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  • Surgical Pathology Criteria

    Low Grade Neuroendocrine Carcinoma of the Breast


    • Low grade breast carcinoma expressing predominant neuroendocrine differentiation

    Alternate / historical names

    • Carcinoid
    • Endocrine carcinoma
    • Spindle cell endocrine carcinoma

    Diagnostic Criteria

    • Diagnosis requires all of the following four criteria
      • At least 50% of cells are neuroendocrine marker positive
        • Most cases positive for chromogranin and/or synaptophysin
        • Neuron specific enolase is not sufficiently specific for this diagnosis
        • Lesser numbers of positive cells are seen in usual type breast carcinomas
      • Growth in solid sheets or insular pattern
        • Peripheral palisading common
      • Stippled chromatin
      • Low grade cytologic features
        • Round, regular to mildly irregular nuclei up to 2-3x the size of a RBC
        • No comedo necrosis
    • Extracellular mucin is common
    • Frequently associated with endocrine DCIS
    • Spindle cell variant
      • Above criteria required
      • Predominantly composed of spindle cells
      • Subset of cells may be cuboidal and form glands
      • Reported cases all low grade
    • High grade neuroendocrine carcinoma and neuroendocrine carcinoma NOS are considered separately

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

    Original posting:: May 1, 2006

    Supplemental studies


    • Diagnosis requires at least 50% of cells to be neuroendocrine marker positive
      • Chromogranin and synaptophysin are most commonly used
      • Argyrophil stains may also be used
      • Electron microscopy may also be used
    • GCDFP15 frequently shows strong, extensive positivity
    • Steroid receptors frequently positive
      • ER 80%
      • PR 35%
      • Androgen receptor 45%

    • 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


    • Most cases over age 60
    • Low grade tumors have an excellent prognosis

    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


    • 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


    • Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991 Nov;19(5):403-10.
    • Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002 May;40(5):403-39.
    • Wick MR, Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT. Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol. 1989 Mar;20(3):281-7.
    • 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 neuroendocrine carcinoma of the breast. Ann Oncol. 2001;12 Suppl 2:S115-7.
    • Sapino A, Righi L, Cassoni P, Papotti M, Gugliotta P, Bussolati G. Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women. Mod Pathol. 2001 Aug;14(8):768-76.
    • 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.
    • Azzopardi JG, Muretto P, Goddeeris P, Eusebi V, Lauweryns JM. 'Carcinoid' tumours of the breast: the morphological spectrum of argyrophil carcinomas. Histopathology. 1982 Sep;6(5):549-69.
    • Clayton F, Sibley RK, Ordonez NG, Hanssen G. Argyrophilic breast carcinomas: evidence of lactational differentiation. Am J Surg Pathol. 1982 Jun;6(4):323-33.
    • Ruffolo EF, Maluf HM, Koerner FC. Spindle cell endocrine carcinoma of the mammary gland. Virchows Arch. 1996 Aug;428(6):319-24.
    • Scopsi L, Andreola S, Pilotti S, Testori A, Baldini MT, Leoni F, Lombardi L, Hutton JC, Shimizu F, Rosa P, et al. Argyrophilia and granin (chromogranin/secretogranin) expression in female breast carcinomas. Their relationship to survival and other disease parameters. Am J Surg Pathol. 1992 Jun;16(6):561-76.
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