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Surgical Pathology Criteria
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Apocrine Carcinoma of the Breast

Definition

  • Breast carcinoma with abundant eosinophilic cytoplasm, large round nuclei and sharp cell borders

Alternate / Historical Names

  • Carcinoma with apocrine metaplasia
  • Sweat gland carcinoma of the breast

Diagnostic Criteria

  • Clinically significant criteria have not generally been agreed upon
    • Most describe some degree of abundant eosinophilic cytoplasm, sharp cell borders, round nuclei and prominent nucleoli
    • Some simply refer to GCDFP15 positive carcinomas as apocrine
  • Japaze 2005 has proposed the following criteria:
    • At least 75% of microscopic fields must demonstrate the following features:
      • Large cells with abundant eosinophilic cytoplasm
        • Usually granular
      • Nucleus to cytoplasm ratio of 1:2 or more
      • Nuclei round, large and vesicular
        • May be pleomorphic
      • Sharply defined cell borders
    • Minor (non-mandatory) criteria
      • Prominent nucleoli in >50% of fields
      • Apical cytoplasmic snouts into lumenal spaces
    • Japaze 2005 reported significantly improved survival when apocrine carcinomas were defined as above

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
Updates: February 9, 2009

Supplemental studies

Immunohistology and Histochemistry

  • GCDFP15 reactivity is generally considered to be strong and universal in apocrine lesions
    • Such reactivitiy is taken by some to define apocrine differentiation
    • Note that the criteria employed by Japaze et al. are not based on immunologic reactivity
  • PASd may show granular cytoplasmic positivity

  • 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

  • CK7 and CK20 have not been tested on a series of apocrine carcinomas, thus their utility is unknown

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

 

Apocrine Carcinoma Secretory Carcinoma
Large vesicular nuclei with prominent nucleoli Low grade nuclei with inconspicuous nucleoli
Cytoplasm granular, eosinophilic Cytoplasm granular or clear and vacuolated
PASd may show granular cytoplasmic staining PASd shows abundant cytoplasmic mucin
No predilection for young patients Most cases <30 years
Many show aggressive behavior Excellent prognosis

 

Histiocytoid Carcinoma Apocrine Carcinoma of the Breast
Amphophilic to weakly eosinophilic cytoplasm Intensely eosinophlic cytoplasm
Cytoplasm vacuolated, occasionally granular Cytoplasm granular
Indistince cytoplasmic borders Sharp cytoplasmic borders
Small nuclei and nucleoli Large vesicular nuclei with prominent nucleoli
Appears to have more aggressive behavior than usual carcinoma Appears to have better behavior than usual carcinoma in some series
Some consider histiocytoid carcinoma to be a variant of breast carcinomas with apocrine features

 

Lipid Rich Carcinoma Apocrine Carcinoma
Cytoplasm clear to multivacuolated Cytoplasm nearly uniformly granular
Cytoplasm at most focally eosinophilic Cytoplasm nearly uniformly eosinophilic
Scant PASd positivity in cells Frequently PASd positive
Fat stains positive Fat stains negative
GCDFP15 variable/weak GCDFP15 strong positive

 

Apocrine Carcinoma Oncocytic Carcinoma
GCDFP15 strong diffuse positive GCDFP15 negative
Anti-mitochondrial stain weak, focal Anti-mitochondrial antibody stain strong, diffuse
Indistinguishable on H&E stain; clinical significance of difference unknown

Clinical

  • Most studies have shown no clear difference in behavior from usual invasive breast carcinoma
  • One study, strictly applying the criteria outlined here, found a significantly better prognosis for apocrine carcinoma compared to infiltrating ductal carcinoma NOS (Japaze 2005)
    • Overall six year survival 72% vs. 52%
    • Grade 3 overall six year survival 83% vs. 51%
  • Another study, not using these criteria, found decreased lymph node metastases and decreased lymphatic invasion (Tanaka 2008)
    • Follow up was too short to evaluate survival

Grading / Staging / Report

Grading

  • The study of Japaze et al. found a better prognosis for apocrine carcinoma compared to grade matched infiltrating carcinoma NOS, raising the possibility that the grading scheme should be modified for apocrine lesions
    • Note that the grading scheme for DCIS is modified for apocrine DCIS

  • 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)

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

  • Japaze H, Emina J, Diaz C, Schwam RJ, Gercovich N, Demonty G, Morgenfeld E, Rivarola E, Gil Deza E, Gercovich FG. 'Pure' invasive apocrine carcinoma of the breast: a new clinicopathological entity? Breast. 2005 Feb;14(1):3-10.
  • Page DL. Apocrine carcinomas of the breast. Breast. 2005 Feb;14(1):1-2.
  • 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.
  • Tanaka K, Imoto S, Wada N, Sakemura N, Hasebe K. Invasive apocrine carcinoma of the breast: clinicopathologic features of 57 patients. Breast J. 2008 Mar-Apr;14(2):164-8.
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