Squamous cell carcinoma of the rectum: The treatment paradigm

Available online at www.sciencedirect.com

ScienceDirect EJSO 41 (2015) 1054e1058

www.ejso.com

Squamous cell carcinoma of the rectum: The treatment paradigm D. Musio a,*, F. De Felice a, S. Manfrida b, M. Balducci b, E. Meldolesi b, G.L. Gravina c, V. Tombolini a, V. Valentini b a b

Department of Radiotherapy, University of Rome “Sapienza”, Viale del Policlinico 155, 00161, Rome, Italy Department of Radiotherapy, Universita Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168, Rome, Italy c Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy Accepted 30 March 2015 Available online 24 April 2015

Abstract Purpose: This study was planned to clarify the optimal treatment for squamous cell carcinoma of the rectum, an histological entity extremely rare. Methods: Ten patients with histologically proven squamous cell carcinoma of the rectum were treated with concomitant radiochemotherapy. Radiation therapy was delivered with a 3Dconformational multiple field technique to a dose ranging from 45 to 76.5 Gy, with 6e15 MV energy photons. Chemotherapy consisted of an antimetabolite drug in association with mitomycin C or oxaliplatin. Overall survival and disease free survival were considered in months from the end of the concomitant treatment. Results: All patients completed programmed radiochemotherapy treatment but two patients were excluded to the analysis. Six patients (75%) presented negative biopsy 6 months after the end of radiochemotherapy. Seven patients (87.5%) showed a tumour regression after initial treatment. Only 1 patient underwent salvage surgery. Considering a mean follow-up of 41.75 months, 7 patients are still disease free survivors. Only 1 patient developed local recurrence at 6 months and he died 14 months after abdomino-perineal resection. Conclusion: Primary radio chemotherapy, with a curative intent, could be considered the treatment modality of choice for squamous carcinoma of the rectum. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Squamous cell carcinoma; Rectal cancer; Radiotherapy; Radiochemotherapy

Introduction The majority of rectal cancer is adenocarcinomas; other histologic type are rare and include carcinoid tumours, lymphomas, leiomyosarcomas and squamous cell cancers. Squamous cell carcinoma is an unusual condition: it represents 0.1e0.25 per 1000 cases of colorectal cancers.1,2 Given the rarity of this disease, strong data, regarding epidemiology, pathogenesis and optimal therapy, is lacking. Although some authors are not sure it exists,3 over the years, four hypotheses have developed to explain the physiopathology of squamous cell carcinoma of the rectum:

* Corresponding author. Tel.: þ39 0649973411, þ39 3403319229 (mobile). E-mail address: [email protected] (D. Musio). http://dx.doi.org/10.1016/j.ejso.2015.03.239 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.

1) squamous metaplasia resulting from inflammation or irritation secondary to infection,4,5 radiation6 or inflammatory bowel disease7e9; 2) possibility of pluripotent stem cells capable of squamous differentiation10,11; 3) malignant transformation of epithelial damage12; 4) malignant transformation of preexisting adenomas.13 Diagnostic criteria for squamous cell carcinoma of the rectum were established by Williams et al.14 and included: absence of any anal canal extension, absence of fistulous tract, absence of evidence of metastasis. Because the low incidence of the disease, only case reports4,6,9,12,13,15,16,21e27 and small case series2,10,17e20,32 have been reported in literature, since Rainford,15 in 1933, had described the first case of squamous cell

D. Musio et al. / EJSO 41 (2015) 1054e1058

carcinoma involving the rectum. Therefore the optimal therapy has not been firmly established for the squamous cell cancer of the rectum. Surgery remains the main therapeutic option; however preoperative radiochemotherapy has been considered a valuable therapeutic choice. This study was planned to report a series of squamous cell carcinoma of the rectum, who were treated with primary radiochemotherapy, and to review the literature to clarify the optimal treatment for patients with this rare tumour. The series include patients treated in the Radiotherapy Department of “Universita Sapienza di Roma” and “Universita Cattolica del Sacro Cuore di Roma”. Methods and materials Eligibility criteria Patients retrospectively reviewed were affected by histologically proven rectal squamous cell carcinoma, without any distant metastases, any anal canal extension and any fistulous tract. Patients were required to have a performance status (PS) 0e2, age 18 years, normal blood parameters and normal renal function. Patients were excluded from the study in case of synchronous tumours, cardiovascular disease, history of neurological or psychiatric disorders or previous pelvic radiotherapy. All patients had a complete work-up including history and careful physical examination, digital rectal examination, blood analyses, rectocolonscopy with a tissue biopsy, trans-rectal ultrasound, CT scan of the abdomen and pelvis and chest X-ray. All female underwent gynaecologic examination to exclude the evidence of squamous cell carcinoma of primary gynaecologic site. Treatment plan All patients were treated with concomitant radiochemotherapy. Radiation therapy was delivered with a 3D-conformational multiple field technique to a dose ranging from 45 to 76.5 Gy, with 6e15 MV energy photons. Target volume included primary tumour, mesorectal and posterior pelvic subsite, and regional node (internal and external iliac, presacral, obturator, inguinal lymph nodes). Chemotherapy consisted of an antimetabolite drug (5-Fluorouracile or Raltitrexed) in association with mitomycin C or oxaliplatin. Response and toxicity assessment Tumour regression was evaluated by clinical examination and radiographic evaluation (trans-rectal ultrasound and total body CT scan). Lesions were classified according to their response in complete regression, partial response, persistent disease or progressive disease. Multiple biopsies were performed 6 months after completion of radiochemotherapy. Toxicity was evaluated according to NCI-CTC version 3.0.30

1055

Follow-up All patients were monitored at 3 months intervals for one year and at 6 months intervals for next years up to 5 years. Overall survival (OS) and disease free survival (DFS) were considered in months from the end of the concomitant treatment. Results Patients’ characteristics From March 2000 to May 2013, 10 consecutive patients with histologically proven squamous cell carcinoma of the rectum were treated with radiochemotherapy. Patients with a suspected liver metastasis (n ¼ 1) and with a second lesion localized in the anal canal (n ¼ 1) were excluded. Therefore, we considered a total of 8 patients (4 female, 4 male; mean age 64.9 years) with required diagnostic criteria for squamous cell carcinoma of the rectum. Patients demographics, stage and treatment of each case are listed in Table 1. The distance of the inferior margin of the tumour lesion was located at least 4 cm from the anal verge. The clinical presentation resulted in rectal bleeding in 7 patients, associated with tenesmus in 3 cases. Only 1 patient began with sub-obstruction. According to AJCC TNM Staging System 2010 for anal squamous cell carcinoma, 6 patients showed pathological lymph-nodes; 3 patients were clinically staged as IIIA (perirectal lymph nodes), 3 patients as IIIB (unilateral iliac and/or inguinal lymph node) and 2 patients as II. Response All patients completed programmed radiochemotherapy treatment. Six months after the end of treatment, all patients had digital examination, trans-rectal ultrasound and total body CT scan, as at baseline. One patient had just finished the concomitant therapy: therefore his clinical response was only evaluated by imaging, with clinically regressing tumour. In total 7 patients (87.5%) showed a tumour regression, both complete (6 patients) and partial (1 patient); whereas 1 patients was classified as persistent disease. Of these response, discordance in evaluation was noticed in 2 patients: positive clinical examination and negative imaging results were found in 2 patients. Abdominal-perineal resection was done and in the operative specimen a complete response was confirmed. Patient with persistent disease, confirmed by biopsies at 6 months after the end of treatment underwent salvage surgery, too. Toxicity Severe acute toxicity associated with therapy was not recorded. Mild (G1) to moderate (G2) gastrointestinal toxicity was recorded in all patients. All patients developed

1056

D. Musio et al. / EJSO 41 (2015) 1054e1058

Table 1 Patients demographics, stage and treatment. Patient

Age

Sex

cTNM

1 2 3 4 5 6 7 8

78 62 77 52 44 56 69 81

F F F M M M F M

T2 T3 T2 T3 T3 T4 T2 T4

N1 N1 N1 N0 N3 N1 N0 N1

M0 M0 M0 M0 M0 M0 M0 M0

Distance from anal verge (cm)

RT (Gy)

CHT

Response

OS

DFS

5 6 5 5 8 4 4 4

59.4 59.4 59.4 59.4 45 70.2 76.5 45

5-FUþMitC 5-FUþMitC 5-FUþMitC 5-FUþMitC 5-FUþMitC Raltitrexed þOXP Raltitrexed þOXP 5-FUþMitC

CR PD CR CR CR CR CR PR

48 6 15 8 164 72 20 1

48 e 15 8 164 72 6 1

a.v.: anal verge; RT: radiotherapy; CHT: chemotherapy; CR: complete response; PR: partial response; PD: persistent disease.

a perineal skin reaction G2. In addition, excluding 1 patient who reported a leukocytes suppression G3, there was no haematological toxicity. Survival Considering a mean follow-up of 41.75 months (range 1e164), 7 patients are still disease free survivors. Only 1 patient developed local recurrence at 6 months and he died 14 months after abdomino-perineal resection. Discussion This study analysed a small series of patients affected by squamous cell carcinoma of the rectum. Review of the literature revealed that this rare entity tends to occur more frequently in women in the sixth decade.1,2,29 In our series the mean age at diagnosis was 64.9 years, but there was no difference in incidence among men and women. Like adenocarcinoma, squamous cell carcinoma of the rectum is usually symptomatic before diagnosis. Common symptoms include rectal bleeding and change in bowel habits, such as constipation or diarrhoea. In our study, 87.5% of patients presented with bleeding and none had risk factors reported in literature, such as concomitant infection and ulcerative colitis.4,7e9,14 Concerning clinical stage and optimal treatment, it is difficult to compare the results from literature because were not used a standard staging system and a uniform management protocol. While some authors did not specify clinical stage21,27e29 and some authors chose to classify tumours according to the TNM classification for adenocarcinoma of the rectum,5,31 several recent analysis have used staging system for anal carcinoma.2,19 Due to the histological nature of the tumour, we considered more appropriate for the staging of these cancer using the TNM classification system for anal squamous cell carcinoma. Moreover we regarded high dose radiotherapy necessary to improve local control and to relegate surgery as a salvage therapy in this rare rectal histology. Six patients (75%) were treated with a total radiation dose of 59.4e76.5 Gy; two patients had received a total dose of 45 Gy. Only 1 patient had local recurrence and underwent salvage surgery. Other patients

are still disease free survivors. Despite the small number of patients, it seems that high dose radiation therapy and concomitant chemotherapy regime could guarantee a complete control of disease, without surgery management. Several small case series2,17e20,32 have evaluated the role of radiochemotherapy as an alternative to surgery or in conjunction with surgery. But a standard protocol has not yet established, because of the rarity of squamous cell carcinoma of the rectum (Table 2). Nahas et al.2 included in their study 12 patients: the majority of patients (9/12) were treated with 5-Fluorouracile and Mitomycin C based chemotherapy regimen given concurrently with external beam radiation for a total dose of 50.4 Gy at 1.8 Gy per day. Of these 9 patients, 2 had a complete clinical response and did not receive further treatment; 7 underwent surgery as a results of partial clinical response, but pathological complete response was observed in 6 of them. This suggests that a more prolonged assessment could be required for a better evaluation of tumour response, considering that in anal squamous cell carcinoma tumour response can continue 6 months after completion of radiochemotherapy. Clark et al.19 and Rasheed et al.20 presented seven and six patients, respectively, treated by primary radiochemotherapy. They have used the same chemotherapeutic regimen adopting for treatment of squamous carcinoma of the anal canal (Mitomycin C and 5-Fluoroiracil), and the radiotherapeutic total dose was similar to the total dose used for treatment of rectal adenocarcinoma (50.4 Gy). All patients showed a good radiological response and only 3 patients underwent surgical resections. These recent papers supported radiochemotherapy as primary treatment, but radiation dose was similar to those used in rectal adenocarcinoma. Yeh et al.32 treated 5 patients, with rectal squamous cell carcinoma, with primary chemoradiation: only one patient received a low dose of radiation (30 Gy), other patients were treated with a radiation dose of 54e60 Gy. Authors concluded that a minimum dose of 54 Gy is advisable for local control of the disease. Unlike previous reports, our series was the first study that reported a radiation therapy dose 59.4 Gy in 75% of patients: we recorded only 1 case of local recurrence, suggesting that high dose radiotherapy plus chemotherapy

D. Musio et al. / EJSO 41 (2015) 1054e1058

1057

Table 2 Treatment regimens employed and patient outcomes. Authors Nahas2 Clark19 Rasheed20 Yeh32 Present study

Patients

12 7 6 5 8

Chemotherapy Mit.C þ 5-FU

Other

6 3 2 4 6

3 4 4 1 2

patients patients patients patients patients

patients patients patients patient patients

RT (Gy)

Surgery

Recurrence

FU (mean)

50.4 50.4 47.7 (45e50.4) 51.6 (30e60) 59.3 (45e70.6)

7 1 4 2 2

e e 1 patient 1 patient 1 patient

30 months 18 months months 44 months 41.75 months

patients patient patients patients patients

RT: radiotherapy; FU: follow-up.

could be a standard treatment in rectal squamous cell carcinoma, based on the efficacy demonstrated in anal canal cancer. Conclusion Compared to adenocarcinoma of the rectum, squamous cell carcinoma of the rectum is a distinct entity and it requires a different therapeutic approach. Primary radio chemotherapy, with a curative intent, could be considered the treatment modality of choice for squamous carcinoma of the rectum. As for the anal carcinoma, surgery should have a limited place in the initial management of this disease. In the squamous cell carcinoma of the rectum, surgery has to be used only with salvage intent. High dose radiation therapy and concomitant chemotherapy regime could guarantee a complete control of disease. Conflict of interest Authors declare that there is no conflict of interest regarding the publication of this article.

References 1. Dyson T, Draganov PV. Squamous cell cancer of the rectum. World J Gastroenterol 2009;15(35):4380–6. 2. Nahas CS, Shia J, Joseph R, Schrag D et al. Squamous-cell carcinoma of the rectum: a rare but curable tumor. Dis Colon Rectum; 50(9): 1393e1400. 3. Balfour TW. Does squamous carcinoma of the colon exist? Br J Surg 1972;59(5):410–2. 4. Wiener MF, Polayes SH, Yidi R. Squamous carcinoma with schistosomiasis of the colon. Am J Gastroenterol 1962;37:48–54. 5. Audeau A, Han HW, Johnston MJ, Whitehead MW, Frizelle FA. Does human papilloma virus have a role in squamous cell carcinoma of the colon and upper rectum? Eur J Surg Oncol 2002;28(6):657–60. 6. Yurdakul G, de Reijke TM, Blank LE, Rauws EA. Rectal squamous cell carcinoma 11 years after brachytherapy for carcinoma of the prostate. J Urol 2003;169(1):280. 7. Fu K, Tsujinaka Y, Hamahata Y, Matsuo K, Tsutsumi O. Squamous metaplasia of the rectum associated with ulcerative colitis diagnosed using narrow-band imaging. Endoscopy 2008;40(Suppl. 2):E45–6. Epub 2008 Feb 26. 8. Bargen JA, Gage RP. Carcinoma and ulcerative colitis: prognosis. Gastroenterology 1960;39:385–93.

9. Zirki RM, Mccord DL. Squamous cell carcinoma of the rectum: report of a case complicating chronic ulcerative colitis. Dis Colon Rectum 1963;6:370–3. 10. Ouban A, Nawab RA, Coppola D. Diagnostic and pathogenetic implications of colorectal carcinomas with multidirectional differentiation: a report of 4 cases. Clin Colorectal Cancer 2002;1(4):243–8. 11. Hicks JD, Cowling DC. Squamous-cell carcinoma of the ascending colon. J Pathol Bacteriol 1955;70(1):205–12. 12. Michelassi F, Mishlove LA, Stipa F, Block GE. Squamous-cell carcinoma of the colon. Experience at the University of Chicago, review of the literature, report of two cases. Dis Colon Rectum 1988;31(3):228– 35. 13. Jaworski RC, Biankin SA, Baird PJ. Squamous cell carcinoma in situ arising in inflammatory cloacogenic polyps: report of two cases with PCR analysis for HPV DNA. Pathology 2001;33(3):312–4. 14. Williams GT, Blackshaw AJ, Morson BC. Squamous carcinoma of the colorectum and its genesis. J Pathol 1979;129(3):139–47. 15. Raiford TS. Epitheliomata of the lower rectum and anus. Surg Gynecol Obstet 1933;57:21–35. 16. Iannacone E, Dionisi F, Musio D, Caiazzo R, Raffetto N, Banelli E. Chemoradiation as definitive treatment for primary squamous cell cancer of the rectum. World J Radiol 2010;2(8):329–33. 17. Frizelle FA, Hobday KS, Batts KP, Nelson H. Adenosquamous and squamous carcinoma of the colon and upper rectum: a clinical and histopathologic study. Dis Colon Rectum 2001;44(3):341–6. 18. Gelas T, Peyrat P, Francois Y, et al. Primary squamous-cell carcinoma of the rectum: report of six cases and review of the literature. Dis Colon Rectum 2002;45(11):1535–40. 19. Clark J, Cleator S, Goldin R, Lowdell C, Darzi A, Ziprin P. Treatment of primary rectal squamous cell carcinoma by primary chemoradiotherapy: should surgery still be considered a standard of care? Eur J Cancer 2008;44(16):2340–3. 20. Rasheed S, Yap T, Zia A, McDonald PJ, Glynne-Jones R. Chemoradiotherapy: an alternative to surgery for squamous cell carcinoma of the rectum–report of six patients and literature review. Colorectal Dis 2009;11(2):191–7. 21. Lafreniere R, Ketcham AS. Primary squamous carcinoma of the rectum. Report of a case and review of the literature. Dis Colon Rectum 1985;28(12):967–72. 22. Pigott JP, Williams GB. Primary squamous cell carcinoma of the colorectum: case report and literature review of a rare entity. J Surg Oncol 1987;35(2):117–9. 23. Woods WG. Squamous cell carcinoma of the rectum arising in an area of squamous metaplasia. Eur J Surg Oncol 1987;13(5):455–8. 24. Prener A, Nielsen K. Primary squamous cell carcinoma of the rectum in Denmark. APMIS 1988;96(9):839–44. 25. Martinez-Gonzalez MD, Takahashi T, Leon-Rodriguez E, et al. Case report of primary squamous carcinoma of the rectum. Rev Invest Clin 1996;48(6):453–6. 26. Anagnostopoulos G, Sakorafas GH, Kostopoulos P, et al. Squamous cell carcinoma of the rectum: a case report and review of the literature. Eur J Cancer Care (Engl) 2005;14(1):70–4.

1058

D. Musio et al. / EJSO 41 (2015) 1054e1058

27. Pikarsky AJ, Belin B, Efron J, et al. Squamous cell carcinoma of the rectum in ulcerative colitis: case report and review of the literature. Int J Colorectal Dis 2007;22(4):445–7. 28. Sameer AS, Syeed N, Chowdri NA, Parray FQ, Siddiqi MA. Squamous cell carcinoma of rectum presenting in a man: a case report. J Med Case Rep 2010;4:392. 29. Al Hallak MN, Hage-Nassar G, Mouchli A. Primary submucosal squamous cell carcinoma of the rectum diagnosed by endoscopic ultrasound: case report and literature review. Case Rep Gastroenterol 2010;4(2):243–9.

30. Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events, Version 3.0 2006. http://ctep.cancer.gov. publish date: August 9, 2006. 31. Tronconi MC, Carnaghi C, Bignardi M, et al. Rectal squamous cell carcinoma treated with chemoradiotherapy: report of six cases. Int J Colorectal Dis 2010;25(12):1435–9. 32. Yeh J, Hastings J, Rao A, Abbas MA. Squamous cell carcinoma of the rectum: a single institution experience. Tech Coloproctol 2012 Oct; 16(5):349–54. Epub 2012 Jun 19.