Squamous cell carcinoma complicating idiopathic inflammatory bowel disease

Journal of Surgical Oncology 59:4&55 (1995)

Squamous Cell Carcinoma Complicating Idiopathic Inflammatory Bowel Disease M A H M O U D N. KULAYLAT, MD, RALPH DOERR, MD, BRIAN BUTLER, MD, SATEESH K. SATCHIDANAND, MD, AND AMARJIT SINGH, MD From the Department of Surgery, Section of Colon and Rectal Surgery, Division of Surgical Oncology, Department of Pathology, State University of New York, School of Medicine and Biomedical Sciences, Buffalo, New York

Squamous cell carcinoma of the colon and rectum, originating proximal to the transitional zone, is a rare complication of idiopathic inflammatory bowel disease (IIBD). To date there are only 15 single case reports of such an occurrence. This carcinoma develops more commonly in females and in patients with pancolonic disease of more than 8 years’ duration. The rectum is affected in two thirds of the cases. Squamous cell changes, in the vicinity of the primary adenocarcinoma, are present in 27% of cases. The carcinoma is in a pathologically advanced stage in one third of the cases. Colectomy is the main therapeutic modality. Survival following surgical resection ranged from 7 months to 21 years. We present an additional case of rectal squamous cell carcinoma (SCC) complicating chronic ulcerative colitis in a 33-year-old woman who had the disease for 15 years. Multiple biopsies of a gross lesion located 5 cm above the dendate line were consistent with invasive basaloid cell carcinoma. The patient received 5-FU, mitomycin C, and radiotherapy prior to a proctocolectomy and ileostomy . The only histopathologic finding at pathologic review of the surgical specimen was severe squamous dysplasia. 0 1995 Wiley-Liss, Inc.

KEY WORDS:chronic ulcerative colitis, colectomy, pancolonic disease

INTRODUCTION Colorectal adenocarcinoma is a well-established complication of idiopathic inflammatory bowel disease (IIBD). The risk increases with increased duration and extent of the disease [ 1-71. The risk in ulcerative protocolitis is 3% after 5-10 years of disease and 12% after 25 years [4,8-lo]. Similarly, there is a 20-fold increase in risk of cancer for extensive Crohn’s proctocolitis of more than 7 years’ duration [6]. The carcinoma is most often adenocarcinoma and, matched for stage, does not have a poorer prognosis than adenocarcinoma presenting in nonIIBD patients [ 111. Dysplasia is considered a marker as well as precursor of the adenocarcinoma [12-141. However unusual carcinomas such as variants of adenocarcinoma [15,16] and squamous cell carcinoma (SCC) are more common in patients with IIBD than in the normal population. To date there are 15 documented case reports of SCC arising proximal to the transitional zone in pa0 1995 Wiley-Liss, Inc.

tients with IIBD, 14 in association with chronic ulcerative colitis (CUC), and one with Crohn’s colitis (CC) [ 17-26]. We recently treated a patient with SCC of the rectum complicating CUC. Endoscopic biopsies obtained from a gross lesion located 5 cm proximal to the dendate line were consistent with invasive basaloid SCC. The patient received 5-FU, mitomycin C, and radiotherapy prior to proctocolectomy. At review of final pathology of the specimen, the only histologic finding was severe dysplasia. The purpose of this paper is to report this case and to highlight the clinicopathologic features and treatment of SCC complicating IIBD.

Accepted for publication December 30, 1994. Address reprint requests to Mahmoud N. Kulaylat, M.D., 100 High Street, Buffalo, NY 14203.

SCC in IIBD

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Fig. 1. Biopsies from a gross rectal lesion located 5 cm from the dentate line demonstrating uniform basaloid cells extending to full thickness of mucosa (open arrows), with a focus of stromal invasion (closed arrows). X60.

CASE REPORT A 33-year-old white woman developed an acute exacerbation of ulcerative proctocolitis following a normal spontaneous delivery. She had had ulcerative colitis for 15 years. On admission to the hospital, she manifested evidence of severe malnutrition, iritis, erythema nodosum, and polyparthritis. A colonoscopy revealed panproctocolitis with a gross circumferential mucosal lesion at 5 cm from the dendate line. Biopsies from the lesion were consistent with invasive basaloid SCC (Figs. 1, 2). Computed tomography (CT) scan of the abdomen and pelvis revealed thickening of the wall of left colon and rectosigmoid. Carcinoembryonic antigen measured 0.3 ng/dl. Nigro protocol with 5-Fu (1,000 mg/m2 continuous infusion for 5 days), mitomycin C (10 mg/m2/day), and external beam radiation (total dose 4,000 cGy with a daily dose of 200 cGy in 20 treatments) was initiated. The patient also received an initial in-hospital total parental nutrition (TPN) regimen and then home TPN. Four weeks following discharge, the patient developed central venous catheter sepsis and bilateral deep vein thrombosis with pulmonary emboli necessitating removal of the catheter, Greenfield filter insertion, and anticoagulant therapy. She underwent proctocolectomy with ileostomy on January 28, 1991 without complications. To date, she has no evidence of disease. Histopathologically, the resected specimen revealed acute and chronic colitis affecting the whole colon and rectum with no gross lesions particularly in the rectum

and severe squamous dysplasia in the lower rectum with no frank neoplasia (Figs. 3,4).

REVIEW OF LITERATURE Fifteen cases of SCC and adenosquamous cell carcinoma (adenoSCC) complicating IIBD were identified in the literature (Tables I, 11). SCC developed in 14 patients with CUC and in one with CC [ 17-26]. Females were affected more frequently than males with a ratio of 3: 1. SCC is diagnosed at a young age, average 38 years, at an age range of 27-52 years. The symptoms of colitis started at an early age, average 22 years. The initial presentation was severe/fulminant disease in three patients, and the course of the disease was unrelenting in three patients [ 19,20,23]. Proctocolitis disease of more than 8 years’ duration was present in all the cases where data were available. SCC was diagnosed on routine follow-up in three patients and on prophylactic proctocolectomy in one patient [17,25]. The rectum was the site of the carcinoma in two-thirds of the cases [17,19,20,23,26]. SCC developed in a rectal remnant in two patients [19,26]. In these cases, the carcinoma was proximal to the transitional zone, except in one in which the cancer was described as “just above the anal margin” [23]. Synchronous nonsquamous neoplastic lesions were found in the colon in three patients and in extracolonic organs in three patients [17-19,251. One patient had two SCC [17].

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Fig. 2. Higher magnification of biopsy specimen demonstrating neoplastic cells with large nuclei and scant cytoplasm. Note cells with pyknotic nuclei (closed arrows). X600.

Fig. 3. Gross pathology of the resected colon and rectum reveals acute and chronic changes affecting the entire colon and rectum with no gross tumor seen. Note the dentate line (closed arrows.)

The treatment offered to the 15 patients is shown in Table 11. None of the patients received preoperative radiotherapy or chemotherapy. Fourteen patients underwent resective surgery [ 17,18,20-23,25,26]. Fourteen percent of the patients developed anastomotic leak following partial colectomy [21,25]. One patient refused surgery and received radiation therapy following fulguration of the tumor [19]. This patient died after 17 months with metastatic disease. One patient received postoperative adjuvant radiotherapy and was alive for more than 7

years [ 171. Survival following surgical resection ranged from 6 months to 21 years, with a mean of 6 years. The histopathologic features of the tumors is depicted in Table 11. Histologically, the carcinoma is SCC in 80% of cases and an adenoSCC in 20% of cases [17-23,25,26]. Squamous cell type is present in the vicinity of the tumor in four patients, epithelial atypia in one patient, replacement of mucosa with squamous cells in one patient, squamous metaplasia in two patients, and carcinoma in situ in one [18,20,23,26]. The tumor, clas-

SCC in IIBD

sified as to its microscopic grade according to Broder, is grade 3 in nine patients [17,22,23,27]. Three patients had regional LN metastasis. None of these LN positive patients survived more than 5 years following surgery [ 17,18,21]. Five patients had no evidence of LN metastasis, two of these patients presented with full thickness penetration of the bowel wall [17,20,23,25]. All those who were lymph node negative survived for more than 2 years, with a range of 2-21 years [20,23,17,25]. In one case, in which the stage of the carcinoma was not specified, the patient was alive 8 years postoperatively [26].

DISCUSSION Primary SCC and adenoSCC of the colon and rectum, originating proximal to the transitional zone, are rare tumors [28-361. The estimated prevalence of these tumors is 0.025-0.1%of all malignant tumors of the colon and rectum [17,18,21,34-361. For the diagnosis of SCC of the colon and rectum to be made, certain criteria must be satisfied: (1) there must be no evidence of squamous cell carcinoma in any other organ that might spread directly to the bowel or provide a source of metastasis to the bowel; (2) the affected bowel should not be involved in the squamous lined fistula tract, a well-recognized site of origin of SCC; (3) SCC arising from the transitional zone are excluded; and/or (4) there should be no continuity between the tumor and the transitional zone [36]. The pathogenesis of SCC is not well understood and at best speculative. The possible pathogenic origin is: proliferation of reserve cells and metaplasia of glandular epithelium; glandular neoplastic cells; squamous epithelium implanted in the bowel wall; heterotrophic nests of

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squamous epithelium in the colorectal mucosa; or squamous differentiation in an adenoma [ 17,18,36-50]. The inciting factor in these metaplastic and dysplastic changes is believed to be chronic irritation by a carcinogen [51] or chronic disease states such as schistosomiasis [52], amebiasis [36], radiation enteritis [53], and chronic malnutrition [36,51-541. The prevalent theory is that of cell hyperplasia-metaplasia-neoplasia sequence. However, squamous metaplasia, though rare, may occur as a primary lesion and has been reported to occur with malignant change [33,45,55,56]. Colorectal adenocarcinoma is a well-established complication of IIBD, a dynamic disease characterized by repeated episodes of destructive inflammation alternating with regenerative processes. Furthermore, the colon of patients with IIBD, like the colon in the normal population, is at risk of adenomatous changes. Histopathologically, the carcinoma may be glandular, squamous, or glandulosquamous in nature. The risk of carcinoma is related to the duration and extent of the disease. The risk of adenocarcinoma in ulcerative pancolitic disease is 3-7% after 5-10 years of disease, increasing further thereafter [10,57,58]. Similarly, there is a 20-fold increase in the risk of adenocarcinoma in extensive Crohn’s colitis (CC) [6]. On the other hand, SCC is 0.07% as frequent as adenocarcinoma in the general population and the frequency rises to 2.4% in patients with CUC [1719,21,22,34,35]. SCC is a rare complication of CC, with only one case report in the literature [26]. The distribution of the squamous cell carcinomas complicating IIBD is similar to that in the normal population, with the rectum as the site of the squamous cell carci-

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TABLE I. Clinical Features of Squamous Cell Carcinoma Complicating IIBD (N = 16)* Case

Colitis duration

Extent of colitis NC

NS 34 WF

CUC NS CUC NS CUC NS CUC NS CUC 10 yr

34 F

CUC 9 Y'

Pancolitis

51 F

CUC 25 yr

Pancolitis

34 F 43 F NS NS 27 WM

NS NS

Cancer found on routine follow-up

NS

Cancer found on routine follow-up

WM

CUC NS CUC NS CUC NS CUC 10 yr CUC 20 yr

Steroid therapy for 7 years, frequent loose bloody stools Cancer diagnosed rectal biopsy performed because of back pain and increased rectal discharge Initial presentation fulminant colitis; frequent exacerbations of disease for 8 years Diagnosis of cancer made on proctoscopy performed because of loss of weight, cramps, and obstipation Initial presentation severe colitis requiring ileostomy; frequent exacerbations for 4 years, then lost to follow-up Diagnosis of cancer made on examination performed because of loss of weight and bloody diarrhea Cancer found on routine follow-up

52 M

CUC 20 yr

Pancolitis

32 F 31 F 33 F

CUC 13 yr CD 24 yr CUC 15 yr

Pancolitis

AgelSex 34 NS 38 NS 41 NS 51

41

\

I

Remarks regarding colitis

NS NS

NS Pancolitis

Pancolitis Pancolitis

Pancolitis Pancolitis

Chronic diarrhea (25) Cancer found in colectomy specimen Intermittent diarrhea Cancer diagnosed on barium enema performed because of large bowel obstruction Initial diagnosis severe colitis requiring emergency colectomy and ileostomy Cancer on examination performed because of bloody discharge Periodic diarrhea and cramps Cancer diagnosed on BE performed because of weight loss Abdominal colectomy and ileorectostomy after 14 years of disease Developed the cancer 10 years later Acute exacerbation after delivery Cancer found on rectal biopsies

*CUC, chronic ulcerative colitis; CD, Crohn's disease; NS, not specified; + , present case.

noma in 66% of cases (Table 11). As in adenocarcinoma or pelvic pouch procedure vs surveillance for markers or complicating IIBD, multicentricity is more common with precancerous lesions [ 13,16,60-641. The reliance on surSCC [59]. Multicentric and synchronous colonic carcino- veillance is not a guarantee that a cancer will not develop mas occurred in 27% of SCC cases [ 17,183. As in adeno- while the patient is under observation [16,60,64] (Table carcinoma complicating IIBD where cellular dysplasia is IV). Moreover, markers and precancerous lesions are not considered a precursor and a marker for the cancer, the always present, severe dysplasia is absent in 10-20% of presence of squamous cell type squamous metaplasial patients in whom adenocarcinoma develops, and atypia may be a precursor and a marker of SCC. squamous cell changes are present in only 25% of paSquamous cell type was present in the vicinity of the tients in whom SCC develops [I61 (Table 11). Prophylactumor in five patients. The degree of cellular change tic proctocolectomy, especially in high-risk groups and ranges from metaplasia to atypia to squamous cell carci- early-onset IIBD, is a rational approach, particularly with the availability of the pelvic pouch procedure. noma in situ (Table 11). The rectal remnant following an abdominal colectomy Although carcinoma is a definite complication of IIBD, there is controversy on the optimal preventive with or without ileoproctostomy is at risk of future develmeasure, prophylactic proctocolectomy with ileostomy opment of cancer. The risk of adenocarcinoma is 5% at

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TABLE 11. Histopathology, Treatment, and Outcome of Squamous Cell Carcinoma Complicating IIBD (n = 16)* Case

Histopathology

Adjacent mucosa

Treatment outcome

G-3 SCC, well above anal verge

-

Colectomy

G3-SCC, well above anal verge

-

Colectomy

G-3 SCC, well above anal verge

-

Colectomy

G-3 SCC, well above anal verge

-

Colectomy

Midrectal SCC invasive to muscularis mucosa with submucosal lymphatic invasion; moderately well differentiated with anaplastic pattern Midrectal G-3 SCC extending to peritoneum G-3 SCC just above anal margin invading vaginal Upper rectal G-3 SCC invading through muscularis Upper rectal G-3 SCC involving regional LN Descending colon G-3, stag A SCC

Squamous metaplasia SCC in situ in whole surface of rectum lymphatics

Proctocolectomy NED at 2 yr

Mucosa above and below tumor replaced by squamous epithelium -

Abdominoperineal resection Survived 13 yr Radical posterior resection Survived 21 yr Abdominoperineal resection Alive at 13 yr Colectomy Died at 2 yr Colectomy ; postoperative radiotherapy Survived 7 yr Abdominal colectomy with ileorectostomy developed anastomotic leak and required ileostomy Died at 1 yr; local and systemic disease (liver, LN, mesentery, diaphragm) Extended (R) colectomy Liver metastasis at 1 mo Died at 7 mo Refused surgery Radiotherapy 5 ,OOO rad Died at 17 mo Transverse colectomy Pelvic recurrence at 7 mo; TAH and sigmoidectomy ; developed rectovaginal fistula and required ileostomy Proctectomy 3 yr 4 mo for pain and chills; lung bone metastasis at 7 mo APR Alive at 8 yr Chemoradiotherapy followed by proctocolectomy and ileostomy NED at 3 yr

-

Descending colon adenoSCC moderately differentiated

-

Transverse colon moderately well-differentiated adenoSCC invading to muscularis propria Rectal stump SCC 5 cm above anal verge

Epithelial atypia -

Transverse adenoSCC invading to muscularis propris, LN positive for metastasis

-

Rectal stump SCC

Squamous metaplasia

Lower rectal invasive SCC on biopsy; squamous dysplasia in final specimen

-

* AdenoSCC, adenosquamous cell carcinoma; APR, abdominoperineal resection; BSO, bilateral salpingo-oophorectomy; CIS, carcinoma in situ; G, grade; LN, lymph node; NS, not specified; SCC, squamous cell carcinoma; TAH, total abdominal hysterectomy; present case.

+,

15-20 years, and of SCC is 16% in the same time frame [19,26,65]. SCC in the latter group developed in the rectal stump 10 years following abdominal colectomy. Anastomotic complications developed in 15% of SCC patients subjected to less than a panproctocolectomy [21,25]. Moreover, 1 6 1 5 % will need conversion to an ileostomy because of complications or unsatisfactory results [66,67] (Tables I, 11). Preoperative chemotherapy and/or radiotherapy is rarely used in the treatment of primary squamous cell

carcinoma of the colon and rectum. This remained true for squamous cell carcinoma complicating IIBD. To date, only two patients with primary squamous cell carcinoma of the colon and rectum were treated with chemotherapy and radiotherapy. One patient received a Nigro protocol following full-thickness local excision of arectal SCC [30], and one received radiotherapy with 5-FU as the primary therapy [30,32]. The former patient was free of disease at 1 year and later died 15 months following therapy. Although our patient did not complete the full

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chemotherapeutic regimen, there is pathologic evidence of down-stagingof the carcinoma from invasive to severe dysplasia. Based on the well-documented efficacy of chemo- and radiotherapy in the treatment of squamous cell carcinoma of the anorectum (anal canal and anal margin), chemo- and radiotherapy may have a place in the treatment of rectal SCC complicating IIBD.

CONCLUSION Patients with IIBD are at risk of the development of cancer, adenocarcinoma, and SCC. Although the risk factors and clinicopathologic features are identical in both carcinomas, SCC develops far less frequently than adenocarcinoma. Surgical resection remains the mainstay therapy. Adjuvant chemo- and radiotherapy may have a place in the treatment of SCC complicating IIBD.

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