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    High Grade Neuroendocrine Carcinoma (Small Cell Carcinoma) of the Breast

    Definition

    • Breast carcinoma with small cell neuroendocrine pattern

    Alternate / historical names

    • Oat cell carcinoma
    • Small cell neuroendocrine carcinoma
    • Small cell undfferentiated carcinoma

    Diagnostic Criteria

    • Scant cytoplasm
    • Fine granular chromatin
      • Inconspicuous nucleoli
    • High mitotic rate
    • Necrosis common
    • In situ small cell component may be present
    • May be associated with other conventional breast carcinoma patterns
    • Very rare large cell neuroendocrine carcinomas may occur in the breast
    • Low 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

    Immunohistology

    • Keratin reactivity is higher than reported for many other small cell neuroendocrine carcinomas
    • CK7/20 pattern is typical of usual breast carcinomas
    • Not all cases have detectable neuroendocrine markers
    • TTF1 has been reported in a subset of non-pulmonary small cell carcinomas of various sites
    • ER is not reported to be positive in small cell carcinomas of other sites (Bacchi 1997)
      • This may support a breast primary
      • PR is not specific in the context of neuroendocrine carcinomas
    Keratin
    10/10
    CK7
    8/10
    CK20
    0/10
    Neuron specific enolase
    17/19
    Synaptophysin
    8/15
    Chromogranin A
    6/16
    Calcitonin
    3/12
    Gastrin releasing peptide
    5/13
    E-cadherin
    11/11
    TTF1
    2/10
    ER
    6/12
    PR
    9/11
    Her2neu
    0/10
    Modified from Shin 2000

    • CK7 and CK20 do not distinguish breast from lung adenocarcinomas but may help in the distinction from ovary, pancreas, bile duct and GI carcinomas.

      CK7 and CK20 expression in carcinomas

      CK7+20+ CK7-20+
      Ovary mucinous 90% Colorectal adeno 80%
      Transitional cell 65% Merkel cell 70%
      Pancreas adeno 65% Gastric adeno 35%
      Cholangio 65%  
      Gastric adeno 40%  
      Excluded tumors 5% or less Carcinoid; Germ cell; Esoph squam; Head/neck squam; Hepato-cellular; Lung small cell & squam; Ovary non-mucinous; Renal adeno Excluded tumors 5% or less Breast; Carcinoid lung; Cholangio; Esoph squam; Germ cell; Lung all types; Hepato-cellular; Ovary; Pancreas adeno; Renal adeno; Transitional cell; Uterus endometrioid
      CK7+20- CK7-20-
      Ovary non-mucinous 100% Adrenal 100%
      Thyroid (all 3 types) 100% Seminoma & Yolk Sac 95%
      Breast 90% Prostate 85%
      Lung adeno 90% Hepatocellular 80%
      Uterus endometrioid 85% Renal adeno 80%
      Embryonal 80% Carcinoid intestinal & lung 80%
      Mesothelioma 65% Lung small cell & squam 75%
      Transitional cell 35% Esoph squam 70%
      Pancreas adeno 30% Head/neck squam 70%
      Cholangio 30% Mesothelioma 35%
      Excluded tumors 5% or less Colorectal adeno; Ovary mucinous; Yolk Sac; Seminoma Excluded tumors 5% or less Breast; Cholangio; Lung adeno; Ovary; Pancreas adeno
    • Derived from Chu PG, Weiss LM. Histopathology 2002, 40:403-439 and other sources

    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

     

    • Neuroendocrine Carcinomas: Low Grade, High Grade or NOS

    • Primary vs. metastatic small cell carcinoma
      • Metastasis must be excluded whenever small cell carcinoma is found in the breast
      • ER positive supports a primary carcinoma
        • Small cell carcinomas of other sites are reported as negative
        • Negative result is non-contributory
      • TTF1 negative supports a breast primary
        • 90% of lung small cell carcinomas are positive
        • Positive result is non-contributory
      • Clinical and imaging search for another primary site may be useful

     

    • Small cell carcinoma vs. merkel cell carcinoma
      • Merkel cell carcinoma is 90% positive for CK20
      • Small cell carcinoma is CK20 negative

    Clinical

    • Prognosis may be stage related
      • Earlier reported cases did poorly
      • More recent report (Shin 2000) found 7/9 without disease

    Grading / Staging / Report

    Grading

    • 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

    Staging

    • 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

    Report

    • 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

    Lists

    Infiltrating Breast Carcinomas

    Bibliography

    • 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.
    • Wade PM Jr, Mills SE, Read M, Cloud W, Lambert MJ 3rd, Smith RE. Small cell neuroendocrine (oat cell) carcinoma of the breast. Cancer. 1983 Jul 1;52(1):121-5.
    • Shin SJ, DeLellis RA, Ying L, Rosen PP. Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol. 2000 Sep;24(9):1231-8.
    • Shin SJ, DeLellis RA, Rosen PP. Small cell carcinoma of the breast--additional immunohistochemical studies. Am J Surg Pathol. 2001 Jun;25(6):831-2.
    • Bacchi CE, Garcia RL, Gown AM. Immunolocalization of estrogen and progesterone receptors in neuroendocrine tumors of the lung, skin, gastrointestinal and female genital tracts. Appl Immunohistochem 1997;5:1722.

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