Cytopathology

Poorly Differentiated Adenocarcinoma with Signet Ring Cell Features, Consistent with Rectal Primary

Guliz Barkan
Loyola University Medical Center
Maywood, IL


Clinical History
A 70-year-old man presented with hematuria, hesitancy, urgency, and nocturia. Imaging studies showed bilateral hydronephrosis. He had a past medical history significant for partial nephrectomy, prostatic hypertrophy with obstruction, and hyperlipidemia. A cystoscopy and bladder barbotage was performed.


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Diagnosis: Poorly differentiated adenocarcinoma with signet ring cell features, consistent with rectal primary

Cytologic Diagnosis:
Poorly differentiated carcinoma with signet ring cell features.

Histologic Diagnosis:
Poorly differentiated adenocarcinoma with signet ring cell features, consistent with rectal primary (Bladder biopsy).

Cytologic Findings:
The ThinPrep smear shows loosely cohesive clusters and single cells with cytoplasmic vacuolization, and intracytoplasmic mucin. The nuclei are hyperchromatic and eccentrically located. Prominent nucleoli could be observed in some of the cells. Especially cells in clusters show high N:C ratio and nuclear hyperchromasia. A background of necrotic debris is evident.

Discussion:
Adenocarcinoma of the urinary bladder can be primary (arising from the bladder wall or urachal remnants) or metastatic (from tumors originating in the stomach, colon, or breast). Primary adenocarcinoma of the bladder is rare, accounting for 0.5-2% of all malignant tumors of the bladder. It is more common in males with a peak incidence at 60 years of age. Patients typically present with hematuria, dysuria and rarely mucusuria. There are two types of adenocarcinomas arising in the bladder: primary bladder adenocarcinoma (more common, accounting for two thirds of the cases) and urachal carcinoma (less common). Outcomes for patients with bladder adenocarcinoma are generally poor, with increased pathologic stage significantly correlating with worsened overall survival in several studies. Although some series have reported that adenocarcinomas of urachal origin may demonstrate more favorable long-term outcomes, this finding has been controversial and may be associated with the younger age at presentation of urachal adenocarcinomas.

There are multiple subtypes of bladder adenocarcinoma including colonic-type adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, clear cell carcinoma, hepatoid carcinoma, and adenocarcinoma not otherwise specified, as well as mixed forms. The signet ring cell carcinoma is a rare variant of mucus-producing adenocarcinoma. It is recognized as an entity for two reasons: its morphology is distinctive, and it follows a highly malignant course. The reported cases of this neoplasm were discovered in advanced stages with dismal outcome. In a recent study, Thomas et al., showed that signet ring cells were found in 76% of the bladder adenocarcinomas (67% in urachal and 79% in nonurachal adenocarcinomas). In their study the volume of signet ring cell differentiation ranged between 5-100%. However, most tumors showed 60% signet ring cell differentiation, and the percentage of signet ring cells correlated with adverse outcome (defined as unresectable primary tumor or lymph node involvement).

When a signet-ring tumor is diagnosed in the bladder, it is most likely a primary. However, a metastatic disease from a GI primary (gastric or colon) is possible, and should be taken into consideration. Therefore, in spite of this rare manifestation, a gastroscopy and possibly a colonoscopy may be considered in the diagnostic work up. This may influence the type of therapy because cystectomy must be considered in the light of poor sensitivity to radiotherapy or chemotherapy of a primary bladder tumor of signet-ring cell histology.

The distinction between primary adenocarcinomas of the bladder and those secondarily involving the bladder either by direct extension or metastatic spread has been the focus of numerous studies. Specifically, most markers examined have concentrated on the differentiation between colon carcinoma and colonic type bladder adenocarcinoma. For this purpose many markers have been examined, including cytokeratin (CK) 7, CK20, villin-1, CDX-2 and β-catenin. Unfortunately, studies have shown that none of these markers are quite reliable in differentiating these entities. In addition, signet ring carcinomas have been shown to have decreased expression of a subset of immunohistochemical markers, making it difficult to distinguish the origin of the neoplasm. See the table for differential staining patterns of adenocarcinoma in the bladder (modified from Bostwick et al, and Thomas et al.).

In conclusion, signet-ring cell adenocarcinoma of the bladder is a rare lesion which may present as either a primary or metastatic tumor. The co-presence of squamous or urothelial carcinoma cells would suggest a primary tumor. A history of previous cancer should raise the possibility of metastatic disease. Occasionally, the bladder may be the first manifestation of an occult primary, usually of GI origin. Searching for such a primary, despite its rarity may have significant clinical and prognostic implications, and should therefore be considered.

Table: Immunohistochemical Differentiation of Adenocarcinoma in the Urinary Bladder.

 HMWCK CK 7 CK 20 PSA CDX 2 VILLIN
PBA, colonic type + +/- +/- - + +/-
PBA, signet ring cell type + +/- + - +/- +/-
Colorectal Adenocarcinoma - - + - + +
Gastric Adenocarcinoma - +/- +/- - +/- +/-
Prostatic Adenocarcinoma - - +/- + - -

PBA= Primary Bladder Adenocarcinoma; + usually positive, - usually negative, +/- variable staining pattern

References:
  1. Saphir O. Signet ring cell carcinoma of the bladder. Am J. Pathol 1955;31: 223-231

  2. Saba NF, Hoening DM, Cohen SI: Metastatic signet ring cell adenocarcinoma to the urinary bladder. Acta Oncol. 1997; 36: 219-20

  3. Thomas AA, Stephenson AJ, Campbell SC, Jones J, Hansel DE: Clinicopathologic features and utility of immunohistochemical markers in signet-ring cell adenocarcinoma of the Human Pathology 2009;40:108–116

  4. Pantanowitz L, Otis CN: Cystitis Glandularis Diagnostic Cytopathology, 2008:36: 181-182

  5. Wright JL, Porter MP, Li CI, Lange PH, Lin DW. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer 2006;107:721-8

  6. Dandekar NP, Dalal AV, Tongaonkar HB, Kamat MR. Adenocarcinoma of bladder. Eur J Surg Oncol 1997;23:157-60

  7. Grignon DJ, Ro JY, Ayala AG, Johnson DE, Ordonez NG. Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases. Cancer 1991;67:2165-72

  8. el-Mekresh MM, el-Baz MA, Abol-Enein H, Ghoneim MA. Primary adenocarcinoma of the urinary bladder: a report of 185 cases. Br J Urol 1998;82:206-12

  9. Susmano D, Rubenstein AB, Dakin AR, Lloyd FA. Cystitis glandularis and adenocarcinoma of the bladder. J Urol 1971;105:671-4

  10. Bullock PS, Thoni DE, Murphy WM. The significance of colonic mucosa (intestinal metaplasia) involving the urinary tract. Cancer 1987;59:2086-90

  11. Grignon DJ, Ro JY, Ayala AG, Johnson DE. Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol 1991;95:13-20.

  12. Blute ML, Engen DE, Travis WD, Kvols LK. Primary signet ring cell adenocarcinoma of the bladder. J Urol 1989;141:17-21.

  13. Young RH, Scully RE. Clear cell adenocarcinoma of the bladder and urethra. A report of three cases and review of the literature. Am J SurgPathol 1985;9:816-26

  14. Johnson DE, Hodge GB, Abdul-Karim FW, Ayala AG. Urachal carcinoma. Urology 1985;26:218-21

  15. Osunkoya AO, Epstein JI. Primary mucin-producing urothelial-type adenocarcinoma of prostate: report of 15 cases. Am J Surg Pathol 2007;31:1323-9

  16. Suh N, Yang XJ, Tretiakova MS, Humphrey PA, Wang HL. Value of CDX2, villin, and alpha-methylacyl coenzyme A racemase immunostains in the distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma. Mod Pathol 2005;18:1217-22

  17. Raspollini MR, Nesi G, Baroni G, Girardi LR, Taddei GL. Immunohistochemistry in the differential diagnosis between primary and secondary intestinal adenocarcinoma of the urinary bladder. Appl Immunohistochem Mol Morphol 2005;13:358-62

  18. Tamboli P, Mohsin SK, Hailemariam S, Amin MB. Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel. Arch Pathol Lab Med 2002;126:1057-63

  19. Urologic Surgical Pathology, Mosby Elsevier, second edition 2008, editors Bostwick D and Cheng L, Chapter 6, pp300-307