Bladder & urothelial tract

Neuroendocrine neoplasms

Large cell neuroendocrine carcinoma



Last author update: 6 April 2023
Last staff update: 6 April 2023

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PubMed Search: Large cell neuroendocrine carcinoma

Daniel A. Anderson, M.D., M.B.A.
Maria Tretiakova, M.D., Ph.D.
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Cite this page: Anderson D, Tretiakova M. Large cell neuroendocrine carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneytumormalignantlargecell.html. Accessed February 26th, 2024.
Definition / general
  • Extremely rare carcinoma composed of large cells with prominent nucleoli and neuroendocrine differentiation
Essential features
  • High grade carcinoma with typical large cell neuroendocrine carcinoma (LCNEC) histology and positivity for ≥ 1 neuroendocrine immunohistochemical marker(s) (e.g., synaptophysin, chromogranin, CD56, INSM1, etc.)
  • Criteria used to define LCNEC are similar to classifying the pulmonary counterpart, including (Adv Anat Pathol 2008;15:218)
    • Neuroendocrine appearance by light microscopy
    • Large polygonal cells with low N:C ratio
    • Coarse chromatin and frequent prominent nucleoli
    • High mitotic rate of > 10 mitoses per 10 high power fields accompanied by areas of necrosis
    • Immunohistochemical or ultrastructural evidence of neuroendocrine differentiation
Terminology
  • Large cell neuroendocrine carcinoma
ICD coding
  • ICD-O: 8013/3 - large cell neuroendocrine carcinoma
  • ICD-10:
    • C64.1 - malignant neoplasm of right kidney, except renal pelvis
    • C64.2 - malignant neoplasm of left kidney, except renal pelvis
    • C66.1 - malignant neoplasm of right ureter
    • C66.2 - malignant neoplasm of left ureter
    • C67.0 - malignant neoplasm of trigone of bladder
    • C67.1 - malignant neoplasm of dome 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
  • ICD-11:
    • 2C94.Y & XH0NL5 - other specified malignant neoplasms of bladder & large cell neuroendocrine carcinoma
    • 2C90.Y & XH0NL5 - other specified malignant neoplasms of kidney, except renal pelvis & large cell neuroendocrine carcinoma
    • 2C9Y & XH0NL5 - other specified malignant neoplasms of urinary tract & large cell neuroendocrine carcinoma
Epidemiology
Sites
Pathophysiology
Etiology
  • Unknown
Clinical features
Diagnosis
  • Diagnosis is made through identification of typical morphology and demonstration of neuroendocrine differentiation through immunohistochemistry
  • Rare neoplasm in the urinary tract which is essentially a diagnosis of exclusion
Prognostic factors
Case reports
Treatment
Gross description
  • Tan to white tumors with gritty or necrotic cut surfaces
  • In the bladder, median size is 4 cm (range: 1 - 9 cm) may be polypoid or nodular or less often flat or ulcerative and often invasive into the muscularis propria (Front Oncol 2020;10:1291)
  • In the kidney, tumors are often large (frequently > 100 mm in diameter) and commonly extend into the renal sinus or perirenal tissue (Indian J Urol 2009;25:274, Urologia 2014;81:57)
Microscopic (histologic) description
  • Medium to large cell size with round to polygonal nuclei, low N:C ratio, vesicular / fine chromatin, frequent nucleoli and nuclear pleomorphism (Am J Surg Pathol 2021;45:1399, Mod Pathol 2009;22:S96)
  • Neuroendocrine growth pattern such as organoid, nesting, palisading, acini, trabeculae, sheet-like or solid growth pattern; peripheral palisading and rosettes may be occasionally seen
  • Usually > 10 mitosis per high power fields (Am J Surg Pathol 2021;45:1399)
  • Frequent necrosis, apoptotic bodies and often with lymphovascular invasion and lymph node metastasis
  • May be pure or mixed with other histologic subtypes; subtypes include conventional urothelial carcinoma, carcinoma in situ, small cell carcinoma, glandular, squamous, etc. or prostatic adenocarcinoma if from the prostate gland (Am J Surg Pathol 2021;45:1399, Mod Pathol 2009;22:S96)
    • Little guidance on terminology but when mixed, may be labeled as mixed tumors with types and percentages of neuroendocrine and nonneuroendocrine components
Microscopic (histologic) images

Contributed by Daniel Anderson, M.D., M.B.A.
Solid growth

Solid growth

Necrosis and nuclear detail

Necrosis and nuclear detail

Mitotic figures

Mitotic figures

CD56

CD56

Ki67

Ki67

Synaptophysin

Synaptophysin

Cytology description
  • Similar to LCNEC of the lung displaying the following features:
    • Pleomorphic medium to large cells
    • Cells are round or polygonal in shape with abundant cytoplasm
    • Nuclei round, oval or polygonal with thin and smooth nuclear membranes
    • Chromatin finely or coarsely granular
    • Nucleoli may be prominent or inconspicuous
    • Cells may appear in clusters, rosettes or singly
    • Necrosis in background and nuclear streaking may be present (Lung Cancer 2005;48:331)
    • Nuclear pleomorphism, molding and mitosis, peripheral nuclear palisading and naked nuclei may also be present (Cancer 2008;114:180)
Cytology images

Images hosted on other servers:
Prominent nucleoli shown in pleural fluid

Prominent nucleoli shown in pleural fluid

Positive stains
Negative stains
Molecular / cytogenetics description
  • Molecular features are unclear due to low prevalence
Sample pathology report
  • Bladder, tumor, transurethral resection:
    • Invasive carcinoma with large cell neuroendocrine carcinoma features; the tumor invades the muscularis propria (detrusor muscle) (see comment)
    • Comment: Immunohistochemistry was performed. The carcinoma cells are positive for synaptophysin, chromogranin and ISM1 and negative for GATA3, NKX3.1, CDX2, p63, LCA (CD45), S100, TTF1, CDX2 and CK20. AE1 / AE3 and CK7 show focal to variable staining in the carcinoma cells. Features of primary conventional urothelial carcinoma and in situ carcinoma are not identified within this specimen. Clinical and radiologic correlation is required to exclude a metastasis. If this tumor is determined to be primary to the bladder, a definitive diagnosis of large cell neuroendocrine carcinoma requires review of the resection specimen.
Differential diagnosis
Board review style question #1

A 63 year old man presents to the urologist with hematuria. Cystoscopy shows a 3 cm polypoid mass in the right lateral wall of the urinary bladder. The tumor is subsequently biopsied which shows a high grade tumor with prominent nucleoli, necrosis, abundant mitosis, low N:C ratio, neuroendocrine differentiation (synaptophysin, CD56, chromogranin positive) and TTF1 positivity by immunohistochemistry. Which is the most correct answer?

  1. Advanced stage is not common
  2. CK20 shows dot-like cytoplasmic positivity
  3. May display conventional urothelial carcinoma or in situ carcinoma
  4. Must be metastatic from the lung due to TTF1 positivity
Board review style answer #1
C. Primary large cell neuroendocrine carcinomas may display conventional urothelial carcinoma or in situ carcinoma. The question describes a large cell neuroendocrine carcinoma, a very rare neoplasm of the bladder and urinary tract. In one study, ~64% of urinary LCNEC were mixed with other histologic types of carcinoma, most commonly urothelial carcinoma or urothelial carcinoma in situ (Am J Surg Pathol 2021;45:1399). These tumors can closely mimic other carcinomas which involve the urinary tract including through metastasis. TTF1 can be positive in primary urothelial large cell neuroendocrine carcinoma and is not a specific marker to determine the origin of the tumor. LCNEC of the bladder usually is diagnosed in an advanced stage and has an overall poor prognosis. CK20 is usually not expressed by LCNEC. Dot-like cytoplasmic CK20 positivity is more common in metastatic Merkel cell carcinoma, a rare neoplasm of the skin, many of which are associated with infection from Merkel cell polyomavirus.

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Reference: Large cell neuroendocrine carcinoma
Board review style question #2

Compared with small cell carcinoma of the urinary bladder, large cell neuroendocrine carcinoma will demonstrate which of the following?

  1. Have a high N:C ratio and no prominent nucleoli
  2. Show a worse prognosis when metastatic
  3. Not be mixed with other nonneuroendocrine histologic types
  4. Not express TTF1
Board review style answer #2
B. Show a worse prognosis when metastatic. Small cell carcinoma and large cell neuroendocrine carcinoma are the 2 recognized histologic subtypes of neuroendocrine carcinomas that are primary to the bladder. These tumors are often mixed with a nonneuroendocrine carcinoma component(s). In small cell carcinomas, the estimate of mixed cases varies from 32 to 67% (Cancer 2004;101:957, Hum Pathol 2018;79:57). The percent of large cell neuroendocrine carcinomas cases with mixed histology vary between 43 and 64% (Front Oncol 2020;10:1291, Am J Surg Pathol 2021;45:1399). According to one study, when compared with a cohort of small cell carcinoma cases of the bladder, LCNEC had a worse median overall survival (8.5 versus 29.0 months, p = 0.26) as well as a worse cancer specific survival (8.9 versus 53 months, p = 0.039) (Am J Surg Pathol 2021;45:1399). The cancer specific survival was not significantly different between LCNEC and small cell carcinoma in stage I through III; however, LCNEC had significantly shorter median survival time compared with small cell carcinoma for patients with distant metastasis (stage IV) (1.6 versus 15.0 months, p = 0.02). Like LCNEC, primary urinary bladder small cell carcinoma may demonstrate TTF1 expression / positivity (Hum Pathol 2005;36:718). Therefore, TTF1 is an unreliable marker to distinguish between a metastatic lung neuroendocrine carcinoma and a primary urinary bladder neuroendocrine carcinoma. Though there is some overlap between small cell carcinoma and LCNEC, as opposed to small cell carcinoma, LCNEC will show lower N:C ratio, prominent nucleoli, more cytoplasm and may show more diffuse rather than dot-like cytokeratin staining.

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Reference: Large cell neuroendocrine carcinoma
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