Overview of Invasive Carcinoma Subtypes



Overview of Invasive Carcinoma Subtypes


Jesse K. McKenney, MD

Mahesha Vankalakunti, MD

Mahul B. Amin, MD








Invasive urothelial carcinoma may show glandular differentiation that is morphologically identical to adenocarcinoma. The presence of a component of conventional urothelial carcinoma is distinctive.






The nested variant of urothelial carcinoma is cytologically bland, but the presence of irregularly distributed nests throughout the lamina propria and the complex epithelial growth is diagnostic.


TERMINOLOGY


Definitions



  • Invasive urothelial carcinoma (UC) with morphology distinct from usual or typical pattern


CLINICAL IMPLICATIONS


Gender



  • Variants are most common in older men



    • Similar to urothelial carcinoma in general


Clinical Presentation



  • Hematuria most common


Treatment



  • Urothelial carcinoma variants are treated similarly to conventional urothelial carcinoma with some exceptions



    • Small cell carcinoma treated by separate chemotherapy regimen


    • Pure lymphoepithelioma-like carcinoma may be more responsive to chemotherapy


    • Micropapillary carcinoma may be treated surgically at low stage (pT1) in some centers


    • Urothelial carcinoma with squamous differentiation is less responsive to adjuvant therapy


Prognosis



  • Variant invasive urothelial carcinomas have poor prognosis



    • Generally present at high stage


    • Uncertain whether prognosis is worse than urothelial carcinoma of similar stage in some variants


MACROSCOPIC FINDINGS


General Features



  • Typically large infiltrative mass lesion


UC WITH ALTERNATIVE/ABERRANT DIFFERENTIATION


Microscopic Features



  • By definition, contains component of typical papillary, in situ, or invasive urothelial carcinoma at least focally



    • Squamous differentiation



      • Keratinization and intracellular bridges


      • May be focal or extensive


    • Glandular differentiation



      • Glandular component identical to adenocarcinoma


    • Trophoblastic differentiation



      • Scattered syncytiotrophoblasts within high-grade urothelial carcinoma


      • Rarely choriocarcinomatous differentiation


NESTED CARCINOMA


Microscopic Features



  • Nests of infiltrative tumor cells with relatively bland cytologic appearance



    • Irregular infiltrating border with lamina propria is characteristic


    • Muscularis propria is commonly involved


    • Tumor nests often have some degree of complex anastomosis at least focally


    • Invasion with surrounding retraction may be present focally


    • Generally show increasing levels of atypia toward deeper portions of tumor



    • May be admixed with urothelial carcinoma with small tubules


Differential Diagnosis



  • von Brunn nests



    • More rounded urothelial nests


    • Lobular configuration


    • Superficial location with sharp border at deep interface with lamina propria


  • Cystitis cystica/glandularis



    • More superficially located


    • Also has sharp border at interface with lamina propria


  • Nephrogenic adenoma



    • More tubular appearance


    • Prominent basement membranes may surround tubules


    • Lining epithelium may have “hobnail” appearance


    • Other admixed patterns may be present: Papillary, solid/diffuse, cystic


UC WITH SMALL TUBULES


Microscopic Features



  • Invasive carcinoma with small gland-like spaces lined by urothelial cells



    • No intracellular mucin


    • No columnar lining


  • May be admixed with nested variant



    • Same differential considerations as nested variant


MICROCYSTIC CARCINOMA


Microscopic Features



  • Dilated microcysts in invasive component



    • Microcysts may reach 1-2 mm in diameter


    • Urothelial lining


  • May be associated with nested variant


Differential Diagnosis



  • Urothelial carcinoma with glandular differentiation



    • Glandular component lined by columnar cells or has abundant intracytoplasmic mucin


  • Nephrogenic adenoma



    • More superficial location


    • No destructive invasion


  • Cystitis cystica/glandularis



    • Sharp linear base at junction with lamina propria


  • Müllerianosis



    • Endocervical, tubal, or endometrial-type glands


    • Bland cytologic features


PLASMACYTOID CARCINOMA


Microscopic Features



  • Malignant cells closely resemble plasma cells set in myxoid or loose edematous stroma



    • Eccentric nuclei


    • Abundant glassy eosinophilic cytoplasm


  • Clusters of neoplastic cells may be surrounded by retraction spaces


  • Concomitant conventional urothelial carcinoma may be admixed


  • Often have more extensive spread in abdominal cavity than other variants of urothelial carcinoma


Differential Diagnosis



  • Plasmacytoma and lymphoma



    • Plasmacytoid carcinoma may express CD138


    • Strong cytokeratin reactivity supports carcinoma


    • Evaluation of κ and λ ratio may be helpful


MICROPAPILLARY CARCINOMA


Microscopic Features



  • Small nests and papillae with surrounding retraction spaces



    • Resembles ovarian serous carcinoma


    • Confluent retraction spaces are characteristic


    • Multiple nests in same retraction space is common


  • Although nuclear grade is typically high, may also have relatively low-grade appearance


  • Most are muscle invasive with vascular invasion



    • CD31, CD34, and Podoplanin(D2-40) may help to distinguish true lymphatic invasion from retraction artifact


  • Immunohistochemically, tumor is reactive for EMA/MUC1, CK7, CK20



    • Immunoreactivity for HER2 and CA125 may also be seen


Differential Diagnosis



  • Ovarian serous carcinoma



    • Clinical/radiographic correlation is needed


    • Immunohistochemical expression of ER and WT1 is common in ovarian primary


  • Typical invasive urothelial carcinoma with stromal retraction



    • Larger nests


    • Does not typically show multiple small nests in same retraction space


    • Significant immunophenotypic overlap with micropapillary carcinoma: May also express EMA/MUC1, CA125, and HER2


    • In some cases, distinction may be very difficult


LYMPHOEPITHELIOMA-LIKE CARCINOMA


Microscopic Features



  • Resembles undifferentiated carcinomas of nasopharynx



    • Individual neoplastic cells arranged in syncytia with obscuring chronic inflammation



      • Cytoplasmic borders are most often indistinct


      • Inflammation consists of a mixture of polyclonal B and T lymphocytes, histiocytes, eosinophils, and plasma cells


  • Pure forms are reportedly more responsive to chemotherapy



    • Percentage of lymphoepithelioma-like areas should be reported



Differential Diagnosis



  • Lymphoma or chronic inflammation



    • CD45(LCA) reactivity in neoplastic cells


    • No cytokeratin-positive population


  • Small cell carcinoma



    • Neuroendocrine chromatin features


    • Cellular molding


    • High mitotic and apoptotic index


    • Coexpress cytokeratin and synaptophysin


    • May also express TTF-1


SMALL CELL CARCINOMA


Microscopic Features



  • Sheets and occasionally nests of cells with scant cytoplasm and high nuclear/cytoplasmic ratio



    • Chromatin is finely stippled, and nucleoli are inconspicuous


    • Geographic areas of necrosis, high mitotic rate, and areas of crush artifact are also frequent


  • Other subtypes of primary bladder carcinoma may be admixed



    • Urothelial carcinoma in situ, invasive urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, or sarcomatoid carcinoma


    • Identical pattern of allelic loss in small cell carcinoma and adjacent conventional urothelial carcinoma suggest shared lineage


  • Highly aggressive clinical behavior


  • Even focal small cell component should be reported


Differential Diagnosis



  • Metastatic small cell carcinoma



    • Histologically and immunophenotypically indistinguishable unless conventional urothelial carcinoma is present


    • CK7(+)/CK20(-) phenotype common


    • Both metastases and primary tumors may express TTF-1


  • Lymphoma



    • Express hematopoietic markers


    • Cytokeratin negative


  • Poorly differentiated urothelial carcinoma



    • Does not express synaptophysin or chromogranin


  • Rhabdomyosarcoma



    • May express synaptophysin


    • Nuclear myogenin reactivity diagnostic of skeletal muscle differentiation


SARCOMATOID UC


Microscopic Features



  • Neoplasms containing both epithelial and mesenchymal differentiation by morphology or immunohistochemistry



    • Epithelial component may be any subtype of bladder carcinoma



      • Urothelial carcinoma in situ, invasive urothelial carcinoma, squamous cell carcinoma, or adenocarcinoma


    • Mesenchymal component usually has high-grade spindle cell morphology


    • Heterologous elements may be present



      • Osteosarcoma, chondrosarcoma, and rhabdomyosarcoma


  • Immunohistochemical expression of HMCK(34βE12) and p63 in both epithelial and spindled component


Differential Diagnosis



  • Pseudosarcomatous myofibroblastic proliferation



    • Fine nuclear chromatin


    • Actin expression common


    • In contrast to carcinoma, cytokeratin expression limited to low molecular weight forms


    • Does not express p63


    • Subset expresses ALK1 by immunohistochemistry


  • Primary leiomyosarcoma



    • Expresses desmin and actin


    • In contrast to carcinoma, cytokeratin expression limited to low molecular weight forms


    • Up to 23% express p63


  • Other primary vesical sarcoma



    • No carcinomatous component or recent history of urothelial carcinoma


    • Nonepithelial immunophenotype


UNDIFFERENTIATED UC WITH OSTEOCLAST-LIKE GIANT CELLS


Microscopic Features



  • Prominent osteoclast-type giant cells are seen in rare undifferentiated carcinomas



    • Giant cells are histiocytic in origin


  • Background spindled and mononuclear cells are cytokeratin positive


UC WITH RHABDOID FEATURES


Microscopic Features



  • Very rare morphologic subtype


  • Neoplastic cells with large vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasmic inclusions



    • Resembles malignant extrarenal rhabdoid tumor


    • Does not have deletion of INI1 at 22q11


    • Usually adult tumor, unlike malignant extrarenal rhabdoid tumor


  • Very aggressive clinical course


UC WITH MYXOID STROMA


Microscopic Features



  • Typical urothelial carcinoma almost always present


  • Prominent myxoid stroma



    • Proportion of tumor highly variable


  • Neoplastic cells may “float” in myxoid matrix in aggregates or chains



    • Small round cells with eosinophilic cytoplasm are common


Differential Diagnosis



  • Myxoid sarcoma




    • Urothelial carcinomas with myxoid stroma maintain epithelial immunophenotype


UC WITH CLEAR CYTOPLASM (GLYCOGEN RICH)


Microscopic Features



  • Abundant clear cytoplasm secondary to glycogen accumulation


  • Typically focal pattern in otherwise typical urothelial carcinoma


Differential Diagnosis



  • Renal cell carcinoma



    • Obvious renal mass present


    • Expression of pax-2 may be seen


  • Clear cell adenocarcinoma, primary or gynecologic



    • Distinct mixed tubulocystic and papillary pattern with “hobnail” cells typical


UC WITH LIPOID FEATURES (LIPID-RICH/LIPID CELL)


Microscopic Features



  • Rare urothelial carcinomas have foci with intracellular lipid



    • Closely resemble lipoblasts


  • Most admixed with typical urothelial carcinoma


  • Maintain cytokeratin immunoreactivity, even in lipid-rich cells


Differential Diagnosis



  • Primary liposarcoma



    • Lack component of typical urothelial carcinoma


    • Epithelioid variant of pleomorphic liposarcoma is close mimic that may express keratin


  • Sarcomatoid urothelial carcinoma with heterologous liposarcoma



    • Usually has pleomorphic spindled component


    • Lipoblasts do not express cytokeratin


    • Other heterologous components may be admixed


  • Signet ring cell adenocarcinoma



    • Smaller cells with single intracytoplasmic vacuoles


    • Often infiltrate as individual cells


LARGE CELL UNDIFFERENTIATED CARCINOMA


Microscopic Features



  • Poorly differentiated pleomorphic carcinoma without histologic features typical of urothelial carcinoma


Differential Diagnosis



  • Lymphoma



    • Expresses hematopoietic markers


  • Secondary carcinoma from another anatomic site



    • Requires clinical correlation


  • Melanoma



    • Expresses S100


DIFFERENTIAL DIAGNOSIS


Secondary Carcinomas from Nonbladder Sites



  • Variant morphologic patterns of urothelial carcinoma may suggest nonbladder primary


  • Most urothelial carcinoma variants maintain urothelial immunophenotype



    • CK7 and CK20 coexpression common


    • Express HMCK(34βE12)


    • Nuclear p63 reactivity


DIAGNOSTIC CHECKLIST


Pathologic Interpretation Pearls



  • Variant morphology carcinoma: Primary carcinoma involving bladder and not conforming to morphology of typical urothelial carcinoma


  • Variant histology must be documented, including percentage, if not pure in histology



    • Variant histology may present at metastatic site; facilitates association with bladder primary


  • Variant histology may have diagnostic, prognostic, or therapeutic significance


  • Metastatic carcinoma or carcinoma secondarily involving bladder must be ruled out in all cases



SELECTED REFERENCES

1. Amin MB: Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 22 Suppl 2:S96-S118, 2009

2. Nigwekar P et al: Plasmacytoid urothelial carcinoma: detailed analysis of morphology with clinicopathologic correlation in 17 cases. Am J Surg Pathol. 33(3):417-24, 2009

3. Drew PA et al: The nested variant of transitional cell carcinoma: an aggressive neoplasm with innocuous histology. Mod Pathol. 9(10):989-94, 1996

4. Amin MB et al: Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol. 18(12):1224-32, 1994

5. Young RH et al: Unusual forms of carcinoma of the urinary bladder. Hum Pathol. 22(10):948-65, 1991






Image Gallery




Carcinoma with Squamous and Glandular Differentiation






(Left) Invasive urothelial carcinomas may show squamous differentiation. The cytoplasm is more eosinophilic than typical urothelial carcinoma, and keratin formation image is seen. These carcinomas are frequently associated with a florid stromal myofibroblastic proliferation image. The presence of typical urothelial carcinoma precludes a diagnosis of primary squamous cell carcinoma. (Right) Squamous differentiation with keratin formation image may also be seen in the noninvasive component.






(Left) Focal keratin formation image is seen in this example of urothelial carcinoma with squamous differentiation. (Right) Keratin pearl formation image is the prototypical feature of squamous differentiation. In contrast to primary squamous cell carcinoma, urothelial carcinoma with squamous differentiation has areas of conventional papillary, invasive, or in situ urothelial carcinoma. In addition, primary squamous cell carcinoma arises in a background of squamous metaplasia/dysplasia.

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Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Overview of Invasive Carcinoma Subtypes

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