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Surgical Pathology Criteria

Histiocytoid Carcinoma of the Breast


  • Rare type of breast carcinoma characterized by abundant vacuolated cytoplasm

Alternate / Historical Names

  • Myoblastomatoid carcinoma

Diagnostic Criteria

  • Abundant finely vacuolated cytoplasm
    • Amphophilic to faintly eosinophilic
    • May appear granular
    • PASd may show granular cytoplasmic mucin stain
  • Indistinct cell borders
  • Uniform, low grade small nuclei
    • Small nucleoli
    • Mitotic count generally 1-2/10 hpf
  • Intracytoplasmic lumens rare to frequent
    • Highlighted by Alcian Blue or EMA stains
    • May result in areas with signet ring appearance
    • PASd may stain intralumenal mucin
  • Frequent single file and targetoid infiltrative pattern
  • Frequent central hyaline fibrosis
  • Fat frequently invaded by single non-cohesive cells
  • Considered by some to represent a variant pattern of lobular carcinoma or of apocrine carcinoma, see Differential Diagnosis

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 and Histochemical Stains

  • PASd shows granular cytoplasmic and/or intracytoplasmic lumenal staining
    • Lacks abundant glycogen
  • Alcian Blue may highlight intracytoplasmic lumenal borders
Keratin positive
EMA positive, highlights intracytoplasmic lumens
GCDFP15 positive
CD68, HAM56, Lysozyme negative
S100 negative, one case reported weak positive
E cadherin 3/11 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

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

    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 cases borderline by one procedure

Differential Diagnosis


Lipid Rich Carcinoma Histiocytoid Carcinoma
Lipid stain positive Lipid stain negative
GCDFP15 variable to weak GCDFP15 strong positive
Mucin negative Mucin positive intracytoplasmic lumens or granular cytoplasm
May have any grade cytology Low grade cytology
Lacks intracytoplasmic lumens May have intracytoplasmic lumens


Glycogen Rich Clear Cell Carcinoma Histiocytoid Carcinoma
Clear cytoplasm Finely vacuolated cytoplasm
PAS shows abundant glycogen PAS shows granular mucin
GCDFP15 variable GCDFP15 strong positive


Histiocytoid Carcinoma Secretory Carcinoma
All reported cases >40 years Most cases <30 years
Scant or granular mucin Abundant cytoplasmic mucin
GCDFP15 strong positive GCDFP15 variable
Aggressive behavior Excellent prognosis


Histiocytoid Carcinoma Granular Cell Tumor
Keratin, EMA positive Keratin, EMA negative
GCDFP15 positive GCDFP15 negative
S100 negative or trace S100 positive


Histiocytoid Carcinoma Fat Necrosis, Inflammation, Histiocytic Infiltrations
Keratin, EMA positive Keratin, EMA negative
GCDFP15 positive GCDFP15 negative
CD68, HAM56 negative CD68, HAM56 positive
Low grade atypia Completely bland nuclei
Granular mucin positivity Mucin stains negative


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


Is Histiocytoid Carcinoma a variant of Lobular Carcinoma?

  • Most cases of histiocytoid carcinoma show linear and targetoid infiltration, are E cadherin negative and have at least focal intracytoplasmic lumens and many have adjacent LCIS
    • These features suggest that at least in many cases, histiocytoid carcinoma could be considered a variant of lobular carcinoma
  • A minority of cases have been reported that show infiltration more characteristic of ductal carcinoma and are E cadherin positve


  • Age range 41-93 years
  • Rare
  • Clinical significance not known but many reported cases have aggressive behavior
    • Frequent reports of metastases to eyelids

Grading / Staging / Report


  • 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


  • 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.
  • Reis-Filho JS, Fulford LG, Freeman A, Lakhani SR. Pathologic quiz case: a 93-year-old woman with an enlarged and tender left breast. Histiocytoid variant of lobular breast carcinoma. Arch Pathol Lab Med. 2003 Dec;127(12):1626-8.
  • Gupta D, Croitoru CM, Ayala AG, Sahin AA, Middleton LP. E-cadherin immunohistochemical analysis of histiocytoid carcinoma of the breast. Ann Diagn Pathol. 2002 Jun;6(3):141-7.
  • Shimizu S, Kitamura H, Ito T, Nakamura T, Fujisawa J, Matsukawa H. Histiocytoid breast carcinoma: histological, immunohistochemical, ultrastructural, cytological and clinicopathological studies. Pathol Int. 1998 Jul;48(7):549-56. Review.
  • Eusebi V, Foschini MP, Bussolati G, Rosen PP. Myoblastomatoid (histiocytoid) carcinoma of the breast. A type of apocrine carcinoma. Am J Surg Pathol. 1995 May;19(5):553-62.
  • Walford N, ten Velden J. Histiocytoid breast carcinoma: an apocrine variant of lobular carcinoma. Histopathology. 1989 May;14(5):515-22.
  • Eisenberg BL, Bagnall JW, Harding CT 3rd. Histiocytoid carcinoma: a variant of breast cancer. J Surg Oncol. 1986 Apr;31(4):271-4.
  • Hood CI, Font RL, Zimmerman LE. Metastatic mammary carcinoma in the eyelid with histiocytoid appearance. Cancer. 1973 Apr;31(4):793-800.
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