Koichi Kodama md, Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. Email: Kokodama@aol.com
Abstract A 47-year-old man underwent a low anterior resection of the rectosigmoid colon with en bloc cystoprostatectomy for vesicorectal fistula due to a locally advanced rectal cancer. Histopathological examination of the bladder revealed two additional primary malignancies: urothelial carcinoma and squamous cell carcinoma. To our knowledge, this is the first reported case of two histologically distinct urothelial malignancies that were diagnosed during a work up of vesicorectal fistula due to adenocarcinoma of the rectum.
Vesicoenteric fistulas represent a relatively rare occurrence and may be generally associated with inflammatory bowel disease such as Crohn disease or diverticulitis.1 Less frequently they may be observed as a complication of bladder or colorectal cancers. It is extremely uncommon to find bladder cancer occurring synchronously in patients with vesicoenteric fistula. We report a unique case of synchronous occurrence of two distinct urothelial malignancies incidentally found in the bladder of a patient undergoing treatment for a primary adenocarcinoma of the rectum.
A 47-year-old Japanese businessman presented with a complaint of a 3-month history of watery diarrhea, 10-kg weight loss, dysuria, and a 1-week history of pneumaturia and fecaluria. Past medical history was not significant for malignancy, previous surgery, radiation exposure, or a history of tobacco use. He denied any family history of cancer. Rectal examination revealed an irregular mass nearly occluding the rectal vault. Cystourethroscopy demonstrated extensively edematous mucosa overlying the trigone while the urethra appeared completely normal. Sigmoidoscopy confirmed narrowing of the rectal lumen 5 cm above the anal verge and a biopsy showed well-differentiated adenocarcinoma of the rectum. Computed tomography documented the absence of lymphadenopathy or metastatic disease while magnetic resonance imaging of the pelvis documented the presence of intravesical air, in addition to a large heterogeneous mass between the bladder and rectum (Fig. 1). On the basis of a diagnosis of vesicorectal fistula caused by rectal cancer, the patient underwent a low anterior resection of the rectosigmoid colon with en bloc cystoprostatectomy and a retroperitoneal lymph node dissection. Subsequently, colorectal anastomosis and ileal neobladder construction were performed which avoided the need for cutaneous diversion of stool and urine.
Histopathological examination confirmed extensive local extension of the rectal adenocarcinoma (Fig. 2a) with invasion of the detrusor base, with no involvement of the bladder epithelium: rectum above the peritoneal reflection and rectosigmoid, 13.5 cm × 7.0 cm, circle, type 3 advanced, well differentiated, direct invasion to other organs, slight invasion to lymphatic vessels in the rectal wall, no invasion to veins in the rectal wall, no invasion to lymphnocles. In addition to a diffuse granulomatous reaction with foreign body giant cells along the fistula tract, the histopathologic examination revealed two distinct malignancies originating from the bladder epithelium: urothelial carcinoma (UC), G1, papillary, pTa (Fig. 2b) and squamous cell carcinoma (SCC), G2, pT1 (Fig. 2c). The lymph nodes were free of tumor. Extensive evaluation has not revealed any other foci of local, regional or distant disease. The patient is currently undergoing chemotherapy with 5-fluorouracil, leucovorin and oral uracil/tegafur. Twenty-two months after surgery the patient remains without evidence of local recurrence or metastatic disease.
The existence of multiple primary malignant neoplasms occurs more frequently than just a result of a random chance. Ward-McQuaid found a total of 340 malignant non-urothelial tumors (5.4%) among 6263 patients with bladder tumors.2 Of these, 12.3% were of colorectal origin. Nonetheless, concomitant transitional cell carcinoma of the bladder occurring synchronously with a locally advanced colorectal malignancy causing a vesicoenteric fistula is extremely rare. Only two previous cases have been reported in the literature.3,4 To our knowlegde, this is the first reported case of concomitant occurrence of three distinct pelvic malignancies.
Urinary carcinoma of the bladder cancer patients may exhibit various degrees of SCC features. An important corollary of this interpretation is that bladder neoplasms may represent a continuous spectrum of lesions ranging from pure UC to pure SCC, with most of the specimens containing both tumor types. In our case, the two tumors were located distinctly, and had different histological feature one another, and we diagnosed the coexistence of UC and SCC in the same bladder.
There have been several theories regarding the cause of multiple primary malignant neoplasms. These include genetic, hormonal, iatrogenic, environmental, and immunologic factors.
Non-physiologic contact of urine and feces clearly predisposed the bowel mucosa to neoplastic change as demonstrated by the increased risk of adenocarcinoma in patients who have previously undergone a ureterosigmoidostomy.5 Typically, anastomotic malignancy originates from the bowel segment epithelium, but rarely is the neoplastic change of transitional cell origin.6 The exact mechanism of carcinogenesis is unknown, but a number of theories have been proposed including chronic inflammation, chronic infection, production of N-nitroso compounds by bacteria, change in mucosal electrolyte composition and/or pH.7 However, in our patient, symptoms of a vesicoenteric fistula existed for only 3 months, and therefore it is highly unlikely that a causal relationship can be theorized between the vesicoenteric fistula and the documented two distinct urothelial malignancies. Therefore, this is a unique case of synchronous occurrence of two distinct urothelial malignancies incidentally found in the bladder of a patient undergoing treatment for a primary adenocarcinoma of the rectum.
Recent advances have contributed to the understanding of the features of the tumorigenetic process of various cancers. Colorectal cancer is a common disease that can be sporadic, familial or inherited. Our case with no familial and inherited predisposition may fall into the sporadic category. A molecular basis for sporadic colorectal cancer as a multistep model of carcinogenesis is well known. Colorectal cancer results from the mutational activation of oncogenes (e.g. ras, c-myc, c-erbB2) and the inactivation of tumor suppressor genes (e.g. p53, DDC, APC).8 Somatic mutations in at least four or five genes of a cell are required for malignant transformation.
Whether it may be possible to adjust pathways by which the normal urothelium undergoes malignant transformation to produce a specific cell type of urothelial cancer remains to be investigated. Several genetic and molecular features of uroepithelial cancers are associated with tumorigenesis.9 It has been reported that urothelial cells can undergo at least three pathways of differentiation, that correlate with the three major types of urothelial neoplasm, UC, SCC, and adenocarcinoma.10 There is the interesting possibility that one may be able to cause interconversion between other types of bladder neoplasm, such as conversion from SCC to UC, which is more amenable to currently available radiotherapies and chemotherapies, can have major biological implications as well as clinical ramifications. Understanding the pathways can ultimately reveal the similarities and differences between tumor evolutions and possibly explain this patient's propensity for neoplastic progression.
We thank Dr Dimitri Kuznetsov for editorial assistance in preparing this manuscript.