| Abstract|| |
Primary adenocarcinoma of the urinary bladder is a rare malignancy with a frequency of less than 2% of all urothelial malignancies. Colonic adenocarcinoma has a much higher prevalence and its infiltration/metastasis in the urinary bladder is a pertinent differential of primary adenocarcinoma of the urinary bladder. However, the distinction of infiltration by colonic adenocarcinoma from synchronous adenocarcinoma in the bladder and colon is not always easy. Here, we report a 42-year-old male, who initially presented with bladder symptoms and subsequently found to have growth in both bladder and colon. A diagnosis of adenocarcinoma was made from the biopsies from both bladder and colon. Further attempts to differentiate synchronous occurrence or secondary involvement from an adjacent organ was made by radiology, and by an immunohistochemistry panel. The loss of MLH1 and PMS2 coupled with histomorphology and radiology helped in the diagnosis of primary colonic adenocarcinoma infiltrating the urinary bladder.
Keywords: Colonic adenocarcinoma, immunohistochemistry, mismatch repair proteins, urinary bladder adenocarcinoma, synchronous malignancy
|How to cite this article:|
Nambiyar K, Mitra S, Das A, Bal A. Adenocarcinoma of the colon and urinary bladder: A fortuitous or an embryological phenomenon?. Indian J Pathol Microbiol 2021;64:132-5
|How to cite this URL:|
Nambiyar K, Mitra S, Das A, Bal A. Adenocarcinoma of the colon and urinary bladder: A fortuitous or an embryological phenomenon?. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Jan 21];64:132-5. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/132/306536
| Introduction|| |
Primary urinary bladder adenocarcinoma is an uncommon malignant neoplasm, accounting for 0.5% to 2.0% of all malignant neoplasms of the urinary bladder. Primary colonic adenocarcinoma is the most common colonic tumor and occurs mainly after the fifth decade. Multiple synchronous primaries involving both the colon and urinary bladder, although rare, do occur in clinical practice. The morphological features are identical, and no diagnostic markers are available currently to confidently distinguish these entities. In the seminal articles by Roy et al. and Rao et al., a panel of immunostains along with histomorphological examination may aid in the diagnosis. Nevertheless, a precise judgment cannot be achieved in some of the cases.
| Case History|| |
A 42-year-old male had a history of hematuria of 3 months duration for which he was admitted in a private hospital. No significant family history was provided. Transurethral resection of bladder tumor (TURBT) was performed, following which he developed fecaluria. Later, he was referred to our institute for further management. Cystoscopy revealed a solid growth of size 5 × 5 cm in the posterior wall and colonoscopy revealed sigmoid colon growth. CECT (Contrast-enhanced computed tomography) showed a heterogeneous symmetrical mural thickening with significant luminal narrowing involving the entire sigmoid colon and short segment of mid-descending colon. In addition, a defect in the posterosuperior wall of the urinary bladder was noted communicating with sigmoid colon. The rectum did not show gross abnormality.
TURBT chips showed mucosal fragments with villous architecture lined by pseudostratified columnar cells with high-grade dysplasia [Figure 1]a and [Figure 1]b. Some of the fragments were rich in goblet cells [Figure 1]c, whereas some were completely devoid of goblet cells. In places the tumor cells showed abundant eosinophilic cytoplasm. The tumor cells invaded the underlying lamina propria and showed desmoplasia. Few of the fragments also showed benign urothelium [Figure 1]d. These tumor cells showed diffuse membranous positivity for β-catenin [Figure 1]e but were negative for GATA3 and CK7. CK20 immunostain showed positivity only in the fragments with goblet cells and was negative in other areas. E-cadherin showed retained membranous positivity in the bladder lesion [Figure 1]f.
|Figure 1: (a) The bladder biopsy showing villous architecture of the lesion (Hematoxylin and Eosin; 40×), (b) The lining showing pseudostratified epithelium with variable degree of dysplasia (Hematoxylin and Eosin; 400×), (c) Goblet cells were seen at places (Hematoxylin and Eosin; 400×), (d) Benign urothelial lining seen in sharp transition with adjacent dysplastic columnar epithelium thrown into villi (Hematoxylin and Eosin; 200×), (e and f) Immunohistochemistry of the bladder tumor showing membranous β-catenin expression (e) and membranous E-cadherin expression (f) (400×)|
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The colonic biopsy showed mucosal fragments lined by dysplastic epithelium with high-grade dysplasia. A villiform architecture was not seen [Figure 2]a. The lamina propria showed dysplastic glands surrounded by desmoplastic stroma [Figure 2]b. A few fragments showed benign colonic mucosa [Figure 2]c. β-catenin showed diffuse membranous positivity in the tumor cells like the bladder biopsy [Figure 2]d. E-cadherin expression showed only focal membranous positivity in the colonic lesion [Figure 2]e. Thrombomodulin was negative in both the biopsies. CDX2 immunostain showed nuclear positivity in both the biopsies [Figure 2]f. Both the biopsies revealed retention of MSH2 and MSH6 with loss of MLH1 and PMS2 immunostains [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. The radiologist and the urologist were unsure of the cysto-colic fistula at the time of biopsies and these were examined as biopsies from the two separate masses: colonic and urinary bladder. The biopsies were reported as adenocarcinoma of colon and urinary bladder respectively, explaining the possibilities of synchronous malignancies or primary colon malignancy involving urinary bladder. Genetic analysis and family screening were recommended based on the MLH1 and PMS2 loss that suggested a mutation in the MLH1 gene.
|Figure 2: (a) The colonic biopsy showing dysplastic epithelium. No villiform architecture was noted (Hematoxylin and Eosin; 40×), (b) The stroma was desmoplastic with focal infiltrating irregular glands (Hematoxylin and Eosin; 100×), (c) A fragment of normal colonic mucosa without dysplasia (Hematoxylin and Eosin; 100×), (d-f) Immunohistochemistry of colonic tumor showed membranous β-catenin expression (d) and focal patchy membranous E-cadherin expression (e) (100×). The bladder tumor also showed nuclear CDX2 positivity (f; 100×)|
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|Figure 3: (a-d) Immunohistochemistry in the bladder biopsy showing nuclear positivity for MSH2 (a) and MSH6 (b) and was negative for MLH1 (c) and PMS2 (d) (400×)|
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The patient was managed with diversion colostomy and intraoperative assessment of transverse colon did not show any abnormality. The patient did not come back for the follow-up and it was conveyed that he succumbed to the illness. No further investigations could be performed to look for malignancies in gastrointestinal or extraintestinal organs.
| Discussion|| |
Primary glandular neoplasms of the bladder are rare, and villous adenoma is a subtype, exhibiting villous configuration lined by intestinal-type epithelium, histologically similar to its colonic counterpart. This similarity and anomalous origin of the villous adenoma in urothelial lined urinary bladder can be explained by the common embryogenesis of the distal colorectum and urinary bladder from the endoderm of cloaca.,
Three possibilities were considered in the present case: synchronous bladder and colonic adenocarcinoma, colonic adenocarcinoma (arising from flat adenoma of the colon) infiltrating the bladder and adenocarcinoma of the bladder (arising from villous adenoma of the bladder) infiltrating the colon. Histomorphologically, the former appeared to be the best probability as both urinary bladder and colon showed dysplasia of the lining epithelium. However, a colonic adenocarcinoma infiltrating the bladder appears to be the Occam's razor. A cocktail of clinical, radiological, and histological information is needed for final diagnosis in most of the cases. The dilemma persists in some of the cases including the index case even after all available information.
Villous adenoma of the urinary bladder usually presents with hematuria, and commonly involve trigone, dome, and urachal remnant. It may progress to invasive malignancy in about 35% of the cases. Although the initial presentation was hematuria in the present case, hematuria can also be seen in secondary colonic adenocarcinoma with bladder involvement. Primary colonic adenocarcinoma infiltrating the bladder commonly arises from sigmoid colon and involves posterior wall of the bladder. Although imaging of the present case revealed posterior wall defect of the urinary bladder communicating with the colonic mass, radiological findings in predicting colonic adenocarcinoma has low specificity (46%). Dysplasia in the epithelial lining of urinary bladder does not rule out a possibility of secondary involvement of colonic origin, as metastatic colonic adenocarcinomas have been reported to colonize the surface urothelium and mimic in situ glandular lesions. However, the discordant morphology of bladder and colonic mucosal biopsy with absence of villous architecture in the colonic biopsy seen in the present case has not been reported in the literature.
To explore the possibility of synchronous malignancies of urinary bladder and colon, we applied the criteria proposed by Warren and Gates. Histopathological evaluation in the index case confirmed malignancy in both the biopsies, however, the radiology was not conclusive of anatomical distinction. Further immunostains were analyzed to entertain a possibility of metastasis and its primary site.
Colonic adenocarcinomas are usually CK20 positive and CK7 negative, while primary villous adenocarcinoma of bladder is usually negative for both, however, a positive CK7 cannot exclude presence of primary colonic adenocarcinoma. In contrast, the villous adenoma of the urinary bladder shows CK20 positivity similar to its colonic counterpart. The index case showed peculiar expression of CK20 in the fragments with goblet cells. The authors in their previous article shared similar experiences in terms of CK20 being an unreliable immunostain in cases of adenocarcinoma arising from villous adenoma of the urinary bladder. CDX2, a marker of colonic adenocarcinoma can also be positive in villous adenocarcinoma of urinary bladder and could not distinguish between a colonic and bladder origin. GATA3, a marker of urothelial differentiation is neither expressed in villous adenocarcinoma nor in colonic adenocarcinoma similar to the index case. However, GATA3 is useful in differentiating urothelial carcinoma with villoglandular differentiation from bladder adenocarcinoma. Thrombomodulin positivity is highly specific for urinary bladder adenocarcinoma, although its negativity does not rule out the possibility of primary bladder origin.
One of the previous studies noted membrano-cytoplasmic and nuclear staining of E-cadherin to be more commonly associated with primary bladder adenocarcinoma. None of the colonic adenocarcinomas expressed nuclear staining of E-cadherin in their study. The patchy loss of cytoplasmic and membranous staining without nuclear localization seen in the present case was not observed in any of the colonic adenocarcinomas reported. The absence of nuclear localization in the villous adenocarcinoma seen in this case did not help to differentiate concurrent malignancies and metastasis of colonic adenocarcinoma. The patchy loss of E-cadherin in the colonic tissue in the index case possibly correlates with the epithelial–mesenchymal transition rather than a distinguishing feature of the urinary bladder or colonic primary.
The nuclear expression of β-catenin more often indicates colonic primary, whereas the membranous expression of β-catenin can be seen in urinary bladder adenocarcinoma. Notably, colonic adenocarcinomas can also occur via mismatch repair pathway defect without β-catenin pathway alteration and show membranous expression of β-catenin. The index case also showed membranous expression of β-catenin and revealed MLH1 and PMS2 loss on subsequent immunohistochemistry. Mismatch repair protein deficiency is most commonly associated with colonic adenocarcinoma of the colon and rare in urinary bladder adenocarcinoma. Hence, the loss of mismatch repair protein expression in the index case also indicates a primary colonic origin. The MLH1 and PMS2 loss also explain the young age of occurrence and the absence of adenomatous polyp in the colon.
This case is unique as we received two separate biopsies of the colon and urinary bladder both showing dysplasia and adenocarcinoma arising from it. Further discordant morphology arose the possibility of synchronous adenocarcinoma of colon and urinary bladder. An immunopanel comprising CK7, CK20, GATA3, CDX2, β-catenin, and E-cadherin failed to identify the primary site of origin in the index case. However, the radiology and the site of the bladder tumor were suggestive of a single tumor, possibly colonic primary infiltrating the urinary bladder. Furthermore, defect in mismatch repair proteins explains the age, histomorphology, and favors a colonic origin.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
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| References|| |
Roy S, Parwani AV. Adenocarcinoma of the urinary bladder. Arch Pathol Lab Med 2011;135:1601-5.
Queiroz RM, Roque D, Febronio EM. Multiple primary malignancies: Synchronous urothelial carcinoma of the bladder and adenocarcinoma of the colon. Radiol Bras 2017;50:64.
Roy S, Smith MA, Cieply KM, Acquafondata MB, Parwani AV. Primary bladder adenocarcinoma versus metastatic colorectal adenocarcinoma: A persisting diagnostic challenge. Diagn Pathol 2012;7:151.
Rao Q, Williamson SR, Lopez-Beltran A, Montironi R, Huang W, Eble JN, 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.
Grignon DJ, Cheville J, Ro JY, Tamboli P. Glandular neoplasms. In: Moch H, Humphrey PA, Ulbright TM, Reuter VE, editors. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th
ed. Lyon: IARC; 2016. p. 112.
Mitra S, Chatterjee D, Das A, Gupta K, Radotra BD, Mandal AK. Urothelial tumors with villous morphology: Histomorphology and role of immunohistochemistry in diagnosis. APMIS 2018;126:191-200.
Wang J, Manucha V. Villous adenoma of the urinary bladder: A brief review of the literature. Arch Pathol Lab Med 2016;140:91-3.
Dadhania V, Czerniak B, Guo CC. Adenocarcinoma of the urinary bladder. Am J Clin Exp Urol 2015;3:51-63.
Woranisarakul V, Ramart P, Phinthusophon K, Chotikawanich E, Prapasrivorakul S, Lohsiriwat V. Accuracy of preoperative urinary symptoms, urinalysis, computed tomography and cystoscopic findings for the diagnosis of urinary bladder invasion in patients with colorectal cancer. Asian Pac J Cancer Prev 2014;15:7241-4.
Hung CY, Ueng SH, Lin YC, Chou WC. Metastatic carcinoma of the urinary bladder in a 67-year-old female with underlying triple primary cancers. J Cancer Res Pract 2016;3:49-53.
Paner GP, Annaiah C, Gulmann C, Rao P, Ro JY, Hansel DE, et al
. Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. Hum Pathol 2014;45:1473-82.
Zhong M, Gersbach E, Rohan SM, Yang XJ. Primary adenocarcinoma of the urinary bladder: Differential diagnosis and clinical relevance. Arch Pathol Lab Med 2013;137:371-81.
Bonneville R, Krook MA, Kautto EA, Miya J, Wing MR, Chen HZ, et al
. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol 2017; 2017. doi: 10.1200/PO.17.00073
Department of Histopathology, 5th Floor, Research Block A, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]