Int Surg 2014;99:669–672 DOI: 10.9738/INTSURG-D-13-00073.1
Case Report
Primary Enteric-Type Mucinous Adenocarcinoma of the Urethra in a Patient With Ulcerative Colitis Dimitrios Dimitroulis, Dimitrios Patsouras, Athanasios Katsargyris, Petros Charalampoudis, Ioannis Anastasiou, Gregory Kouraklis 2nd Propedeutic Department of Surgery, Athens University Medical School, Laikon Hospital Athens, Greece
Primary carcinoma of the male urethra accounts for less than 1% of malignancies in men. Mucinous adenocarcinoma of the urethra is extremely rare, and its biologic behavior is poorly understood. We present herein a rare case of mucinous urethral adenocarcinoma in a male patient with longstanding ulcerative colitis and multiple sclerosis. The patient presented with a voluminous pelvic mass; core biopsy of the lesion demonstrated a mucus-producing adenocarcinoma. Given the patient’s history of subtotal colectomy, preoperative diagnosis was oriented towards a rectal stump adenocarcinoma. The patient underwent a pelvic exenteration: surprisingly, histology marked the prostatic urethra as the primary lesion site. Key words: Urethra – Adenocarcinoma – Mucinous – Ulcerative colitis
P
rimary enteric-type mucinous adenocarcinoma of the urethra is an extremely rare entity with aggressive clinical course regardless of treatment. Interestingly, it has been implied that inflammatory bowel disease and multiple sclerosis share common mechanisms of impaired histocompatibility. Moreover, patients with inflammatory bower disease who receive prolonged immunosuppression such as azathioprine tend to increasingly develop urinary tract malignancies. We report herein a complex case of enteric-type mucinous adenocarcinoma of ure-
thral origin in a male with a longstanding history of ulcerative colitis and multiple sclerosis.
Case Report A 39-year-old male patient with a history of longstanding severe ulcerative colitis (UC) presented with lower urinary tract obstructive symptoms of acute onset and lower abdominal pain. Renal function was also impaired (creatinine, 2.8 mg/dL, range 0.61.2 mg/dL). The patient had a long
Reprint requests: Petros Charalampoudis, MD, 2nd Propedeutic Department of Surgery, Athens University Medical School, Laikon Hospital Athens, Greece. Tel.: þ302107456371; Fax: þ302107456972; E-mail: [email protected] Int Surg 2014;99
669
DIMITROULIS
Fig. 1 T2-weighted MRI caption of the lesion-saggital view.
history of severe UC. At 11 years he had undergone a subtotal colectomy with end ileostomy for toxic megacolon. Due to clinical deterioration, he had subsequently undergone a proctectomy with a retained rectal stump of 3 cm in order to allow potential ileoanal pouch formation in the future. However, an ileoanal pouch was never tailored. At the age of 24 years he was diagnosed with multiple sclerosis. During the last decade the patient experienced recurrent perianal fistulas and abscesses that were attributed to his colitis and were treated with placement of setons and fistulotomies. Two years ago he had a proctoscopy and random biopsies were taken that showed severe active UC but no evidence of malignancy. Routine medication included interferon beta and azathioprine. Upon admission to our department, abdominal ultrasound demonstrated a major bilateral ureteral dilation implying obstruction due to the pelvic lesion. After a failed attempt to implant a pigtail through the bladder, bilateral percutaneous nephrostomies were placed and renal function improved. A contrast-enhanced CT of the abdomen and pelvis revealed a large lower abdominal-pelvic mass causing obstruction of the lower portion of both ureters. Further investigation with an abdominalpelvic magnetic resonance imaging demonstrated a 670
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
Fig. 2 T1-weighted MRI caption of the lesion-saggital view.
large, cystic-type space-occupying lesion noted within the pelvis (Figures 1, 2, and 3). The lesion exhibited a high T2 signal and contained internal solid elements and septae in an inhomogeneous fashion. It appeared lobulated in contour and extended from the level of fifth lumbar vertebral body down to the perineum. The mass projected from the anterior pelvic wall, in contact with the medial aspect of the muscular wall and the symphysis pubis, towards the anterior surface of the sacrum. The craniocaudal diameter of the lesion measured 27 cm long while the transverse diameters were 14 and 16 cm, respectively. The lesion displaced the bladder anteriorly and invaded it through its posterior wall. It was in contact with the common iliac vessels bilaterally and the right external iliac vessels. The mass was slightly projecting through the sciatic foramen and was fistulating to the skin inferiorly. Differential diagnosis included mucinous adenocarcinoma and sarcoma. The patient underwent a preoperative needle core biopsy of the tumor, which revealed a mucinous adenocarcinoma. The most probable diagnosis being that of rectal stump adenocarcinoma, we proceeded with surgery. A pelvic exenteration was performed and the tumor was successfully removed along with the lower third of ureters, the urinary bladder and prostate gland. Int Surg 2014;99
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
Fig. 3 T1-weighted MRI caption of the lesion-axial view.
Postoperative course was uneventful apart from a left ureter stump leak that was treated percutaneously with glue. The patient was discharged on the 20th postoperative day. Surprisingly, histology demonstrated an enteric type adenocarcinoma of the urethra of low differentiation. Based on the histopathology report, consulting urologists advocated penile resection and chemotherapy; however, the patient denied any further treatment and died 20 months later due to extensive local recurrence.
Discussion Urethral cancer represents a rare malignancy with an annual incidence of 4.3 per 1 million male patients and 1.5 per 1 million female patients in the United States.1 The majority of cases correspond to squamous cell carcinomas; however, there are several reports in the literature concerning transitional cell carcinomas and urethral adenocarcinomas of debated origin.2,3 Since data on urethral cancer are quite scarce, there is no management consensus on the treatment of these tumors. Surgical resection, radiotherapy, chemotherapy or combinations thereof have been advocated.4 Primary enterictype mucinous adenocarcinoma of the urethra is extremely rare and data from the pertinent literature Int Surg 2014;99
DIMITROULIS
are scarce with only 20 cases reported in men to date. Patients with urethral enteric-type adenocarcinomas tend to present in the sixth decade of life or later (age range, 5593 years). The majority of patients present with urinary obstruction; hematuria and mucosuria have also been described as other symptoms. Such lesions have a rather aggressive clinical course, regardless of treatment. Metastatic colonic adenocarcinoma is the main differential diagnosis, given the morphologic and immunohistochemical overlapping between these two entities.5 It is widely accepted that immunosuppression is a risk factor for the development of tumors and there is a substantial body of evidence that thiopurines specifically contribute to carcinogenesis. Azathioprine (AZA) is classified as a carcinogen by the International Agency for Research on Cancer (IARC).6 It has been shown that patients with inflammatory bowel disease (IBD) who receive long-term immunosuppressive therapy with azathioprine or 6-mercaptopurine may experience a fourfold increase in risk of lymphoma relative to the general population.7 This appears to be supported by findings from previous studies in patients who underwent prolonged immunosuppressive therapy due to organ transplantation or steroidresistant rheumatoid arthritis.811 Azathioprine has also been recently linked to increased occurrence of urinary tract cancers in patients with inflammatory bowel disease, although direct causality is yet unclear.12 Pasternak et al looked at 115 patients with IBD who developed urinary tract cancers. Seven out of 115 patients had received AZA while 108 had not. The majority of urinary malignancies represented bladder and renal cancers. Only one urethral cancer was observed in the non-AZA subgroup, while it was absent in the AZA group. To our best of our knowledge, urethral cancer and IBD association remains unclear and is yet to be explored.12 Moreover, several investigators have addressed the link between inflammatory bowel disease and multiple sclerosis.1315 In a cohort study by Gupta et al, the incidence of multiple sclerosis, demyelination disorders other than multiple sclerosis and optical neuritis was higher in patients with Crohn’s disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis.16 It has been suggested that harboring of multiple alleles in the major histocompatibility complex (MHC) could represent a common causality mechanism for development of both inflammatory bowel disease, most notably ulcerative colitis as well as multiple sclerosis.17 671
DIMITROULIS
In the present case one could expect the development of a rectal cancer according to the patient’s history. However, histopathology examination, though, revealed urethral adenocarcinoma, implying that immunosuppressed patients are prone to develop rare types of malignancies in unexpected sites. To the best of our knowledge, this is the first report of primary mucinous urethral adenocarcinoma in a patient with ulcerative colitis and multiple sclerosis.
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
8. Sheil AG, Disney AP, Mathew TH, Livingston BE, Keogh AM. Lymphoma incidence, cyclosporine, and the evolution and major impact of malignancy following organ transplantation. Transpl P 1997;29(1–2):825–827 [PMID: 9123543] 9. Kishikawa H, Ichikawa Y, Yazawa K, Hanafusa T, Fukunishi T, Ebisui C, et al. Malignant neoplasm in kidney transplantation. Int J Urol 1998;5(6):521–525 [PMID: 9855118] 10. Gaya SB, Rees AJ, Lechler RI, Williams G, Mason PD. Malignant disease in patients with long-term renal transplants. Transplantation 1995;59(12):1705–1709 [PMID: 7604441] 11. Asten P, Barrett J, Symmons D. Risk of developing certain
References
malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol
1. Swartz MA, Porter MP, Lin DW, Weiss NS. Incidence of primary urethral carcinoma in the United States. Urology 2006; 68(6):1164–1168 [PMID: 17141838] 2. Chan YM, Ka-Leung Cheng D, Nga-Yin Cheung A, YuenSheung Ngan H, Wong LC. Female urethral adenocarcinoma arising from urethritis glandularis. Gynecol Oncol 2000;79(3): 511–514 [PMID: 11104631] 3. Taylor RN, Lacey CG, Shuman MA. Adenocarcinoma of Skene’s duct associated with a systemic coagulopathy. Gynecol Oncol 1985;22(2):250–256 [PMID: 4054720] 4. Reis LO, Ferreira F, Almeida M, Ferreira U. Urethral carcinoma: critical view on contemporary consecutive series. Med Oncol 2011;28(4):1405–1410 [PMID: 20596803]
1999;26(8):1705–1714 [PMID: 10451066] 12. Pasternak B, Svanstrom H, Schmiegelow K, Jess T, Hviid A. Use of azathioprine and the risk of cancer in inflammatory bowel disease. Am J Epidemiol 2013;177(11):1296–1305 [PMID: 23514635] 13. Rang EH, Brooke BN, Hermon-Taylor J. Association of ulcerative colitis with multiple sclerosis. Lancet 1982;2(8297): 555 [PMID: 6125706] 14. Mayr WT, Pittock SJ, McClelland RL, Jorgensen NW, Noseworthy JH, Rodriguez M. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 19852000. Neurology 2003;61(10):1373–1377 [PMID: 14638958] 15. Edwards LJ, Constantinescu CS. A prospective study of
5. Osunkoya AO, Netto GJ, Epstein JI. Colorectal adenocarcino-
conditions associated with multiple sclerosis in a cohort of
ma involving the prostate: report of 9 cases. Hum Pathol 2007;
658 consecutive outpatients attending a multiple sclerosis
38(12):1836–1841 [PMID: 17868775] 6. Hyams JS, Markowitz JF. Can we alter the natural history of Crohn disease in children? J Pediatr Gastroenterol Nutr 2005; 40(3):262–272 [PMID: 15735477]
clinic. Mult Scler 2004;10(5):575–581 [PMID: 15471376] 16. Gupta G, Gelfand JM, Lewis JD. Increased risk for demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129(3):819–826 [PMID: 16143121]
7. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD.
17. Alkhawajah MM, Caminero AB, Freeman HJ, Oger JJ.
Increased risk of lymphoma among inflammatory bowel
Multiple sclerosis and inflammatory bowel diseases: what
disease patients treated with azathioprine and 6-mercaptopu-
we know and what we would need to know! Mult Scler 2013;
rine. Gut 2005;54(8):1121–1125 [PMID: 16009685]
19(3):259–265 [PMID: 23027881]
672
Int Surg 2014;99
Case Report
Primary Enteric-Type Mucinous Adenocarcinoma of the Urethra in a Patient With Ulcerative Colitis Dimitrios Dimitroulis, Dimitrios Patsouras, Athanasios Katsargyris, Petros Charalampoudis, Ioannis Anastasiou, Gregory Kouraklis 2nd Propedeutic Department of Surgery, Athens University Medical School, Laikon Hospital Athens, Greece
Primary carcinoma of the male urethra accounts for less than 1% of malignancies in men. Mucinous adenocarcinoma of the urethra is extremely rare, and its biologic behavior is poorly understood. We present herein a rare case of mucinous urethral adenocarcinoma in a male patient with longstanding ulcerative colitis and multiple sclerosis. The patient presented with a voluminous pelvic mass; core biopsy of the lesion demonstrated a mucus-producing adenocarcinoma. Given the patient’s history of subtotal colectomy, preoperative diagnosis was oriented towards a rectal stump adenocarcinoma. The patient underwent a pelvic exenteration: surprisingly, histology marked the prostatic urethra as the primary lesion site. Key words: Urethra – Adenocarcinoma – Mucinous – Ulcerative colitis
P
rimary enteric-type mucinous adenocarcinoma of the urethra is an extremely rare entity with aggressive clinical course regardless of treatment. Interestingly, it has been implied that inflammatory bowel disease and multiple sclerosis share common mechanisms of impaired histocompatibility. Moreover, patients with inflammatory bower disease who receive prolonged immunosuppression such as azathioprine tend to increasingly develop urinary tract malignancies. We report herein a complex case of enteric-type mucinous adenocarcinoma of ure-
thral origin in a male with a longstanding history of ulcerative colitis and multiple sclerosis.
Case Report A 39-year-old male patient with a history of longstanding severe ulcerative colitis (UC) presented with lower urinary tract obstructive symptoms of acute onset and lower abdominal pain. Renal function was also impaired (creatinine, 2.8 mg/dL, range 0.61.2 mg/dL). The patient had a long
Reprint requests: Petros Charalampoudis, MD, 2nd Propedeutic Department of Surgery, Athens University Medical School, Laikon Hospital Athens, Greece. Tel.: þ302107456371; Fax: þ302107456972; E-mail: [email protected] Int Surg 2014;99
669
DIMITROULIS
Fig. 1 T2-weighted MRI caption of the lesion-saggital view.
history of severe UC. At 11 years he had undergone a subtotal colectomy with end ileostomy for toxic megacolon. Due to clinical deterioration, he had subsequently undergone a proctectomy with a retained rectal stump of 3 cm in order to allow potential ileoanal pouch formation in the future. However, an ileoanal pouch was never tailored. At the age of 24 years he was diagnosed with multiple sclerosis. During the last decade the patient experienced recurrent perianal fistulas and abscesses that were attributed to his colitis and were treated with placement of setons and fistulotomies. Two years ago he had a proctoscopy and random biopsies were taken that showed severe active UC but no evidence of malignancy. Routine medication included interferon beta and azathioprine. Upon admission to our department, abdominal ultrasound demonstrated a major bilateral ureteral dilation implying obstruction due to the pelvic lesion. After a failed attempt to implant a pigtail through the bladder, bilateral percutaneous nephrostomies were placed and renal function improved. A contrast-enhanced CT of the abdomen and pelvis revealed a large lower abdominal-pelvic mass causing obstruction of the lower portion of both ureters. Further investigation with an abdominalpelvic magnetic resonance imaging demonstrated a 670
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
Fig. 2 T1-weighted MRI caption of the lesion-saggital view.
large, cystic-type space-occupying lesion noted within the pelvis (Figures 1, 2, and 3). The lesion exhibited a high T2 signal and contained internal solid elements and septae in an inhomogeneous fashion. It appeared lobulated in contour and extended from the level of fifth lumbar vertebral body down to the perineum. The mass projected from the anterior pelvic wall, in contact with the medial aspect of the muscular wall and the symphysis pubis, towards the anterior surface of the sacrum. The craniocaudal diameter of the lesion measured 27 cm long while the transverse diameters were 14 and 16 cm, respectively. The lesion displaced the bladder anteriorly and invaded it through its posterior wall. It was in contact with the common iliac vessels bilaterally and the right external iliac vessels. The mass was slightly projecting through the sciatic foramen and was fistulating to the skin inferiorly. Differential diagnosis included mucinous adenocarcinoma and sarcoma. The patient underwent a preoperative needle core biopsy of the tumor, which revealed a mucinous adenocarcinoma. The most probable diagnosis being that of rectal stump adenocarcinoma, we proceeded with surgery. A pelvic exenteration was performed and the tumor was successfully removed along with the lower third of ureters, the urinary bladder and prostate gland. Int Surg 2014;99
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
Fig. 3 T1-weighted MRI caption of the lesion-axial view.
Postoperative course was uneventful apart from a left ureter stump leak that was treated percutaneously with glue. The patient was discharged on the 20th postoperative day. Surprisingly, histology demonstrated an enteric type adenocarcinoma of the urethra of low differentiation. Based on the histopathology report, consulting urologists advocated penile resection and chemotherapy; however, the patient denied any further treatment and died 20 months later due to extensive local recurrence.
Discussion Urethral cancer represents a rare malignancy with an annual incidence of 4.3 per 1 million male patients and 1.5 per 1 million female patients in the United States.1 The majority of cases correspond to squamous cell carcinomas; however, there are several reports in the literature concerning transitional cell carcinomas and urethral adenocarcinomas of debated origin.2,3 Since data on urethral cancer are quite scarce, there is no management consensus on the treatment of these tumors. Surgical resection, radiotherapy, chemotherapy or combinations thereof have been advocated.4 Primary enterictype mucinous adenocarcinoma of the urethra is extremely rare and data from the pertinent literature Int Surg 2014;99
DIMITROULIS
are scarce with only 20 cases reported in men to date. Patients with urethral enteric-type adenocarcinomas tend to present in the sixth decade of life or later (age range, 5593 years). The majority of patients present with urinary obstruction; hematuria and mucosuria have also been described as other symptoms. Such lesions have a rather aggressive clinical course, regardless of treatment. Metastatic colonic adenocarcinoma is the main differential diagnosis, given the morphologic and immunohistochemical overlapping between these two entities.5 It is widely accepted that immunosuppression is a risk factor for the development of tumors and there is a substantial body of evidence that thiopurines specifically contribute to carcinogenesis. Azathioprine (AZA) is classified as a carcinogen by the International Agency for Research on Cancer (IARC).6 It has been shown that patients with inflammatory bowel disease (IBD) who receive long-term immunosuppressive therapy with azathioprine or 6-mercaptopurine may experience a fourfold increase in risk of lymphoma relative to the general population.7 This appears to be supported by findings from previous studies in patients who underwent prolonged immunosuppressive therapy due to organ transplantation or steroidresistant rheumatoid arthritis.811 Azathioprine has also been recently linked to increased occurrence of urinary tract cancers in patients with inflammatory bowel disease, although direct causality is yet unclear.12 Pasternak et al looked at 115 patients with IBD who developed urinary tract cancers. Seven out of 115 patients had received AZA while 108 had not. The majority of urinary malignancies represented bladder and renal cancers. Only one urethral cancer was observed in the non-AZA subgroup, while it was absent in the AZA group. To our best of our knowledge, urethral cancer and IBD association remains unclear and is yet to be explored.12 Moreover, several investigators have addressed the link between inflammatory bowel disease and multiple sclerosis.1315 In a cohort study by Gupta et al, the incidence of multiple sclerosis, demyelination disorders other than multiple sclerosis and optical neuritis was higher in patients with Crohn’s disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis.16 It has been suggested that harboring of multiple alleles in the major histocompatibility complex (MHC) could represent a common causality mechanism for development of both inflammatory bowel disease, most notably ulcerative colitis as well as multiple sclerosis.17 671
DIMITROULIS
In the present case one could expect the development of a rectal cancer according to the patient’s history. However, histopathology examination, though, revealed urethral adenocarcinoma, implying that immunosuppressed patients are prone to develop rare types of malignancies in unexpected sites. To the best of our knowledge, this is the first report of primary mucinous urethral adenocarcinoma in a patient with ulcerative colitis and multiple sclerosis.
MUCINOUS ADENOCARCINOMA OF THE MALE URETHRA
8. Sheil AG, Disney AP, Mathew TH, Livingston BE, Keogh AM. Lymphoma incidence, cyclosporine, and the evolution and major impact of malignancy following organ transplantation. Transpl P 1997;29(1–2):825–827 [PMID: 9123543] 9. Kishikawa H, Ichikawa Y, Yazawa K, Hanafusa T, Fukunishi T, Ebisui C, et al. Malignant neoplasm in kidney transplantation. Int J Urol 1998;5(6):521–525 [PMID: 9855118] 10. Gaya SB, Rees AJ, Lechler RI, Williams G, Mason PD. Malignant disease in patients with long-term renal transplants. Transplantation 1995;59(12):1705–1709 [PMID: 7604441] 11. Asten P, Barrett J, Symmons D. Risk of developing certain
References
malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol
1. Swartz MA, Porter MP, Lin DW, Weiss NS. Incidence of primary urethral carcinoma in the United States. Urology 2006; 68(6):1164–1168 [PMID: 17141838] 2. Chan YM, Ka-Leung Cheng D, Nga-Yin Cheung A, YuenSheung Ngan H, Wong LC. Female urethral adenocarcinoma arising from urethritis glandularis. Gynecol Oncol 2000;79(3): 511–514 [PMID: 11104631] 3. Taylor RN, Lacey CG, Shuman MA. Adenocarcinoma of Skene’s duct associated with a systemic coagulopathy. Gynecol Oncol 1985;22(2):250–256 [PMID: 4054720] 4. Reis LO, Ferreira F, Almeida M, Ferreira U. Urethral carcinoma: critical view on contemporary consecutive series. Med Oncol 2011;28(4):1405–1410 [PMID: 20596803]
1999;26(8):1705–1714 [PMID: 10451066] 12. Pasternak B, Svanstrom H, Schmiegelow K, Jess T, Hviid A. Use of azathioprine and the risk of cancer in inflammatory bowel disease. Am J Epidemiol 2013;177(11):1296–1305 [PMID: 23514635] 13. Rang EH, Brooke BN, Hermon-Taylor J. Association of ulcerative colitis with multiple sclerosis. Lancet 1982;2(8297): 555 [PMID: 6125706] 14. Mayr WT, Pittock SJ, McClelland RL, Jorgensen NW, Noseworthy JH, Rodriguez M. Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 19852000. Neurology 2003;61(10):1373–1377 [PMID: 14638958] 15. Edwards LJ, Constantinescu CS. A prospective study of
5. Osunkoya AO, Netto GJ, Epstein JI. Colorectal adenocarcino-
conditions associated with multiple sclerosis in a cohort of
ma involving the prostate: report of 9 cases. Hum Pathol 2007;
658 consecutive outpatients attending a multiple sclerosis
38(12):1836–1841 [PMID: 17868775] 6. Hyams JS, Markowitz JF. Can we alter the natural history of Crohn disease in children? J Pediatr Gastroenterol Nutr 2005; 40(3):262–272 [PMID: 15735477]
clinic. Mult Scler 2004;10(5):575–581 [PMID: 15471376] 16. Gupta G, Gelfand JM, Lewis JD. Increased risk for demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129(3):819–826 [PMID: 16143121]
7. Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD.
17. Alkhawajah MM, Caminero AB, Freeman HJ, Oger JJ.
Increased risk of lymphoma among inflammatory bowel
Multiple sclerosis and inflammatory bowel diseases: what
disease patients treated with azathioprine and 6-mercaptopu-
we know and what we would need to know! Mult Scler 2013;
rine. Gut 2005;54(8):1121–1125 [PMID: 16009685]
19(3):259–265 [PMID: 23027881]
672
Int Surg 2014;99
