Bladder & urothelial tract

• Aggressive variant of urothelial carcinoma (UC) characterized by single infiltrating cells with eccentrically placed nuclei and abundant eosinophilic cytoplasm similar to plasmacytes or resembling signet ring cells due to intracytoplasmic vacuoles

• Bladder
• Renal pelvis
• Ureter (primary PUC rare) (Am J Case Rep 2018;19:158)

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• More likely to receive neoadjuvant chemotherapy compared with conventional UC because it is discovered at a higher stage (J Urol 2020;204:215)
  • Literature review found overall pathological complete response to neoadjuvant chemotherapy to be 21% (J Urol 2020;204:215)
• Same treatment for urothelial carcinoma of the same stage (Eur Urol Focus 2020;6:653)
  • Wider resection is important because margins are more often positive (Eur Urol Focus 2020;6:653)
• Role of neoadjuvant therapy before cystectomy has been questioned for PUC
  • In a study of 64 cases, neoadjuvant chemotherapy for PUC variant was not associated with improved overall survival compared with radical cystectomy alone (Bladder Cancer 2020;6:71)
  • In study with 2 cases of plasmacytoid variant, no response to neoadjuvant chemotherapy (Clin Genitourin Cancer 2021 Jul 20 [Epub ahead of print])

Contributed by Timothy Isaac Miller, M.D., M.A. and Maria Tretiakova, M.D., Ph.D.

• Discohesive single cells with eccentrically placed nuclei and abundant eosinophilic cytoplasm
• Often deeply infiltrative but with minimal stromal reaction (Eur Urol Focus 2020;6:653)
• Further subclassified into classic, pleomorphic and desmoplastic subtypes:
  • Classic: signet ring-like morphology, singly scattered and discohesive in loose aggregates forming cords (Hum Pathol 2019;90:27)
  • Pleomorphic: similar to classic but with pleomorphic nuclei and more atypia; can be rhabdoid and bizarre appearing (Hum Pathol 2019;90:27)
  • Desmoplastic: plasmacytoid neoplastic cells with a surrounding desmoplastic stromal response (Hum Pathol 2019;90:27)
• Associated with sarcomatoid variant in 31% of cases (Hum Pathol 2019;90:27)
• Often mixed with other histologic subtypes; in 1 case series, 53% of PUC had mixed histologic subtypes (Am J Clin Pathol 2017;147:500)
• Despite resemblance to signet ring carcinoma cells, notably lack extracellular mucin, contrasting to signet ring adenocarcinoma (Acta Cytol 1991;35:277, Am J Surg Pathol 1991;15:569)

Contributed by Timothy Isaac Miller, M.D., M.A., Nicole K. Andeen, M.D. and Maria Tretiakova, M.D., Ph.D.





Contributed by Lisa Han, M.D. and Ricardo Lastra, M.D. (Case #510)

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• E-cadherin (57 - 87% loss of membranous staining) (Hum Pathol 2019;90:27, BMC Urol 2020;20:72, Am J Clin Pathol 2017;147:500, Hum Pathol 2020;102:54, Int J Cancer 2011;129:346)
• p120 (73% had loss of membranous staining) (Hum Pathol 2020;102:54)
  • 94% concordance with E-cadherin loss (Hum Pathol 2020;102:54)
• ER, PR, mammoglobin, GCDFP-15 (76% loss) (Hum Pathol 2019;90:27, Am J Surg Pathol 2017;41:1570)
• Alcian blue / mucicarmine (Am J Surg Pathol 2008;32:752)
• CDX2 (Am J Surg Pathol 2017;41:1570)
• S100, CD45, synaptophysin, chromogranin (Am J Surg Pathol 2008;32:752, Int J Clin Exp Pathol 2012;5:601)
• MUM1 (Int J Cancer 2011;129:346)

• Factors favoring plasmacytoid urothelial cell carcinoma (Am J Surg Pathol 2008;32:752):
  • In situ urothelial carcinoma present
  • Foci of cohesive growth
  • Consistent immunohistochemical profile for urothelial carcinoma (GATA3, uroplakin II, CK7, CK20 positive)
  • Other urothelial carcinoma histologic variants present
• Plasmacytoma:
  • Positive for MUM1, CD45 / LCA
  • Negative for GATA3, keratins, uroplakin II
  • Cannot use CD138 to differentiate, as PUC is often positive for it
• Metastatic signet ring adenocarcinoma:
  • Positive for extracellular mucin
  • Negative for GATA3, uroplakin II (Am J Surg Pathol 2017;41:1570)
• Metastatic lobular breast carcinoma:
  • Negative for uroplakin II (Am J Surg Pathol 2017;41:1570)
  • Positive for ER
  • Cannot use GATA3 or loss of E-cadherin to differentiate
• Chronic inflammation:
  • More dysplasia in PUC
  • Polymorphous inflammatory infiltrate in chronic inflammation
• Lymphoma:
  • Positive for CD45 / LCA
  • Negative for GATA3, keratins, uroplakin II
• Melanoma:
  • More cohesive growth, prominent nucleoli
  • Positive for S100, melanocytic markers (HMB45)
• Neuroendocrine carcinoma:
  • More cohesive growth
  • Positive for chromogranin, synaptophysin
• Paraganglioma:
  • More cohesive growth
  • Sustentacular S100 staining
• Rhabdomyosarcoma:
  • More cohesive growth
  • Negative for CK7, CK20
  • Positive for desmin

Which of the following is true regarding the histologic variant of urothelial carcinoma shown above?

1. Neoplastic cells usually express CD138
2. Mutations / loss of CDH1 are uncommon
3. Patients are less likely to present at an advanced stage compared with conventional urothelial carcinoma
4. Primary ureteral carcinoma of this variant is common
5. Neoplastic cells are usually positive for mucin

A. Neoplastic cells usually express CD138. The histologic variant of urothelial carcinoma shown above is the plasmacytoid variant, consisting of discohesive cells with eccentrically placed nuclei and abundant cytoplasm. The neoplastic cells are usually positive for CD138 (making choice A the correct answer). Choice B is false, as truncating CDH1 mutations are common, causing loss of E-cadherin. Choice C is false, as these patients are generally diagnosed at an advanced stage and thus, have a worse prognosis. Choice D is incorrect because the primary ureteral of the variant has rarely been reported. Choice E is false since the cells do not express mucin, making it possible to distinguish from metastatic signet ring cell adenocarcinoma. (Hum Pathol 2019;90:27, Int J Clin Exp Pathol 2012;5:601, Nat Genet 2016;48:356, Eur Urol Focus 2019;5:104, Urology 2017;102:143, Bladder Cancer 2020;6:71, Am J Case Rep 2018;19:158, Am J Surg Pathol 2008;32:752).

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Reference: Plasmacytoid

Which of the following immunoprofiles would be most helpful to differentiate primary plasmacytoid urothelial carcinoma of the bladder from metastatic lobular breast carcinoma?

1. CK7, E-cadherin
2. E-cadherin, uroplakin II
3. GATA3, CK7
4. GATA3, GCDFP-15
5. Uroplakin II, ER

E. Uroplakin II, ER. Membranous loss of E-cadherin will be seen in both lobular breast carcinoma and plasmacytoid UC. GATA3 and CK7 are usually expressed by both. GCDFP-15 can be positive in some cases of plasmacytoid UC (~25% in 1 study) and also positive in lobular breast carcinoma. ER is positive in most cases of lobular breast carcinoma and negative in plasmacytoid UC. Uroplakin II is negative in lobular breast carcinoma and may be positive in plasmacytoid UC. Overall, given these patterns, the immunoprofile most likely to discriminate between the 2 are uroplakin II and ER (choice E). (Breast Cancer Res 2015;17:12, Hum Pathol 2019;90:27, BMC Urol 2020;20:72, Ann Diagn Pathol 2015;19:6, Am J Surg Pathol 2017;41:1570, Cancers (Basel) 2021;13:3695, BMC Cancer 2014;14:546, Am J Clin Pathol 2017;147:500).

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Reference: Plasmacytoid

Which panel of immunohistochemical stains would be most helpful to distinguish plasmacytoid urothelial carcinoma from its mimickers at other primary sites?

1. CD138, CK20, CK7, ER, PR
2. CD138, CK20, CDX2, GCDFP-15
3. p63, GATA3, E-cadherin
4. GATA3, mammaglobin, ER, Uroplakin II

D. GATA3, mammaglobin, ER, Uroplakin II. A panel including GATA3, mammaglobin, ER and uroplakin II would be helpful. GATA3, more so than p63, is positive in plasmacytoid urothelial carcinoma (PUC) and while it does not differentiate between breast and urothelial origin, is helpful in ruling out gastrointestinal metastases. Mammaglobin and ER are consistently negative in PUC, which helps differentiate PUC from breast metastasis, particularly lobular carcinoma, which is more often ER positive. UroplakinII is helpful as it is negative in nonurothelial mimickers. CD138 has been reported to be positive in PUC although it is nonspecific with expression reported in squamous cell carcinoma, normal urothelium and other epithelial and lymphoid malignancies (Int J Surg Pathol 2016;24:614). E-cadherin expression is typically abnormal in both PUC and breast lobular carcinoma, which includes complete absence of staining or aberrant cytoplasmic staining. Of note, E-cadherin staining was normal in 27% of PUC cases in a recent study (Hum Pathol 2020;102:54).

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Reference: Plasmacytoid