Histologic Variants of Urothelial Carcinoma

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Histologic Variants of Urothelial Carcinoma

• Medical College of Georgia
• 12/04/2006

Jeremy S. Miller, MD
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Histologic variants of urothelial carcinoma
differential diagnosis and clinical implications
Antonio Lopez-Beltran MD and Liang Cheng
MD Cordoba University Medical School, Cordoba,
Spain Indiana University School of Medicine,
Indiana
Human Pathology (November 2006) Volume 37,
1371-1388
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Why is this important?

• A wide array of histologic variants of urothelial
  carcinoma have been recognized in recent years
• The principal danger is the misinterpretation of
  these cancer variants as benign
• Also, some variants require a specific
  therapeutic approach

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Background

• Urothelial carcinoma (TCC) is the most common
  tumor of the urinary bladder (90 of tumors)
• Propensity for divergent differentiation
• 1. Squamous 2. Glandular
• A variety of histologic patterns can be seen in
  an individual TCC, mimicking the following benign
  lesions
• Brunns nests, cystitis cystica and glandularis
• Inverted papilloma
• Paraganglioma
• Nephrogenic metaplasia (aka nephrogenic adenoma)

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Brunns nests
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Cystitis cystica
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Cystitis glandularis
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Intestinal metaplasia
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Inverted papilloma
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Paraganglioma
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Nephrogenic metaplasia
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TCC Variants

• Nested
• Inverted papilloma-like
• Micropapillary
• Microcystic
• Lymphoepithelioma-like (LELC)
• Plasmacytoid
• Clear cell (glycogen-rich)
• Lipoid cell
• TCC w/ syncytiotrophoblastic giant cells
• Sarcomatoid carcinoma
• Small cell
• Mixed (Specify type and )
• Large cell undifferentiated
• TCC w/ unusual stromal reaction

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Nested variant

• Aggressive
• Male predominance
• Deceptively benign closely resembles Brunns
  nests in the lamina propria
• Majority of lesion often shows little nuclear
  atypia however, malignant cytology is a
  requirement and is often most apparent deep in
  the nests

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Nested pattern TCC
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Nested pattern TCC
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Nested variant

• Differential Diagnosis
• Hyperplasia of Brunns nests
• Cystitis cystica, glandularis
• Inverted papilloma
• Nephrogenic metaplasia
• Carcinoid tumor
• Paraganglioma

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Inverted papilloma-like variant

• By definition, this is an inverted papilloma with
  significant nuclear pleomorphism, mitotic
  figures, architectural abnormalities, and high
  proliferation index (PI) via Ki-67 labeling
• Inverted papilloma with atypia As above with
  rare mitoses and low PI via Ki-67
• Prognosis unclear however, likelihood of
  metastases appears to be minimal

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Inverted pattern TCC
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Inverted pattern TCC
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Micropapillary variant

• Male predominance mean age 66 years
• Resembles serous carcinoma of the ovary
• Extremely rare for this pattern to be found alone
• When present as gt 10 of the overall pattern,
  muscular or vascular invasion is likely (and
  metastases are the norm)
• Cells have reversed polarity
• MUC1 expression on the basal aspect of cells is
  both specific diagnostically and responsible for
  the high rate of metastases

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Micropapillary pattern TCC
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Micropapillary pattern TCC
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Micropapillary pattern TCC
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Micropapillary pattern TCC
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Micropapillary pattern TCC, metastatic to lymph
node
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Micropapillary variant

• Differential Diagnosis
• Metastatic serous carcinoma (CK20-)
• vs. micropapillary TCC (CK20)
• Metastatic mesothelioma (LeuM1 CD15 -)
• vs. micropapillary TCC (LeuM1 CD15 )

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Microcystic variant

• Formation of microcysts, macrocysts, and tubular
  structures that often contain necrotic debris or
  mucin
• Prognosis similar to standard TCC
• Preferred name is now
• Urothelial carcinoma with gland-like lumina

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Microcystic pattern TCC
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Bladder Adenocarcinoma
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Microcystic variant

• Differential diagnosis
• Adenocarcinoma
• Florid cystitis cystica, glandularis
• Nephrogenic metaplasia
• Metastatic prostate adenocarcinoma
• Use PSA, PAP

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Lymphoepithelioma-like variant (LELC)

• Male predominance mean age 69 years
• Resembles lymphoepithelioma of nasopharynx (but
  not related to EBV)
• Nests, sheets, and cords of cells with
  significant pleomorphism in a background of a
  polyclonal lymphoid stroma
• High grade, but responsive to high-dose
  chemotherapy

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LELC
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LELC
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SCCA, bladder
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Lymphoepithelioma-like variant (LELC)

• Differential diagnosis
• Poorly-differentiated TCC with lymphoid stroma
• Poorly-differentiated SCCA
• Neither of the above will have the syncytial
  pattern required for a diagnosis of LELC

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Plasmacytoid variant

• Male predominance mean age 58 years
• Diffuse, high-grade and stage tumors composed of
  medium-sized cells with eosinophilic cytoplasm
  and eccentric nuclei
• Cells keratin positive, CD138 negative
• Mean survival less than 2 years

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Plasmacytoid variant
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Pankeratin
Plasmacytoid variant
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Lymphoma, bladder
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Plasmacytoid variant

• Differential diagnosis
• Lymphoma (predominantly plasmacytoid type)
• Myeloma
• Staining with epithelial markers required

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Clear cell (glycogen-rich) variant

• Clear cell change is common in TCC (reportedly
  present in over 60 of all cases)
• Cytoplasmic clearing is a result of abundant
  glycogen
• Clear cell (glycogen-rich) variant is used when
  this is the predominant pattern and the cells
  stain for CK7

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Clear cell (glycogen-rich) variant
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PAS stain
Clear cell (glycogen-rich) variant
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Clear cell adenocarcinoma, bladder
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Clear cell (glycogen-rich) variant

• Differential diagnosis
• Clear cell adenocarcinoma
• Metastatic clear cell carcinoma of the kidney
• Paraganglioma

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Lipoid cell variant

• Male predominance mean age 74 years
• High-grade and -stage urothelial carcinomas with
  areas of cells resembling signet ring lipoblasts
• Lipoid cells must stain for epithelial markers

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Lipoid cell variant
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Lipoid cell variant

• Differential diagnosis
• Carcinosarcoma with liposarcomatous component
• Reactivity of the lipoid cells for epithelial
  markers can be used in this setting

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TCC with syncytiotrophoblastic giant cells

• Syncytiotrophoblastic giant cells, which produce
  ß-HCG to varying degrees, can be found in up to
  10 of TCCs
• Radiation treatment is useful
• Serum levels of ß-HCG are used to monitor
  response to radiation therapy

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TCC with syncytiotrophoblastic giant cells
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Choriocarcinoma, metastatic to bladder
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TCC with osteoclast-like giant cells
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TCC with syncytiotrophoblastic giant cells

• Differential Diagnosis
• Choriocarcinoma (ß-HCG and HPL)
• Metastatic - uncommon
• Primary - exceedingly rare (lt 10 cases reported)
• Sarcomatoid carcinoma of bladder with
  trophoblastic differentiation
• TCC with osteoclast-like giant cells

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Sarcomatoid carcinoma

• Mean age 66 years
• Biphasic malignant neoplasms with both epithelial
  and mesenchymal components
• Also known by many previous and current names
• Carcinosarcoma
• Pseudosarcomatous TCC
• MMMT
• Spindle cell carcinoma
• Metaplastic carcinoma
• Previous history of carcinoma treated with
  radiation or cyclophosphamide is common
• Whether or not the tumor harbors heterologous
  elements should be a component of the final report

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Sarcomatoid carcinoma

• Epithelial component
• Urothelium
• Squamous
• Glandular
• Small cell
• Large cell neuroendocrine (rare)
• Mesenchymal component
• Undifferentiated high grade spindle cell (most
  common)
• Osteosarcoma, chondrosarcoma, rhabdomyosarcoma,
  leiomyosarcoma, liposarcoma, angiosarcoma

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Sarcomatoid carcinoma
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Leiomyosarcoma
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Sarcomatoid carcinoma

• Differential Diagnosis
• TCC with pseudosarcomatous stroma
• Reactive, polyclonal stroma
• Sarcoma
• Primarily leiomyosarcoma
• Inflammatory myofibroblastic tumor (ALK-1)
• Neurofibroma

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Small cell variant

• Male predominance mean age 66 years
• Malignant cells with neuroendocrine features
• Mitoses and necrosis common
• Recent molecular evidence has indicated that
  small cell carcinoma and TCC are derived from the
  same clonal population most authors now
  consider this a variant of TCC rather than a
  separate entity

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Small cell variant

• Dismal prognosis, regardless of treatment
• Recent study of 64 patients
• 98 had muscle-invasive disease at presentation
• 66 had lymph node metastases at cystectomy
• 32 pure, 68 mixed with TCC, SCCA, others
• Genetically unstable commonly exhibit multiple
  cytogenetic abnormalities
• 3 year survival is 23

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Small cell variant
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Small cell variant

• Differential diagnosis
• Metastatic small cell carcinoma from another site
  (predominantly lung)
• Lymphoma
• LELC
• Plasmacytoid variant of TCC

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Mixed variant

• Squamous and/or glandular differentiation is
  found in over 20 of TCCs
• These mixed variants have a less favorable
  response to therapy, and have a higher recurrence
  rate

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Squamous differentiation (elsewhere this tumor
had TCC)
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Glandular differentiation (elsewhere this tumor
had TCC)
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Mixed variant

• Differential diagnosis
• Squamous cell carcinoma, bladder
• Adenocarcinoma, bladder
• Metastases
• All of the above will have, by definition, no
  urothelial component to the tumor

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Large cell undifferentiated

• Rare, high-grade and stage tumors with large
  undifferentiated cells
• Reactivity with epithelial and mesenchymal
  markers are inconsistent
• Prognosis extremely poor, regardless of therapy

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Large cell undifferentiated carcinoma
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Large cell undifferentiated

• Differential diagnosis
• Sarcomatoid carcinoma with giant cells
• Metastatic large cell carcinoma (often lung
  primary)
• TCC with syncytiotrophoblastic giant cells
• TCC with osteoclast-like giant cells

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Unusual stromal reaction

• Invasive TCCs often have a significant stromal
  reaction
• Osseous and/or chondroid metaplasia can sometimes
  be found, but will be histologically benign
• Osteoclast-like giant cells have been noted in a
  subset of TCCs these seem to have no effect on
  prognosis
• Intense mononuclear inflammation is indicative of
  a better prognosis when compared to TCCs with no
  inflammation

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Pseudosarcomatous stroma
Osseus metaplasia
Osteoclast-like giant cells
Lymphoid infiltrate
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Unusual stromal reaction

• Differential diagnosis
• Sarcoma
• Sarcomatoid carcinoma
• TCC with syncytiotrophoblastic giant cells
• LELC

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Rare variants

• Some TCCs mimic morphology usually found in other
  organs
• Infiltrating lobular carcinoma of the breast
• Diffuse gastric carcinoma
• All express bladder markers rather than breast or
  gastric markers

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TCC mimicking lobular carcinoma of the breast
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Summary TCC variants

• POOR PROGNOSIS/ AGGRESSIVE
• Nested
• Micropapillary
• Plasmacytoid
• Lipoid cell
• Sarcomatoid carcinoma
• Small cell
• Large cell undifferentiated
• SIMILAR PROGNOSIS TO TCC/ RECOGNITION IS KEY
• Inverted papilloma-like
• Microcystic
• Lymphoepithelioma-like (LELC)
• Clear cell (glycogen-rich)
• TCC w/ syncytiotrophoblastic giant cells
• Mixed (Specify type and )
• TCC w/ unusual stromal reaction