Case Report
A Case of Advanced Mucinous Adenocarcinoma of Bladder in an Adult Patient Treated With Capecitabine-Based Chemotherapy and Review of Literature Carlo Messina,1 Chiara Dellepiane,1 Cinzia Caroti,1 Francesca Sarocchi,2 Gian Luigi Ravetti,2 Francesco Boccardo,1,3 Bruno Spina2 Clinical Practice Points Primary bladder adenocarcinoma is an extremely rare
tumor, representing the second most common nonurothelial bladder cancer, comprising 0.5% to 2% of all malignant primary tumors. The morphology is similar to that of colorectal adenocarcinoma, and sometimes it causes a diagnostic challenge for the pathologist. We describe the case of a patient who underwent radical cystectomy and urinary diversion with orthotopic neobladder because of locally advanced
mucinous primary adenocarcinoma. Capecitabinebased chemotherapy was administered to the patient after systemic metastatic spread of the disease. Currently, no role for chemotherapy or radiotherapy has been defined given the absence of data from clinical randomized trial supporting their use; therefore, we aim to provide a comprehensive review of literature on primary bladder adenocarcinoma, focusing on the pathologic diagnosis and therapeutic management of this rare neoplasm.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Capecitabine-based chemotherapy, Mucinous bladder adenocarcinoma, Nonurothelial bladder cancer
Introduction Bladder cancer is the most common tumor of the urinary system and the ninth most common malignancy worldwide. It is estimated that there are 386,000 new cases resulting in 150,000 deaths worldwide.1 Bladder cancers are categorized as urothelial and nonurothelial histologic types. Urothelial carcinoma (transitional-cell carcinoma) is the predominant histologic type in Western Europe and the United States, where it accounts for approximately 90% of bladder cancers.2 Nonurothelial histologies are further classified as
CM and CD contributed equally as first authors. 1 IRCCS San Martino University Hospital - IST National Cancer Research Institute, Academic Unit of Medical Oncology, Genoa, Italy 2 Pathology Unit, University of Genoa and IRCCS San Martino, University Hospital, Genoa, Italy 3 Department of Internal Medicine, University of Genoa, School of Medicine, Genoa, Italy
Submitted: Jan 25, 2015; Revised: Mar 28, 2015; Accepted: Apr 9, 2015 Address for correspondence: Carlo Messina, MD, Department of Internal Medicine, University of Genoa, School of Medicine, Viale Benedetto XV 6, 16132 Genoa, Italy E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.04.002
epithelial and nonepithelial. Approximately 90% of these cancers are epithelial in origin, including adenocarcinoma, squamous cell carcinoma, and small cell tumors. Nonepithelial cancers are rare and represent a heterogeneous group of neoplasms, including sarcomas, paragangliomas, melanomas, and lymphomas.3 In Western Europe and the United States, primary bladder adenocarcinoma (PBA) is an extremely rare nonurothelial tumor, representing the third most common type of epithelial tumor among all bladder cancers.4 Among the proposed theories to explain the cause of PBA, the 2 mainly accepted are the embryologic inclusion of endodermal tissue and the metaplastic change of normal urothelium.5 Both the bladder and the rectum are derived embryologically from the primitive cloaca. Therefore, the first theory proposes that cystitis glandularis of the bladder may develop from persistent inclusions displaced in the separation of the rectum from the urogenital sinus or embryologic nests in the urachus.6 The second theory, known as “intestinal metaplasia,” suggests that chronic inflammatory processes of the bladder mucosa induce a change to a more protective squamous or glandular-type epithelium.7 PBA must be distinguished from tumors arising from other adjacent organs that extend into or metastasize to the bladder.
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Advanced Mucinous Adenocarcinoma of Bladder The distinction between a PBA and a secondary tumor involving the bladder is important to define staging and prognosis and to deliver appropriate therapy. Unfortunately, sometimes the distinction causes a diagnostic challenge for the pathologist, particularly when the diagnostic material is a small biopsy and clinical information is incomplete. We describe the case of a patient who underwent radical cystectomy, bilateral lymphadenectomy, partial resection of sigmarectum, terminal colostomy, and urinary diversion with orthotopic neobladder because of locally advanced mucinous primary adenocarcinoma of the bladder. After systemic metastatic spread of the disease, the patient was started on capecitabine-based chemotherapy. The following attempts to provide a comprehensive review of the literature on PBA, focusing on the pathologic diagnosis and therapeutic management of this rare neoplasm that is mainly derived from retrospective case series and case reports.
Case Presentation A 64-year-old man who smoked cigarettes was admitted to the Urology Department of IRCCS San Martino- IST Hospital, Genoa University for macroscopic hematuria. After the detection of an intravesical mass with ultrasonography, the patient underwent cystoscopy and transurethral resection of the tumor. The histologic examination revealed the presence of muscle-invasive mucinous intestinal-type bladder adenocarcinoma. Preoperative total-body computed tomography (CT) scan revealed the presence of a bulky lesion arising from the bladder wall and involving perivesical soft
tissue with lombo-aortic and iliac adenopathy; no distant metastases were detected. Therefore, the patient underwent radical cystectomy, bilateral pelvic lymphadenectomy, partial resection of the sigmarectum (Hartmann’s procedure), terminal colostomy, and urinary diversion based on orthotopic ileal neobladder. The histologic examination revealed the presence of muscle-invasive mucinous intestinal-type bladder adenocarcinoma involving perirectal and perivisceral fat tissue, namely, pT4b, G2, pN0/31, pMx (Figure 1). The immunohistochemical evaluation revealed a positive staining for CDX-2 and CK20, cytoplasmic and membranous staining for b-catenin and a negative staining for CK7 (Figure 1A-D). After 4 months, the patient underwent re-laparotomy for intestinal recanalization with colon-rectal anastomosis and protective lateral ileostomy. Subsequently, the patient underwent anterior re-resection for anastomotic stricture, and histologic examination revealed the presence of mucinous adenocarcinomatous fragments involving perirectal fat tissue resembling previous histology. After a long period of recovery from surgery, the patient was referred to our department. Total-body CT scan and positron emission tomography/CT were performed to determine actual disease status showing pelvic recurrence, pulmonary embolism, multiple pulmonary, and liver metastases. Carcinoembryonic antigen and cancer antigen 19.9 blood test revealed elevated values of 48 ng/mL and 101 U/mL, respectively. With the lack of randomized trials to define the optimal treatment for metastatic disease, capecitabine 2000 mg daily (1-14 q21) was started because of histologic similarity with colon cancer. Pulmonary embolism was managed by synchronous administration of therapeutic
Figure 1 Histologic Examination Revealed the Presence of Muscle-Invasive Mucinous Intestinal-Type Bladder Adenocarcinoma (A). Immunohistochemical Evaluation Revealed a Cytoplasmic and Membranous Staining for b-Catenin (B), Posititive Staining for CK20 (C), and CDX-2 (D), Negative Staining for CK7 (E)
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Carlo Messina et al doses of low-molecular-weight heparin. However, after 3 cycles of chemotherapy, total-body CT scan demonstrated both liver and pulmonary progression of disease. Carcinoembryonic antigen and cancer antigen 19.9 blood test revealed elevated values of 237 ng/mL and 443 U/mL, respectively. Because of poor general condition and rapid progression disease, the patient was started on best supportive care.
Discussion In Western Europe and the United States, PBA represents the second most common nonurothelial bladder cancer, comprising 0.5% to 2% of all malignant primary tumors.2 PBA occurs more frequently in geographic regions where schistosomiasis is endemic8 and is the most common cancer arising in the bladder of patients with extrophy, who have a higher risk than the general population for developing this type of malignancy.9 PBA is categorized as urachal and nonurachal adenocarcinoma because of the different natural history, pathologic diagnosis, and prognosis and treatment. Approximately two thirds of PBA cases arise in the bladder cavity, especially in the posterior wall and trigon, and approximately one third originate from the urachal remnant near the dome and anterior wall of the bladder.10,11 Urachal adenocarcinoma presents at an earlier median age than nonurachal adenocarcinoma (56 vs. 69 years); moreover, it more frequently affects women than men (45% vs. 36%), is less likely to be high grade (35% vs. 66%), and shows a better 5-year overall survival rate (48% vs. 35%).12 Clinically, the distinction of urachal and nonurachal adenocarcinoma may be difficult. Criteria that have been proposed to distinguish these 2 entities include the presence of an urachal remnant, an intact or ulcerated urothelium without metaplastic change, a predominant invasion of the muscularis wall of the bladder, anterior abdominal wall, or umbilicus.13 The primary symptoms of nonurachal bladder adenocarcinoma at presentation are hematuria and irritative urinary symptoms, whereas mucusuria is present in approximately 90% of urachal cases and is suggestive for clinical diagnosis. PBA is an epithelial neoplasm characterized by a neoplastic glandular structure lined by mucin-secreting cells similar to intestinal carcinoma. Grignon et al14 identified 5 subtypes of bladder adenocarcinoma: (1) papillary, when architectural and cytologic features resemble those of intestinal-type adenocarcinoma; (2) mucinous, when the tumor is characterized by single cells or nets of cells floating in extracellular mucin; (3) signet-ring cell, when the tumor is composed of single signet-ring cells diffusely permeating the tissue and the surface usually is associated with glandular metaplasia or cystitis glandularis; (4) adenocarcinoma not otherwise specified, when the morphologic pattern does not fit into previous categories; and (5) mixed, when the tumor shows 2 or more previous patterns with no single pattern accounting for more than 75% of the material. The signet-ring variant appears to have an unfavorable prognosis being associated with a poorer prognosis than other forms of adenocarcinoma.15 Morphologically, PBA often causes a diagnostic dilemma for pathologists because it is difficult to differentiate from secondary involvement of the bladder by adenocarcinomas arising in adjacent organs, typically the colorectum, prostate cancer, and female genital malignancy.11,16 Immunohistochemical staining may be helpful to distinguish PBA from secondary neoplasm involving the bladder, in particular colorectal adenocarcinoma, which represents the most common
tumor involving the bladder, accounting for 20% of all secondary neoplasms of the bladder.11,14 K903 is a marker of normal urothelium and prostatic basal cells with a cytoplasmatic positivity pattern. P63 is another marker of normal urothelium and prostatic basal cells with a nuclear positivity pattern. A negative result for K903 and P63 is suggestive for a derivation from normal urothelium.17 CK7 and CK20 staining profiles have been used to distinguish tumors from different sites. Gastrointestinal tumors, including colorectal cancers, tend to be CK20þ and CK7; for urothelial neoplasms, the staining is the exact opposite; PBA usually shows mixed staining pattern CK20þ and CK7þ.18 Nevertheless, several studies highlight that immunohistochemical profile of PBAs may be variable.19 Roy et al20 reported that only 33.3% of PBAs are CK7þ, whereas all cases are CK20þ.20 Zhou and Magi-Galluzzi19 and Wang et al21 investigated whether adenocarcinomas of the bladder and colon were pathogenically related by comparing their immunostaining for b-catenin, whose dysregulation has been recognized to play a role in the development of colorectal adenocarcinoma. Positive immunostaining for b-catenin was observed in 81% of colorectal adenocarcinoma involving the bladder but in none of PBA. Several authors suggest that b-catenin has a crucial role in the differential diagnosis between colorectal adenocarcinomas and PBAs.19,21 Nuclear and cytoplasmic immunostaining pattern for b-catenin is observed in 92% of colorectal adenocarcinomas involving the bladder, whereas a membranous and cytoplasmic pattern is typically observed only in PBAs (92%) and urothelial carcinomas with glandular differentiation (100%); in these cases, nuclei are entirely negative.22 CDX 2 is a mammalian home-box gene encoding a nuclear transcription factor, which is implicated as a tumor suppressor. Nuclear staining is seen in normal colonic epithelial cells and colonic adenocarcinoma. CDX 2 is expressed in all cases of colorectal adenocarcinoma and can be helpful to distinguish PBA from secondary adenocarcinoma involving the bladder.23 GATA-3 is a novel marker that is expressed in urothelial and breast cancer.24 Ellis et al25 showed that GATA-3 immunoreactivity was negative in PBA and can be helpful in excluding spread from secondary colorectal cancer, particularly if the lesion is a poorly differentiated adenocarcinoma with signet-ring cells and lacks extracellular mucin production. Currently, there are no prospective randomized trials on the treatment of PBA, so clinical decisions are based on case series with a limited numbers of patients and case reports. The natural history and clinical behavior of urachal carcinoma are distinct from those of nonurachal carcinoma, a fact that has important treatment and prognostic implications. Clinically, all adenocarcinomas of the dome should be considered as urachal in origin until proven otherwise, and treated as such.13 Radical cystectomy, pelvic lymph nodes dissection, and en bloc surgical resection of the urachal ligament, umbilicus, and anterior abdominal wall comprise the primary treatment option for most patients.26 The prognosis of urachal adenocarcinoma is poor, with 5-year survival rates ranging from 11% to 55%.13 According to M.D. Anderson Cancer Center experience, survival correlates with local tumor extent; in addition, negative surgical margin, low tumor grade, and the absence of lymph nodes involvement are considered favorable prognostic factors and important predictors of outcome.26 Likewise, the
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Advanced Mucinous Adenocarcinoma of Bladder survival of patients with nonurachal carcinoma is generally poor, with 5-year survival of 35%. Survival correlates with advanced local tumor stage at diagnosis and lymph node metastasis.12 In a large series of 185 patients with PBA, el-Mekresh et al8 reported that nonurachal adenocarcinoma related to schistosomiasis seems to have a better prognosis, showing a 5-year survival rate of 55%. The majority of these patients had a low-grade tumor, and this feature may affect overall survival. Radical cystectomy with pelvic lymph nodes dissection is considered the treatment of choice for patients with nonurachal bladder adenocarcinoma.8 Local relapse after radical cystectomy is common, and in some centers postoperative radiotherapy is adopted. The nonrandomized retrospective series of the Egyptian National Cancer Institute showed that disease-free survival was 37% in patients who underwent cystectomy alone compared with 61% of patients treated with cystectomy followed by radiotherapy. Despite the limitations provided by retrospective studies, this result was significant on univariate and multivariate analyses.27 There are no randomized trials of chemotherapy for metastatic disease. To date, there is no evidence of established chemotherapy for patients with metastatic urachal adenocarcinoma. In a series of M.D. Anderson Cancer Center, 20 patients with metastatic urachal adenocarcinoma of the bladder treated with multimodality chemotherapy (largely 5-fluorouracil and cisplatinbased regimen) had a median survival of 20 months. Only 4 of 20 patients responded to chemotherapy without a significant survival improvement.26 In a prospective study of ifosfamide, paclitaxel, and cisplatin in men with advanced nonurothelial bladder cancer (11/20 were adenocarcinomas), Galsky et al28 reported a response rate of 38% and median overall survival of 25 months. In a series of 21 patients, including 14 with adenocarcinoma, Hong JH et al29 reported a 36% response rate to cisplatin-based chemotherapy. Several published case reports on the histologic similarity to colon cancer have described treatment with 5-fluorouracil alone or in combination with other agents.29,30
Conclusions This review highlights the clinical importance of the distinction between PBA and secondary tumor involving the bladder in terms of staging, determining appropriate therapy, and assessing prognosis. Immunohistochemical staining may be helpful for pathologists to solve this diagnostic “dilemma.” Although there are no data from randomized clinical trials, radical cystectomy and lymph node dissection should be performed as the initial management of all patients with muscle-invasive PBA.8 In addition, en bloc surgical resection of the urachal ligament, umbilicus, and anterior abdominal wall is the primary treatment option for muscle-invasive bladder adenocarcinoma.26 No role for chemotherapy or radiotherapy currently has been defined given the absence of data supporting their use. Patients interested in receiving chemotherapy should be included in formal studies or clinical trials.
Disclosure The authors have stated that they have no conflicts of interest.
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References 1. Chavan S, Bray F, Lortet-Tieulent J, et al. International variations in bladder cancer incidence and mortality. Eur Urol 2014; 66:59-73. 2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90, Erratum in: CA Cancer J Clin 2011;61:134. 3. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York NY: Springer; 2010:497-505. 4. Thomas DC, Ward AM, Williams JL. A study of 52 cases of adenocarcinoma of the bladder. Br J Urol 1971; 43:4-15. 5. Edwards PD, Hurm RA, Jaeschke WH. Conversion of cystitis glandularis to adenocarcinoma. J Urol 1972; 108:568-70. 6. Susmano D, Rubenstein AB, Dakin AR, et al. Cystitis glandularis and adenocarcinoma of the bladder. J Urol 1971; 105:671-4. 7. Bullock PS, Thoni DE, Murphy WM. The significance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer 1987; 59:2086-90. 8. el-Mekresh MM, el-Baz MA, Abol-Enein H, et al. Primary adenocarcinoma of the urinary bladder: a report of 185 cases. Br J Urol 1998; 82:206-12. 9. Smeulders N, Woodhouse CR. Neoplasia in adult extrophy patients. BJU Int 2001; 87:623-8. 10. Wilson TG, Pricchet TR, Lieskowvsky G, et al. Primary adenocarcinoma of bladder. Urology 1991; 38:223-6. 11. Melicow MM. Tumors of the urinary bladder: a clinico-pathological analysis of over 2500 specimens and biopsies. J Urol 1955; 74:498-521. 12. Wright JL, Porter MP, Li CI, et al. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer 2006; 107:721-8. 13. Sheldon CA, Clayman RV, Gonzalez R, et al. Malignant urachal lesions. J Urol 1984; 131:1-8. 14. Grignon DJ, Ro JY, Ayala AG, et al. Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases. Cancer 1991; 67:2165-72. 15. Filter L, Gimeno F, Martin L, et al. Signet-ring cell adenocarcinoma of bladder. Urology 1993; 41:30. 16. Bates AW, Baithun SI. Secondary neoplasms of the bladder are histological mimics of nontransitional cell primary tumours: clinicopathological and histological features of 282 cases. Histopathology 2000; 36:32-40. 17. Curtis MW, Evans AJ, Srigley JR. Mucin-producing urothelial-type adenocarcinoma of prostate: report of two cases of a rare and diagnostically challenging entity. Mod Pathol 2005; 18:585-90. 18. Raspollini MR, Nesi G, Baroni G, et al. Immunohistochemistry in the differential diagnosis between primary and secondary intestinal adenocarcinoma of the urinary bladder. Appl Immunohistochem Mol Morphol 2005; 13:358-62. 19. Zhou M, Magi-Galluzzi C. Chapter 4, Neoplasms of the urinary bladder. In: Goldblum John R, ed. Genitourinary Pathology: A Volume in Foundations in Diagnostic Pathology Series. Philadelphia, PA: Churchill Livingstone, Elsevier; 2007: 151-250. 20. Roy S, Smith MA, Cieply KM, et al. Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: a persisting diagnostic challenge. Diagn Pathol 2012; 7:151. 21. Wang HL, Lu DW, Yerian LM, et al. Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Am J Surg Pathol 2001; 25:1380-7. 22. Rao Q, Williamson SR, Lopez-Beltran A, et al. Distinguishing primary adenocarcinoma of the urinary bladder from secondary involvement by colorectal adenocarcinoma: extended immunohistochemical profiles emphasizing novel markers. Mod Pathol 2013; 26:725-32. 23. Suh N, Yang XJ, Tretiakova MS, et al. Value of CDX2, villin, and alphamethylacyl coenzyme A racemase immunostains in the distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Mod Pathol 2005; 18:1217-22. 24. Higgins JP, Kaygusuz G, Wang L, et al. Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol 2007; 31:673-80. 25. Ellis CL, Chang AG, Cimino-Mathews A, et al. GATA-3 immunohistochemistry in the differential diagnosis of adenocarcinoma of the urinary bladder. Am J Surg Pathol 2013; 37:1756-60. 26. Siefker-Radtke AO, Gee J, Shen Y, et al. Multimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience. J Urol 2003; 169: 1295-8. 27. Zaghloul MS, Nouh A, Nazmy M, et al. Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol 2006; 24: 13-20. 28. Galsky MD, Iasonos A, Mironov S, et al. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial tract. Urology 2007; 69:255-9. 29. Hong JY, Choi MK, Uhm JE, et al. Palliative chemotherapy for non-transitional cell carcinomas of the urothelial tract. Med Oncol 2009; 26:186. 30. Tatli AM, Uysal M, Goksu SS, Gunduz S, Arslan D, Ozdogan M. Complete response of primary bladder adenocarcinoma with the FOLFOX4 regimen. Urol Int 2015; 94:363-5.
A Case of Advanced Mucinous Adenocarcinoma of Bladder in an Adult Patient Treated With Capecitabine-Based Chemotherapy and Review of Literature Carlo Messina,1 Chiara Dellepiane,1 Cinzia Caroti,1 Francesca Sarocchi,2 Gian Luigi Ravetti,2 Francesco Boccardo,1,3 Bruno Spina2 Clinical Practice Points Primary bladder adenocarcinoma is an extremely rare
tumor, representing the second most common nonurothelial bladder cancer, comprising 0.5% to 2% of all malignant primary tumors. The morphology is similar to that of colorectal adenocarcinoma, and sometimes it causes a diagnostic challenge for the pathologist. We describe the case of a patient who underwent radical cystectomy and urinary diversion with orthotopic neobladder because of locally advanced
mucinous primary adenocarcinoma. Capecitabinebased chemotherapy was administered to the patient after systemic metastatic spread of the disease. Currently, no role for chemotherapy or radiotherapy has been defined given the absence of data from clinical randomized trial supporting their use; therefore, we aim to provide a comprehensive review of literature on primary bladder adenocarcinoma, focusing on the pathologic diagnosis and therapeutic management of this rare neoplasm.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Capecitabine-based chemotherapy, Mucinous bladder adenocarcinoma, Nonurothelial bladder cancer
Introduction Bladder cancer is the most common tumor of the urinary system and the ninth most common malignancy worldwide. It is estimated that there are 386,000 new cases resulting in 150,000 deaths worldwide.1 Bladder cancers are categorized as urothelial and nonurothelial histologic types. Urothelial carcinoma (transitional-cell carcinoma) is the predominant histologic type in Western Europe and the United States, where it accounts for approximately 90% of bladder cancers.2 Nonurothelial histologies are further classified as
CM and CD contributed equally as first authors. 1 IRCCS San Martino University Hospital - IST National Cancer Research Institute, Academic Unit of Medical Oncology, Genoa, Italy 2 Pathology Unit, University of Genoa and IRCCS San Martino, University Hospital, Genoa, Italy 3 Department of Internal Medicine, University of Genoa, School of Medicine, Genoa, Italy
Submitted: Jan 25, 2015; Revised: Mar 28, 2015; Accepted: Apr 9, 2015 Address for correspondence: Carlo Messina, MD, Department of Internal Medicine, University of Genoa, School of Medicine, Viale Benedetto XV 6, 16132 Genoa, Italy E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.04.002
epithelial and nonepithelial. Approximately 90% of these cancers are epithelial in origin, including adenocarcinoma, squamous cell carcinoma, and small cell tumors. Nonepithelial cancers are rare and represent a heterogeneous group of neoplasms, including sarcomas, paragangliomas, melanomas, and lymphomas.3 In Western Europe and the United States, primary bladder adenocarcinoma (PBA) is an extremely rare nonurothelial tumor, representing the third most common type of epithelial tumor among all bladder cancers.4 Among the proposed theories to explain the cause of PBA, the 2 mainly accepted are the embryologic inclusion of endodermal tissue and the metaplastic change of normal urothelium.5 Both the bladder and the rectum are derived embryologically from the primitive cloaca. Therefore, the first theory proposes that cystitis glandularis of the bladder may develop from persistent inclusions displaced in the separation of the rectum from the urogenital sinus or embryologic nests in the urachus.6 The second theory, known as “intestinal metaplasia,” suggests that chronic inflammatory processes of the bladder mucosa induce a change to a more protective squamous or glandular-type epithelium.7 PBA must be distinguished from tumors arising from other adjacent organs that extend into or metastasize to the bladder.
Clinical Genitourinary Cancer Month 2015
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Advanced Mucinous Adenocarcinoma of Bladder The distinction between a PBA and a secondary tumor involving the bladder is important to define staging and prognosis and to deliver appropriate therapy. Unfortunately, sometimes the distinction causes a diagnostic challenge for the pathologist, particularly when the diagnostic material is a small biopsy and clinical information is incomplete. We describe the case of a patient who underwent radical cystectomy, bilateral lymphadenectomy, partial resection of sigmarectum, terminal colostomy, and urinary diversion with orthotopic neobladder because of locally advanced mucinous primary adenocarcinoma of the bladder. After systemic metastatic spread of the disease, the patient was started on capecitabine-based chemotherapy. The following attempts to provide a comprehensive review of the literature on PBA, focusing on the pathologic diagnosis and therapeutic management of this rare neoplasm that is mainly derived from retrospective case series and case reports.
Case Presentation A 64-year-old man who smoked cigarettes was admitted to the Urology Department of IRCCS San Martino- IST Hospital, Genoa University for macroscopic hematuria. After the detection of an intravesical mass with ultrasonography, the patient underwent cystoscopy and transurethral resection of the tumor. The histologic examination revealed the presence of muscle-invasive mucinous intestinal-type bladder adenocarcinoma. Preoperative total-body computed tomography (CT) scan revealed the presence of a bulky lesion arising from the bladder wall and involving perivesical soft
tissue with lombo-aortic and iliac adenopathy; no distant metastases were detected. Therefore, the patient underwent radical cystectomy, bilateral pelvic lymphadenectomy, partial resection of the sigmarectum (Hartmann’s procedure), terminal colostomy, and urinary diversion based on orthotopic ileal neobladder. The histologic examination revealed the presence of muscle-invasive mucinous intestinal-type bladder adenocarcinoma involving perirectal and perivisceral fat tissue, namely, pT4b, G2, pN0/31, pMx (Figure 1). The immunohistochemical evaluation revealed a positive staining for CDX-2 and CK20, cytoplasmic and membranous staining for b-catenin and a negative staining for CK7 (Figure 1A-D). After 4 months, the patient underwent re-laparotomy for intestinal recanalization with colon-rectal anastomosis and protective lateral ileostomy. Subsequently, the patient underwent anterior re-resection for anastomotic stricture, and histologic examination revealed the presence of mucinous adenocarcinomatous fragments involving perirectal fat tissue resembling previous histology. After a long period of recovery from surgery, the patient was referred to our department. Total-body CT scan and positron emission tomography/CT were performed to determine actual disease status showing pelvic recurrence, pulmonary embolism, multiple pulmonary, and liver metastases. Carcinoembryonic antigen and cancer antigen 19.9 blood test revealed elevated values of 48 ng/mL and 101 U/mL, respectively. With the lack of randomized trials to define the optimal treatment for metastatic disease, capecitabine 2000 mg daily (1-14 q21) was started because of histologic similarity with colon cancer. Pulmonary embolism was managed by synchronous administration of therapeutic
Figure 1 Histologic Examination Revealed the Presence of Muscle-Invasive Mucinous Intestinal-Type Bladder Adenocarcinoma (A). Immunohistochemical Evaluation Revealed a Cytoplasmic and Membranous Staining for b-Catenin (B), Posititive Staining for CK20 (C), and CDX-2 (D), Negative Staining for CK7 (E)
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Carlo Messina et al doses of low-molecular-weight heparin. However, after 3 cycles of chemotherapy, total-body CT scan demonstrated both liver and pulmonary progression of disease. Carcinoembryonic antigen and cancer antigen 19.9 blood test revealed elevated values of 237 ng/mL and 443 U/mL, respectively. Because of poor general condition and rapid progression disease, the patient was started on best supportive care.
Discussion In Western Europe and the United States, PBA represents the second most common nonurothelial bladder cancer, comprising 0.5% to 2% of all malignant primary tumors.2 PBA occurs more frequently in geographic regions where schistosomiasis is endemic8 and is the most common cancer arising in the bladder of patients with extrophy, who have a higher risk than the general population for developing this type of malignancy.9 PBA is categorized as urachal and nonurachal adenocarcinoma because of the different natural history, pathologic diagnosis, and prognosis and treatment. Approximately two thirds of PBA cases arise in the bladder cavity, especially in the posterior wall and trigon, and approximately one third originate from the urachal remnant near the dome and anterior wall of the bladder.10,11 Urachal adenocarcinoma presents at an earlier median age than nonurachal adenocarcinoma (56 vs. 69 years); moreover, it more frequently affects women than men (45% vs. 36%), is less likely to be high grade (35% vs. 66%), and shows a better 5-year overall survival rate (48% vs. 35%).12 Clinically, the distinction of urachal and nonurachal adenocarcinoma may be difficult. Criteria that have been proposed to distinguish these 2 entities include the presence of an urachal remnant, an intact or ulcerated urothelium without metaplastic change, a predominant invasion of the muscularis wall of the bladder, anterior abdominal wall, or umbilicus.13 The primary symptoms of nonurachal bladder adenocarcinoma at presentation are hematuria and irritative urinary symptoms, whereas mucusuria is present in approximately 90% of urachal cases and is suggestive for clinical diagnosis. PBA is an epithelial neoplasm characterized by a neoplastic glandular structure lined by mucin-secreting cells similar to intestinal carcinoma. Grignon et al14 identified 5 subtypes of bladder adenocarcinoma: (1) papillary, when architectural and cytologic features resemble those of intestinal-type adenocarcinoma; (2) mucinous, when the tumor is characterized by single cells or nets of cells floating in extracellular mucin; (3) signet-ring cell, when the tumor is composed of single signet-ring cells diffusely permeating the tissue and the surface usually is associated with glandular metaplasia or cystitis glandularis; (4) adenocarcinoma not otherwise specified, when the morphologic pattern does not fit into previous categories; and (5) mixed, when the tumor shows 2 or more previous patterns with no single pattern accounting for more than 75% of the material. The signet-ring variant appears to have an unfavorable prognosis being associated with a poorer prognosis than other forms of adenocarcinoma.15 Morphologically, PBA often causes a diagnostic dilemma for pathologists because it is difficult to differentiate from secondary involvement of the bladder by adenocarcinomas arising in adjacent organs, typically the colorectum, prostate cancer, and female genital malignancy.11,16 Immunohistochemical staining may be helpful to distinguish PBA from secondary neoplasm involving the bladder, in particular colorectal adenocarcinoma, which represents the most common
tumor involving the bladder, accounting for 20% of all secondary neoplasms of the bladder.11,14 K903 is a marker of normal urothelium and prostatic basal cells with a cytoplasmatic positivity pattern. P63 is another marker of normal urothelium and prostatic basal cells with a nuclear positivity pattern. A negative result for K903 and P63 is suggestive for a derivation from normal urothelium.17 CK7 and CK20 staining profiles have been used to distinguish tumors from different sites. Gastrointestinal tumors, including colorectal cancers, tend to be CK20þ and CK7; for urothelial neoplasms, the staining is the exact opposite; PBA usually shows mixed staining pattern CK20þ and CK7þ.18 Nevertheless, several studies highlight that immunohistochemical profile of PBAs may be variable.19 Roy et al20 reported that only 33.3% of PBAs are CK7þ, whereas all cases are CK20þ.20 Zhou and Magi-Galluzzi19 and Wang et al21 investigated whether adenocarcinomas of the bladder and colon were pathogenically related by comparing their immunostaining for b-catenin, whose dysregulation has been recognized to play a role in the development of colorectal adenocarcinoma. Positive immunostaining for b-catenin was observed in 81% of colorectal adenocarcinoma involving the bladder but in none of PBA. Several authors suggest that b-catenin has a crucial role in the differential diagnosis between colorectal adenocarcinomas and PBAs.19,21 Nuclear and cytoplasmic immunostaining pattern for b-catenin is observed in 92% of colorectal adenocarcinomas involving the bladder, whereas a membranous and cytoplasmic pattern is typically observed only in PBAs (92%) and urothelial carcinomas with glandular differentiation (100%); in these cases, nuclei are entirely negative.22 CDX 2 is a mammalian home-box gene encoding a nuclear transcription factor, which is implicated as a tumor suppressor. Nuclear staining is seen in normal colonic epithelial cells and colonic adenocarcinoma. CDX 2 is expressed in all cases of colorectal adenocarcinoma and can be helpful to distinguish PBA from secondary adenocarcinoma involving the bladder.23 GATA-3 is a novel marker that is expressed in urothelial and breast cancer.24 Ellis et al25 showed that GATA-3 immunoreactivity was negative in PBA and can be helpful in excluding spread from secondary colorectal cancer, particularly if the lesion is a poorly differentiated adenocarcinoma with signet-ring cells and lacks extracellular mucin production. Currently, there are no prospective randomized trials on the treatment of PBA, so clinical decisions are based on case series with a limited numbers of patients and case reports. The natural history and clinical behavior of urachal carcinoma are distinct from those of nonurachal carcinoma, a fact that has important treatment and prognostic implications. Clinically, all adenocarcinomas of the dome should be considered as urachal in origin until proven otherwise, and treated as such.13 Radical cystectomy, pelvic lymph nodes dissection, and en bloc surgical resection of the urachal ligament, umbilicus, and anterior abdominal wall comprise the primary treatment option for most patients.26 The prognosis of urachal adenocarcinoma is poor, with 5-year survival rates ranging from 11% to 55%.13 According to M.D. Anderson Cancer Center experience, survival correlates with local tumor extent; in addition, negative surgical margin, low tumor grade, and the absence of lymph nodes involvement are considered favorable prognostic factors and important predictors of outcome.26 Likewise, the
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Advanced Mucinous Adenocarcinoma of Bladder survival of patients with nonurachal carcinoma is generally poor, with 5-year survival of 35%. Survival correlates with advanced local tumor stage at diagnosis and lymph node metastasis.12 In a large series of 185 patients with PBA, el-Mekresh et al8 reported that nonurachal adenocarcinoma related to schistosomiasis seems to have a better prognosis, showing a 5-year survival rate of 55%. The majority of these patients had a low-grade tumor, and this feature may affect overall survival. Radical cystectomy with pelvic lymph nodes dissection is considered the treatment of choice for patients with nonurachal bladder adenocarcinoma.8 Local relapse after radical cystectomy is common, and in some centers postoperative radiotherapy is adopted. The nonrandomized retrospective series of the Egyptian National Cancer Institute showed that disease-free survival was 37% in patients who underwent cystectomy alone compared with 61% of patients treated with cystectomy followed by radiotherapy. Despite the limitations provided by retrospective studies, this result was significant on univariate and multivariate analyses.27 There are no randomized trials of chemotherapy for metastatic disease. To date, there is no evidence of established chemotherapy for patients with metastatic urachal adenocarcinoma. In a series of M.D. Anderson Cancer Center, 20 patients with metastatic urachal adenocarcinoma of the bladder treated with multimodality chemotherapy (largely 5-fluorouracil and cisplatinbased regimen) had a median survival of 20 months. Only 4 of 20 patients responded to chemotherapy without a significant survival improvement.26 In a prospective study of ifosfamide, paclitaxel, and cisplatin in men with advanced nonurothelial bladder cancer (11/20 were adenocarcinomas), Galsky et al28 reported a response rate of 38% and median overall survival of 25 months. In a series of 21 patients, including 14 with adenocarcinoma, Hong JH et al29 reported a 36% response rate to cisplatin-based chemotherapy. Several published case reports on the histologic similarity to colon cancer have described treatment with 5-fluorouracil alone or in combination with other agents.29,30
Conclusions This review highlights the clinical importance of the distinction between PBA and secondary tumor involving the bladder in terms of staging, determining appropriate therapy, and assessing prognosis. Immunohistochemical staining may be helpful for pathologists to solve this diagnostic “dilemma.” Although there are no data from randomized clinical trials, radical cystectomy and lymph node dissection should be performed as the initial management of all patients with muscle-invasive PBA.8 In addition, en bloc surgical resection of the urachal ligament, umbilicus, and anterior abdominal wall is the primary treatment option for muscle-invasive bladder adenocarcinoma.26 No role for chemotherapy or radiotherapy currently has been defined given the absence of data supporting their use. Patients interested in receiving chemotherapy should be included in formal studies or clinical trials.
Disclosure The authors have stated that they have no conflicts of interest.
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