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Bladder & urothelial tract

Neuroendocrine neoplasms

Small cell neuroendocrine carcinoma


Editorial Board Member: Debra L. Zynger, M.D.
Deputy Editor-in-Chief: Maria Tretiakova, M.D., Ph.D.
Hunter Monroe, B.S.
Reima El Naili, M.D.

Last author update: 15 January 2024
Last staff update: 5 February 2024

Copyright: 2003-2024, PathologyOutlines.com, Inc.

PubMed Search: Small cell neuroendocrine carcinoma

Hunter Monroe, B.S.
Reima El Naili, M.D.
Page views in 2023: 703
Page views in 2024 to date: 3,290
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Monroe H, El Naili R. Small cell neuroendocrine carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bladdersmallcell.html. Accessed April 18th, 2024.
Definition / general
  • High grade neuroendocrine neoplasm characterized by small to medium sized cells with high N:C ratio and indistinct nucleoli arising from urothelium of urinary bladder, renal pelvis and ureters
Essential features
  • Histologically characterized by small to medium sized cells with scant cytoplasm, large nuclei with absent or inconspicuous nucleoli, finely granular salt and pepper chromatin, nuclear molding, Azzopardi phenomenon (crush artifact), abundant mitoses and often pervasive necrosis
  • In the genitourinary tract, small cell neuroendocrine carcinoma most commonly arises from the bladder and less commonly from the renal pelvis and ureters
  • Usually shows mixed histology; a concomitant urothelial carcinoma, adenocarcinoma or other carcinomatous / sarcomatous component(s) is common
  • Typically reaches advanced clinical stage characterized by muscularis propria invasion, lymphovascular invasion or distant metastases by time of diagnosis and is thus associated with a poor prognosis
  • Treatment regimens are variable but surgical resection with platinum agent based neoadjuvant or adjuvant chemotherapy is most commonly implemented
Terminology
  • Small cell neuroendocrine carcinoma (preferred terminology)
  • Small cell carcinoma
  • Oat cell carcinoma (no longer in use)
ICD coding
  • ICD-10
    • C65 - malignant neoplasm of renal pelvis
      • C65.1 - malignant neoplasm of right renal pelvis
      • C65.2 - malignant neoplasm of left renal pelvis
      • C65.9 - malignant neoplasm of unspecified renal pelvis
    • C66 - malignant neoplasm of ureter
      • C66.1 - malignant neoplasm of right ureter
      • C66.2 - malignant neoplasm of left ureter
      • C66.9 - malignant neoplasm of unspecified ureter
    • C67 - malignant neoplasm of bladder
      • C67.1 - malignant neoplasm of trigone of bladder
      • C67.2 - malignant neoplasm of lateral wall of bladder
      • C67.3 - malignant neoplasm of anterior wall of bladder
      • C67.4 - malignant neoplasm of posterior wall of bladder
      • C67.5 - malignant neoplasm of bladder neck
      • C67.6 - malignant neoplasm of ureteric orifice
      • C67.7 - malignant neoplasm of urachus
      • C67.8 - malignant neoplasm of overlapping sites of bladder
      • C67.9 - malignant neoplasm of bladder, unspecified
Epidemiology
Sites
Pathophysiology
  • Transdifferentiation / dedifferentiation of urothelial carcinoma (iScience 2020;23:101201, Clin Cancer Res 2018;24:1965)
    • BRCA1 / BRCA2, TP53 and RB1 with or without APOBEC mutations create high mutation rate and predisposition to malignancy in basal subtype conventional urothelial carcinoma
    • Urothelial to neural plasticity and activation of epithelial - mesenchymal transition
      • Urothelial to neural plasticity: downregulation of genes responsible for urothelial differentiation and upregulation of genes responsible for neural / neuroendocrine differentiation
      • Activation of epithelial mesenchymal transition: downregulation of p53 and p63 pathways in addition to loss of epithelial adhesion molecules (E-cadherin, claudin1, tight junction protein 1)
    • Overexpression of ADORA2A (adenosine receptor 2A) and loss of expression of immunostimulatory genes leads to immune desert phenotype
  • Other theories regarding pathogenesis
    • Multipotent / pluripotent stem cell in urothelium differentiates into small cell neuroendocrine carcinoma and other common bladder carcinomas (i.e., shares same clonal cell of origin as other bladder carcinomas) (Hum Pathol 2018;79:57)
    • Malignant transformation of endemic Kulchitsky or enterochromaffin cells in urothelial mucosa or submucosa (Hum Pathol 2018;79:57)
Etiology
  • Smoking
  • Other proposed etiologies in bladder (Mol Clin Oncol 2018;9:335)
    • Chronic cystitis
    • Bladder calculi
    • History of cystoplasty
Clinical features
Diagnosis
  • Urinalysis
  • Urine / bladder washing cytology (Oncol Lett 2014;7:369)
  • Cystoscopy
  • Imaging (Clujul Med 2017;90:13)
    • Ultrasound (US): usually first line and may identify hydronephrosis
    • Computerized tomography (CT): identifies masses and tumoral extension
    • Magnetic resonance imaging (MRI): used to identify extravesical or extranephroureteric extension and distant metastases
      • Gadolinium enhanced MRI: may identify brain metastases
    • 99mTc MDP bone scan may identify bone metastases
  • Transurethral resection of the bladder (TURBT) or resection for confirmation
Laboratory
Radiology description
Radiology images

Images hosted on other servers
CT Bladder

CT of bladder

CT Ureter

CT of ureter

US Bladder

US of bladder

MRI Bladder

MRI of bladder

Gadolinium enhanced MRI Renal Pelvis

Gadolinium enhanced MRI of renal pelvis

Prognostic factors
Case reports
Treatment
Gross description
Gross images

Images hosted on other servers:
Right ureter mass

Right ureter mass

Renal pelvic lesion

Renal pelvic lesion

Microscopic (histologic) description
  • General histologic features (Pol J Pathol 2014;65:15)
    • Solid sheet-like, nested and trabecular architectures
    • Small to medium sized cells with scant cytoplasm and large round to oval nuclei (i.e., high N:C ratio)
    • Finely granular, stippled salt and pepper chromatin
    • Absent or inconspicuous nucleoli
    • Nuclear molding
    • Azzopardi phenomenon (crush artifact)
    • Brisk mitotic activity and atypical mitoses
    • Extensive, often geographic necrosis
  • Frequently coexists with other malignant cell populations
    • Prevalence of additional histologic components (Hum Pathol 2018;79:57)
      • Urothelial carcinoma (59%)
      • Urothelial carcinoma in situ (48%)
      • Adenocarcinoma (26%)
      • Sarcomatoid carcinoma (7.4%)
      • Micropapillary carcinoma (7.4%)
      • Squamous cell carcinoma (5.6%)
      • Plasmacytoid carcinoma (1.9%)
      • Sarcomas (chondrosarcoma, leiomyosarcoma and rhabdomyosarcoma) have been described in rare case reports (Onco Targets Ther 2017;10:4105)
      • Lymphoma described in 1 case report (Onco Targets Ther 2017;10:4105)
    • May be triphasic or even tetraphasic in rare cases (World J Surg Oncol 2017;15:33)
Microscopic (histologic) images

Contributed by Reima El Naili, M.D.
Sheets of basophilic cells.

Sheets of basophilic cells

Pleomorphism and nuclear molding.

Pleomorphism and nuclear molding

High N:C ratio.

High N:C ratio

Brisk mitotic activity.

Brisk mitotic activity

Hemorrhage and atypical mitoses.

Hemorrhage and atypical mitoses

Necrosis and Azzopardi effect.

Necrosis and Azzopardi effect



Mixed urothelial neuroendocrine carcinoma.

Mixed urothelial neuroendocrine carcinoma

Carcinoma with normal urothelium.

Carcinoma with normal urothelium

CK AE1 / AE3.

CK AE1 / AE3

Synaptophysin.

Synaptophysin

CD56.

CD56

TTF1.

TTF1



Ki67.

Ki67

CD56 in mixed tumor.

CD56 in mixed tumor

GATA3 in mixed tumor.

GATA3 in mixed tumor

INSM1.

INSM1

Cytology description
  • Reciprocates histologic features, including small to medium cell size, scant cytoplasm, round to oval nuclei, salt and pepper chromatin and nuclear molding
  • Cells are most commonly arranged into small clusters
  • Variable abundance or paucity of tumor cells
  • Inflammatory background primarily comprised of neutrophils
  • Tumor diathesis may be present
  • Limitation: additional histologic component, especially high grade urothelial carcinoma, may obfuscate the diagnosis
  • Reference: Oncol Lett 2014;7:369
Cytology images

Contributed by Bonnie Choy, M.D.
Hypercellular specimen

Hypercellular specimen



Images hosted on other servers
Bladder, pap

Bladder, Pap

Positive stains
Negative stains
Electron microscopy description
Molecular / cytogenetics description
Videos

Bladder small cell neuroendocrine carcinoma

Sample pathology report
  • Bladder, lateral wall, transurethral resection:
    • Small cell neuroendocrine carcinoma with invasion into muscularis propria (see comment)
    • Comment: The tumor consists of cohesive, small blue cells with nuclear molding and extensive necrosis. The tumor cells are positive for CK AE1 / AE3 (moderate, dot-like), synaptophysin (strong, diffuse), chromogranin A (moderate, diffuse), INSM1 (strong, diffuse) and TTF1 (strong, diffuse). GATA3 is negative. Ki67 index is > 95%. Small cell neuroendocrine carcinoma of the urinary bladder is the primary consideration based on the anatomical site of the specimen and absence of evidence of pulmonary or other extrapulmonary site of origin. The findings above should be considered in the context of imaging and clinical history.

  • Bladder, posterior wall, transurethral resection:
    • Small cell neuroendocrine carcinoma mixed with high grade invasive urothelial carcinoma (see comment)
    • Comment: Histologic evaluation shows small cell neuroendocrine carcinoma and adjacent high grade urothelial carcinoma. The small cell neuroendocrine carcinoma component is positive for synaptophysin, INSM1, CD56 and chromogranin while negative for GATA3. In contrast, the urothelial carcinoma component is positive for GATA3 while negative for the aforementioned neuroendocrine markers.
Differential diagnosis
  • Large cell neuroendocrine carcinoma (Clujul Med 2017;90:13)
    • Shares high grade features including necrosis, mitotic activity and high Ki67 index
    • Comprised of larger polygonal cells
    • Lower N:C ratio with vesicular chromatin and prominent nucleoli
    • Positive for neuroendocrine markers
    • Diffuse cytoplasmic staining pattern of CAM5.2 and CK7
  • Metastatic pulmonary small cell neuroendocrine carcinoma:
    • Both entities may be positive for TTF1
    • Lacks TERT promoter mutation
    • Mixed histomorphology is rare
  • Metastatic prostatic small cell neuroendocrine carcinoma (Hum Pathol 2018;79:57):
    • Mixed histomorphology similar to small cell neuroendocrine carcinoma of urothelial origin may be present
    • Often arises in a setting of concomitant prostatic adenocarcinoma
    • PSA may be elevated
    • TMPRSS2::ERG fusion may be present
    • Lacks TERT promoter mutation
  • Well differentiated neuroendocrine tumor (Hum Pathol 2018;79:57):
    • In upper genitourinary tract, originates most commonly from kidneys
    • Histologically characterized by well defined cords, trabeculae and ribbons containing columnar or cuboidal tumor cells
    • Granular eosinophilic (oncocytic) cytoplasm is common
    • Substantially lower mitotic count and Ki67 index, especially if grade < 3
    • Necrosis is absent or less prominent
    • Also positive for neuroendocrine markers
  • Lymphoepithelioma-like carcinoma (Hum Pathol 2018;79:57):
    • Derivation of urothelial carcinoma characterized by large pleomorphic nuclei and prominent nucleoli, often with abundant mitoses
    • Cells are arranged into syncytial sheets with infiltration of epithelium by mixed inflammatory cells
    • Frequently mixed with other malignant cell populations
    • Positive for GATA3 and p63
    • Negative for neuroendocrine markers
  • Neuroblastoma (Pol J Pathol 2014;65:15):
    • Most commonly located in adrenal gland
    • Most common in kids
    • Serum and urine catecholamine assays may be positive
    • Differentiated type is characterized by Homer-Wright pseudorosettes containing central eosinophilic neurofilaments
    • Undifferentiated type is characterized by small to medium sized cells with scant cytoplasm, salt and pepper chromatin and prominent nucleoli may be present
      • Prominent nucleoli may be present
    • ALK1 may be positive in up to 90% of cases
    • May harbor N-MYC amplification
  • Ewing sarcoma (Pol J Pathol 2014;65:15):
    • Comprised of small round cells with sheet-like growth
    • Dense fibrous tissue often surrounds islands of tumor cells
    • Positive for CD99, FLI1 and NKX2.2
    • Variably positive for neuroendocrine markers (NSE is most common [50%])
    • Associated with pathognomonic EWSR1::FLI fusion
    • Elevated erythrocyte sedimentation rate (ESR) may be present
  • Pheochromocytoma / paraganglioma (Anticancer Res 2017;37:4529):
    • Classic clinical triad of episodic headaches, sweating and tachycardia in addition to palpitations, anxiety, paroxysmal hypertension and syncope
    • Serum and urine assays for catecholamine metabolites (e.g., VMA) may be positive
    • Comprised of nests (zellballen) or solid sheets of large polygonal cells with granular, red-purple cytoplasm
    • Chief cells are positive for neuroendocrine markers
    • Sustentacular cells are positive for S100 and often GATA3
    • Negative for cytokeratin stains
    • VHL, RET, NF1 and SDHB mutations may be present
  • Nephroblastoma / Wilms tumor (Pol J Pathol 2014;65:15):
    • Most common in kids
    • Monophasic blastema predominant type is histomorphologically similar
    • Focal epithelial and stromal components may be present
    • Blastema component is positive for WT1, PAX8 and vimentin
    • May be variably positive for CD56 but is negative for other neuroendocrine markers
  • Lymphoma (Pol J Pathol 2014;65:15, Case Rep Hematol 2015;2015:934374):
    • MALT lymphoma is the most common primary lymphoma of bladder
    • Nuclei are usually cleaved or lobulated
    • All lymphomas are positive for CD45 and often either CD3 or CD20
  • Desmoplastic small round cell tumor (Pol J Pathol 2014;65:15):
    • Comprised of nests and trabeculae of small uniform round cells abounded by diffuse desmoplastic stroma
    • Peripheral palisading may be observed
    • Solid pattern lacks desmoplastic stroma and may appear nearly identical to small cell carcinoma
    • Most common in kids and young adults
    • Positive for WT1, CD99, desmin and vimentin
    • EWSR1::WT1 fusion present
  • Melanoma (Pol J Pathol 2014;65:15):
    • Comprised of epithelioid or spindle tumor cells
    • Exhibits extensive nuclear pleomorphism with prominent eosinophilic nucleoli
    • Positive for melanocytic markers (S100, SOX10, HMB45 and MelanA)
  • Embryonal rhabdomyosarcoma (Pol J Pathol 2014;65:15):
    • Most common in kids and infants
    • Nuclear molding may be prominent
    • Mixed hypercellular and hypocellular areas are usually present
    • Typically harbors eosinophilic (rhabdoid) or clear cytoplasm
    • May harbor striations consistent with rhabdoid differentiation
    • Positive for desmin, myogenin, MyoD1 and vimentin
  • Poorly differentiated synovial sarcoma (Pol J Pathol 2014;65:15, Pathol Oncol Res 2001;7:63):
    • Comprised of overlapping round cells with hyperchromatic nuclei, brisk mitotic activity and extensive necrosis
    • Positive for TLE1, CD99 and BCL2
    • May be positive for select neuroendocrine markers including CD56
    • Fusions of SS18 and SSX1 / SSX2 / SSX4 are present
Additional references
Board review style question #1
Brq image


A 68 year old man with a 48 pack year smoking history presents with gross hematuria of 1 month's duration. Urinalysis reveals 9 red blood cells (RBCs) while a complete blood count (CBC) displays hemoglobin of 9.8 g/dL. An abdominopelvic ultrasound reveals a thickened lateral vesical wall while computerized tomography (CT) elucidates a 4.6 cm heterogeneous mass in the greatest dimension with possible extravesical extension into locoregional lymph nodes. Cystoscopy reveals a nodular mass with overlying necrosis. Due to suspicion of a bladder malignancy, a radical cystectomy is performed. An H&E stained image from this specimen is shown above. Immunohistochemistry is pertinent for positive staining with synaptophysin, CD56, NSE, INSM1 and CK AE1 / AE3, the latter of which exhibits a perinuclear dot-like pattern. Lesional cells are negative for GATA3, p63, CD99, WT1, HMB45, CD45, vimentin, desmin and NKX2.2. The Ki67 index exceeds 95%. What is the most likely diagnosis?

  1. Desmoplastic small round cell tumor
  2. Ewing sarcoma
  3. Large cell neuroendocrine carcinoma
  4. Pheochromocytoma
  5. Small cell neuroendocrine carcinoma
Board review style answer #1
E. Small cell neuroendocrine carcinoma. The high N:C ratio, nuclear molding, abundant mitoses and karyorrhectic debris on histology in tandem with the neuroendocrine immunohistochemical profile and history of smoking is most consistent with small cell neuroendocrine carcinoma. Answer A is incorrect because although the solid form of desmoplastic small round cell tumor may mimic the histomorphology of small cell carcinoma, the tumor cells in question are negative for CD99, desmin, vimentin and WT1. Answer B is incorrect because the tumor cells are negative for CD99 and NKX2.2. Answer C is incorrect because the tumor in question displays a high N:C ratio, stippled chromatin and inconspicuous nucleoli rather than the lower N:C ratio, vesicular chromatin and prominent nucleoli associated with large cell neuroendocrine carcinoma. Answer D is incorrect because the tumor cells do not exhibit granular reddish purple cytoplasm or GATA3 staining and are positive for cytokeratins; moreover, the patient does not display the characteristic symptoms of excess catecholamine secretion.

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Reference: Small cell neuroendocrine carcinoma
Board review style question #2
Brq image


Which of the following is true of primary upper genitourinary tract small cell neuroendocrine carcinomas?

  1. History of smoking tobacco use is common
  2. Surgery with neoadjuvant or adjuvant cyclophosphamide-based chemotherapy is the mainstay of treatment
  3. TERT promoter mutations are specific for small cell neuroendocrine carcinomas of renal origin
  4. The nephroureter is the most common site of origin within this region
  5. TMPRSS2::ERG fusions are prevalent in small cell neuroendocrine carcinomas of bladder origin
Board review style answer #2
A. History of smoking tobacco use is common. As with other carcinomas from this region, smoking tobacco use is a common historical factor in patients with upper genitourinary tract small cell neuroendocrine carcinomas. Answer B is incorrect because platinum based agents, especially cisplatin, are used most often in tandem with surgical removal of tumors, not cyclophosphamide based regimens. Answer C is incorrect because TERT promoter mutations have only been reported in small cell neuroendocrine carcinomas of bladder origin. Answer D is incorrect as the majority of reported upper genitourinary tract small cell neuroendocrine carcinomas arise from the bladder rather than the kidney and ureters. Answer E is incorrect because TMPRSS2::ERG fusions have only been reported in small cell neuroendocrine carcinomas of prostatic origin.

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Reference: Small cell neuroendocrine carcinoma
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