patient. The tumor was confined to the anterior sacral cortex in five patients. The resection was marginal in 10, contaminated marginal in 11, and intralesional in two patients. At 19 to 54 months of followup, five patients are alive without evidence of disease and four are alive with disease. Twelve patients died of their disease, and two died of other causes. There was a mean survival of 32.9 months for the patients who were alive at followup. Kaplan-Meier survival for all patients was 82% at 1 year and 73% at 2 years, with death of disease as an endpoint.
Thirteen (57%) patients had another local recurrence develop at a mean of 17.2 months. Eight (35%) patients had metastatic disease develop at a mean of 16.3 months. Proper patients selection is important in ensuring a favorable outcome from this aggressive surgery.
TREATMENT Management of anal epidermoid carcinoma--an evaluation of treatment results in two population-based series.
Goldman S, Glimelius B, Glas U, Lundell G, Pahlman L, Stahle E.
Department of Surgery, Sodersjukhuset, Stockholm, Sweden.
Int J Colorectal Dis 1989 Dec;4(4):234-43 Abstract quote
Between 1978 and 1984, two unselected population-based groups of patients with anal epidermoid carcinoma were analysed: (1) a retrospective group (Stockholm region, 90 cases), where the treatment varied considerably (partly radiation therapy +/- chemotherapy +/- surgery, partly surgery alone), and (2) a prospective group (Uppsala region, 51 cases) mainly treated by primary irradiation +/- chemotherapy followed by surgery in some cases.
At diagnosis, 106 of the patients were free from metastases. Two of these patients died before treatment began. Of the remaining 104 patients, 77 received primary radiotherapy +/- chemotherapy, 44 to a dose of 30-40 Gy and 33 to a higher dose level, 55-65 Gy. Radiotherapy was followed by surgery in 28 cases. Twenty-seven patients were operated on primarily. The projected 5-year survival rate was significantly higher in the Uppsala than in the Stockholm region (all patients: 55% versus 43%; patients with no initial dissemination: 75% versus 48%). The prognosis was better in patients initially treated with radiotherapy than in those initially treated with surgery. Long-term disease-free survival was 88% in patients treated with radiation alone to an adequate (high) dose level. Multivariate analyses indicated that besides stage and sex, initial treatment and region gave statistically significant prognostic information. There was no evidence that chemotherapy (Bleomycin) conferred any additional benefit.
It is concluded that the initial treatment in anal carcinoma should be radiotherapy (+/- chemotherapy). In patients with no initial dissemination, this therapy seems to improve 5-year survival by 25-30% compared with primary surgery.
Respective roles of radiotherapy and surgery in the management of epidermoid carcinoma of the anal margin. Series of 57 patients.
Papillon J, Chassard JL.
Radiotherapy Department, Centre Leon Berard, Lyon, France.
Dis Colon Rectum 1992 May;35(5):422-9 Abstract quote
The study of 54 patients treated curatively by irradiation with or without surgery is reported.
The crude and cancer-specific five-year survival rates are 59.2 percent and 79.7 percent. Three patients were treated palliatively. The great variation in histologic type, clinical appearance, disease stage, and patient status justifies the definition of a treatment strategy using radiotherapy, surgery, or a combination of the two methods. T1 and T2 squamous- or basal-cell carcinomas are suitable for local excision followed by irradiation or for irradiation alone. T3 tumors and Bowen's disease should be treated by irradiation first. Verrucous carcinoma is suitable for local surgery followed by irradiation. Mucoepidermoid carcinoma and T4 tumors are suitable for preoperative irradiation and delayed surgery.
The optimal radiation technique consists of delivering a dose of 40 Gy in 17 days by cobalt-60 with bolus and in combination with concomitant chemotherapy (5-fluorouracil and mitomycin C). Prophylactic irradiation of the inguinal area is recommended in all NO tumors except for T1 lesions and basal-cell carcinomas.
Conservative versus nonconservative treatment of epidermoid carcinoma of the anal canal for tumors longer than or equal to 5 centimeters. A retrospective comparison.
Touboul E, Schlienger M, Buffat L, Ozsahin M, Belkacemi Y, Pene F, Balosso J, Lefkopoulos D, Parc R, Tiret E, et al.
Services de Cancerologie-Radiotherapie A, Hopital Tenon, Paris, France.
Cancer 1995 Feb 1;75(3):786-93 Abstract quote
BACKGROUND. The role of radiotherapy alone in the sterilization of anal canal epidermoid carcinomas of 5 cm or more remains to be assessed. Thus, the outcomes of patients treated with radiotherapy alone (RT) versus those treated with preoperative radiotherapy and surgery (RS) were compared retrospectively.
METHODS. Between 1972 and 1990, 185 patients were treated with curative intent either with RT alone (n = 147) or with RS (n = 38). The Mean tumor length was 6.18 +/- 1.14 cm and was significantly longer in the RS group (6.55 +/- 1.29 cm) than in the RT group (6.08 +/- 1.08 cm) (P = 0.02). The median follow-up was 77 +/- 57 months and 93 +/- 60 months (P = 0.23) for the RT and RS groups, respectively. For the RT group, the first course of radiotherapy was 40 to 45 Gy in the pelvis for 4 to 5 weeks; after a rest of 4 to 6 weeks, radiotherapy was boosted an additional 15 to 20 Gy for 2 weeks. The RS patients received 40 to 45 Gy in the pelvis for 4 to 5 weeks, then received surgery after a median period of 54 days.
RESULTS. The overall 10-year cancer specific survival rates were 58% in the RT group and 66% in the RS group (P = 0.48). The T-stage 10-year cancer specific survival rates were 68% in the RT group and 67% in the RS group for T2 tumors (P = 0.96); 57% in the RT group and 53% in the RS group for T3 tumors (P = 0.85); and 42% in the RT group and 40% in the RS group for T4 tumors (P = 0.05). In the RS group, the local control rate was 75% (3/4) for T2 tumors; 74% (17/23) for T3 tumors; and 82% (9/11) for T4 tumors. In the RT group, the local control rate was 77% (34/44) for T2 tumors; 70% (58/82) for T3 tumors; and 60% (12/20) for T4 tumors. In the RT group, the anal conservation rate was 61% (27/44) for T2 tumors, 59% (48/82) for T3 tumors, and 55% (11/20) for T4 tumors. Local tumoral control and a functioning anus were present in 72 out of 147 (49%) patients [52% (23/44) for T2 patients, 52% (43/82) for T3 tumors, and 30% (6/20) for T4 patients]. In the RS group, the grade 3 complication rate was 9% (13/146) and in the RS group, 5% (2/38).
CONCLUSION. For patients with T4 tumors, preoperative radiotherapy and surgery seemed to be better in terms of survival and local tumor control rate, but the difference was not significant probably because the number of patients in the RS group was small. For these large tumors, the treatment should probably be more aggressive, combining chemotherapy and radiation therapy, but the increase of local control in relation with the addition of cytotoxic chemotherapy to irradiation is not proved.
Immunohistochemical assessment of Ki-67 as prognostic cellular proliferation marker in anal canal carcinoma.
Indinnimeo M, Cicchini C, Stazi A, Limiti MR, Ghini C, Mingazzini P, Vecchione A.
Dept. of Surgery Pietro Valdoni, University of Rome La Sapienza, Italy
Exp Clin Cancer Res 2000 Dec;19(4):471-5 Abstract quote
In order to define new prognostic factors useful for therapeutic decision-making, the Authors conducted a study on anal canal carcinomas in which Ki-67 proliferation index is correlated with pathological variables and clinical outcome. The Ki-67-detectable antigen is expressed in all stages of the cells cycle except G0. Thus, Ki-67 index can measure cell proliferation and it could be considered an indicator of prognosis.
Thirty-one patients with anal canal carcinoma were evaluated. The specimens were formalin-fixed, paraffin-embedded and used for immunostaining of Ki-67 antigen. We found a significant correlation between Ki-67 score and depth of invasion and lymh node involvement. No correlation was found between high Ki-67 value and neoplastic relapse.
\These results suggest that Ki-67 positivity carries different significance in different cancers. Additional studies are required to ascertain whether more aggressive therapeutic procedures should be applied in the subset of patients with a high growth fraction.
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.
Gerard JP, Chapet O, Samiei F, Morignat E, Isaac S, Paulin C, Romestaing P, Favrel V, Mornex F, Bobin JY.
Department of Radiotherapy-Oncology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France.
Cancer 2001 Jul 1;92(1):77-84 Abstract quote
BACKGROUND: The authors performed a specific analysis of the clinical significance of inguinal lymph nodes metastases in patients with anal canal carcinoma (ACC).
METHODS: A retrospective analysis was conducted of 270 patients who were treated in Lyon between 1980 and 1996 with radiotherapy with curative intent for ACC: No elective irradiation of clinically normal inguinal areas was performed. Patients with metastatic inguinal lymph nodes were treated with inguinal dissection and postoperative irradiation with a dose of 50 grays over 5 weeks. Concomitant chemoradiation, usually with a regimen of fluorouracil and cisplatinum, was given to 159 patients.
RESULTS: The median follow-up for the whole series was 72 months. Synchronous inguinal metastases were observed in 10% of patients (n = 27; the rate was 16% for patients with T3--T4 lesions), and the 5-year overall survival rate was 54.4%. Metachronous inguinal metastases were seen in 19 patients (7.8%), and the 5-year overall survival rate of these patients was 41.4%. An original finding was that, when the primary tumor clearly was located on a single lateral side of the anal canal, the inguinal lymphatic metastases was always homolateral to it (36 of 36 synchronous plus metachronous tumors).
CONCLUSIONS: The data from this series of patients and a review of the literature are in favor of a selective approach in the management of inguinal lymph node involvement for patients with ACC, depending on the disease stage and the location of the primary tumors.
Squamous cell carcinoma of the anal canal.
Mitchell SE, Mendenhall WM, Zlotecki RA, Carroll RR.
Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL 32610-0385, USA.
Int J Radiat Oncol Biol Phys 2001 Mar 15;49(4):1007-13 Abstract quote
PURPOSE: To report the results of primary radiotherapy for treatment of anal canal carcinoma from the University of Florida series and review issues related to treatment of this disease.
METHODS AND MATERIALS: Forty-nine patients were treated with primary radiation therapy (RT) for cure. Patients had a minimum 2-year follow-up (median, 9.8 years). After 1990, patients with lesions of at least 3 cm also received chemotherapy with fluorouracil (1000 mg/m(2)) plus cisplatin (100 mg/m(2)) or mitomycin (10-15 mg/m(2)) if medically fit (n = 26). RT was delivered with a 4-field box technique to deliver 45 Gy in 25 fractions. The inguinal nodes were treated daily using electrons to supplement the dose in that region to a total dose of 45 Gy if clinically negative or about 60 Gy if involved. There were no planned breaks. A 10- to 15-Gy boost was delivered using interstitial iridium 192 implant (n = 32), en face (60)Co field (n = 5), or external-beam photon fields (n = 11).
RESULTS: Local control rates at 5 years were 100% for T1N0, 92% for T2N0 or N1, 75% for T3N0, 67% for T4N0, 88% for T4N(pos) or T(any)N2-3, and 85% overall. With surgical salvage, ultimate local control rates were 100%, 100%, 81%, 100%, and 88%, respectively, with 92% overall. Cause-specific survival rates at 5 years were 100% for Stage I, 88% for Stage II, 100% for Stage IIIA, and 70% for Stage IIIB. Absolute survival rates at 5 years were 62%, 68%, 100%, and 70%. Sphincter preservation rates were 83%, 79%, 75%, and 100% by stage and 81% overall. There was an improvement in local control with the addition of chemotherapy in more advanced disease, but it was not significant. There was an increase in acute toxicity with the addition of chemotherapy (12% > or = Grade 4) but not long-term toxicity. Late toxicity requiring colostomy occurred in 6% of patients and consisted of soft tissue necrosis.
CONCLUSIONS: The majority of patients with anal canal carcinoma can be treated with curative intent using a sphincter-sparing approach of radiation with or without chemotherapy even with advanced disease. With the addition of chemotherapy to radiation, there is an increased risk of acute toxicity and about 1-2% incidence of toxic death. Smaller tumors (T1 and early T2) probably do not require the addition of chemotherapy.
Experience with split-course external beam irradiation +/- chemotherapy and integrated Ir-192 high-dose-rate brachytherapy in the treatment of primary carcinomas of the anal canal.
Kapp KS, Geyer E, Gebhart FH, Oechs AC, Berger A, Hebenstreit J, Stoeger H.
Division of Radiation Oncology, Department of Radiology, Karl-Franzens University Medical School, Graz, Austria.
Int J Radiat Oncol Biol Phys 2001 Mar 15;49(4):997-1005 Abstract quote
PURPOSE: The effect of the treatment of anal cancer by performing a high-dose-rate (HDR) brachytherapy boost during a short split between the external beam radiotherapy series (EBR) +/- chemotherapy was investigated.
METHODS AND MATERIALS: Thirty-nine patients with anal canal cancers, stages T1-T4 N0-2 M0, were treated with split-course EBR (50-50.4 Gy) and a Iridium 192 ((192)Ir-) HDR boost (6 Gy) performed during the 1-2-week split. Patients who failed to achieve a complete tumor response received additional brachytherapy. Chemotherapy with 5-fluorouracil and mitomycin C was offered to patients with tumors > 3 cm and employed concomitantly on days 1-5 and day 1, respectively, of each EBR series.
RESULTS: Follow-up ranged from 3 to 140 months (median 31). Median treatment duration was 56 days. The 3-year (5-year) actuarial rates of locoregional control (LRC) and disease-specific survival (DSS) were 81% (76%) and 80% (76%), respectively. The crude rate of anal preservation was 77% overall, and 97% in patients in whom LRC was achieved. Uncompromised anal function was recorded in 93% of these patients. The actuarial 3-year (5-year) rate of colostomy-free survival (CFS) was 78% (73%). There was a statistically significant difference in LRC and DSS according to stage, tumor size, and nodal status. Complications requiring surgical intervention occurred in 7.6% of patients.
CONCLUSION: The integration of the HDR boost in a split-course EBR regimen +/- chemotherapy resulted in excellent sphincter function without an increase of severe complications and with rates of LRC, DSS, and CFS, which compare favorably with those reported in the literature.
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