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Surgical Pathology Criteria

Neuroendocrine Carcinoma of the Breast, NOS


  • Breast carcinoma expressing predominant neuroendocrine differentiation but lacking specific cyto-architectural features of low grade or high grade neuroendocrine carcinoma

Diagnostic Criteria

  • At least 50% of cells are neuroendocrine marker positive
    • We require either synaptophysin or chromogranin
    • We do not consider neuron specific enolase to be sufficiently specific for this diagnosis
  • Any conventional breast carcinoma pattern excluding those of:
  • Small numbers reported but there is no clear clinical difference from conventional carcinoma

Richard L Kempson MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting:: November 15, 2006

Supplemental studies


  • Diagnosis requires at least 50% of cells to be neuroendocrine marker positive
    • We require chromogranin or synaptophysin
      • We do not consider neuron specific enolase to be sufficiently specific for this diagnosis
    • Argyrophil stains have ben used
    • Electron microscopy has been used
  • GCDFP15 may be positive

  • Demonstration of myoepithelial cells can confirm the in situ nature of a process while their absence supports invasion
    • We prefer to use both p63 and calponin on problematic cases
    • A variety of markers have been used for myoepithelial cells:
    Marker Sensitivity Specificity
    Calponin Excellent Very good
    p63 Excellent Excellent
    Smooth muscle myosin heavy chain Good Excellent
    CD10 (CALLA) Good Good
    High molecular weight cytokeratin Very good Poor
    Maspin Good Poor
    S100 Good Very poor
    Actin Good Very poor
  • E-cadherin appears to be a sensitive marker of ductal differentiation vs lobular differentiation; its utility in borderline lesions is currently uncertain

  • Immunologic markers useful for identification of breast carcinoma
  • GCDFP15 (BRST2) Estrogen Receptor Progesterone Receptor PAX8
    Infiltrating ductal carcinoma 60-70% 75% 50-60% 0%
    Infiltrating lobular carcinoma 60-70% >95% 80% 0%
    Lung adenocarcinoma 0-1% <5% <5% 0%
    Ovarian adenocarcinoma 1-5% 50-100% 40-90% 90-100%
    Endometrioid adenocarcinoma negative 70% 70%  
    GI adenocarcinoma negative <5% 1-10% 0%
    Pancreatic adenocarcinoma negative negative 0-5% 0%
    Cholangiocarcinoma negative negative 30%  
    Thyroid carcinoma negative 20% 30% 100%
  • Sweat gland and salivary gland neoplasms may also be positive for GCDFP15, ER and PR
  • Prostatic adenocarcinoma may be positive for GCDFP15
  • We are not aware of a series of breast neuroendocrine carcinomas tested for CK7/20

Prognostic/Therapeutic Markers

  • Estrogen receptor (ER) and progesterone receptor (PR) are important markers for directing therapy and determining prognosis
    • Current consensus is that any level of positivity should be reported as positive
  • Her2neu status can be determined by either immunohistology or by FISH
    • The other technique can be used for borderline case

Genetic analysis

  • Her2neu status can be determined by either immunohistology or by FISH
    • The other technique can be used for borderline cases

Differential Diagnosis

  • Metastatic neuroendocrine carcinoma must be ruled out clinically
  • Neuroendocrine Carcinomas: Low Grade, High Grade or NOS


  • Studies using thresholds of both <50% and >50% cellular reactivity for neuroendocrine markers have found no independent clinical significance in carcinomas with conventional patterns
    • Prognosis appears to be driven by grade in such cases

Grading / Staging / Report


  • Low grade neuroendocrine carcinoma by definition has low grade cytologic features
    • Round, regular to mildly irregular nuclei up to 2-3x the size of a RBC
    • No comedo necrosis
  • Neuroendocrine carcinoma NOS
    • Behavior appears to be related to conventional Bloom-Scarff-Richardson grading
  • High grade neuroendocrine carcinoma
    • Most demonstrate features of small cell carcinoma
    • Very rare carcinomas have been reported that demonstrate features similar to pulmonary large cell neuroendocrine carcinomas

  • Bloom-Scarff-Richardson grading scheme is most widely used
  • Total score and each of the three components should be reported
  • Based on invasive area only
Tubule formation Score
>75% tubules 1
10-75% tubules 2
<10% tubules 3


Nuclear pleomorphism (most anaplastic area) Score
Small, regular, uniform nuclei, uniform chromatin 1
Moderate varibility in size and shape, vesicular, with visible nucleoli 2
Marked variation, vesicular, often with multiple nucleoli 3


Mitotic figure count per 10 40x fields (depends on area of field, see key below) Score
0.096 mm2 0.12 mm2 0.16 mm2 0.27 mm2 0.31 mm2
0-3 0-4 0-5 0-9 0-11 1
4-7 5-8 6-10 10-19 12-22 2
>7 >8 >10 >19 >22 3
  • Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece: 0.096 mm2
  • AO with 10x eyepiece: 0.12 mm2
  • Nikon or Olympus with 10x eyepiece: 0.16 mm2
  • Leitz Ortholux: 0.27 mm2
  • Leitz Diaplan: 0.31 mm2
  • Mitotic count figures based on original data presented for Leitz Ortholux by Elston and Ellis 1991, with modifications based on pubished and measured areas of view
  • Evaluate regions of most active growth, usually in cellular areas at periphery
  • We employ strict criteria for identification of mitotic figures
Sum of above three components Overall grade
3-5 points Grade I (well differentiated)
6-7 points Grade II (moderately differentiated)
8-9 points Grade III (poorly differentiated)


  • TNM staging is the most widely used scheme for breast carcinomas but is not universally employed
  • Critical staging criteria for regional lymph nodes
    • Isolated tumor cell clusters
      • Usually identified by immunohistochemistry
        • Term also applies if cells identified by close examination of H&E stain
      • No cluster may be greater than 0.2 mm
      • Multiple such clusters may be present in the same or other nodes
    • Micrometastasis
        • Greater than 0.2 mm, none greater than 2.0 mm
    • Metastasis
      • At least one carcinoma focus over 2.0 mm
        • If one node qualifies as >2.0 mm, count all other nodes even with smaller foci as involved
      • Critical numbers of involved nodes: 1-3, 4-9 and 10 and over
    • Note extranodal extension


  • Excisions: the following are important elements that must be addressed in the report for infiltrative breast carcinomas
    • Grade
      • Total score and individual components
    • Size of neoplasm
      • Give 3 dimensions or greatest dimension
      • Critical cutoffs occur at 0.5 cm and at 2 cm
    • Margins of resection
      • Measure and report the actual distance of both invasive and in situ carcinoma
    • Angiolymphatic invasion
      • Indicate if confined to tumor mass, outside tumor mass or in dermis
    • (Extensive DCIS is not currently felt to be a significant predictor of behavior)
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies performed
      • ER, PR, Proliferation marker, Her2neu
      • If studies were performed on a prior specimen, refer to that report and give results
  • Needle or core biopsies
    • Provisional grade may be given but may defer to excision for definitive grade
    • Presence of absence of angiolymphatic invasion
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies if performed
      • ER, PR, Proliferation marker, Her2neu
      • State if studies are deferred for a later excision specimen
  • Regional lymph nodes
    • Report findings as described above


Infiltrating Breast Carcinomas


  • Sapino A, Bussolati G. Is detection of endocrine cells in breast adenocarcinoma of diagnostic and clinical significance? Histopathology. 2002 Mar;40(3):211-4.
  • Sapino A, Papotti M, Righi L, Cassoni P, Chiusa L, Bussolati G. Clinical significance of low grade neuroendocrine carcinoma of the breast. Ann Oncol. 2001;12 Suppl 2:S115-7.
  • Makretsov N, Gilks CB, Coldman AJ, Hayes M, Huntsman D. Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer. Hum Pathol. 2003 Oct;34(10):1001-8.
  • Miremadi A, Pinder SE, Lee AH, Bell JA, Paish EC, Wencyk P, Elston CW, Nicholson RI, Blamey RW, Robertson JF, Ellis IO. Neuroendocrine differentiation and prognosis in breast adenocarcinoma. Histopathology. 2002 Mar;40(3):215-22. (All cases had <50% of neuroendocrine cells)
  • Tse GM, Ma TK, Chu WC, Lam WW, Poon CS, Chan WC. Neuroendocrine differentiation in pure type mammary mucinous carcinoma is associated with favorable histologic and immunohistochemical parameters. Mod Pathol. 2004 May;17(5):568-72.
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