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Surgical Pathology Criteria
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Infiltrating Lobular Carcinoma of the Breast

Definition

  • Infiltrating carcinoma typically composed of uniform cells often arranged in a linear infiltrative pattern

Diagnostic Criteria

  • Classic type
    • Uniform cells with grade I cytologic features
      • Signet ring differentiation may be prominent
      • Nuclear molding is often prominent
    • Linear infiltrative pattern
      • Rows of cells no more than one or two cells wide
      • Frequent target-like concentric pattern around ducts
      • Poorly cohesive cells
    • E-cadherin negative
  • Pleomorphic variant
    • Larger pleomorphic cells with grade III nuclei
      • Irregular nuclearl membranes, prominent nucleoli
      • Frequently with abundant eosinophilic cytoplasm
  • Tubulolobular carcinoma is considered by some to be a variant of lobular carcinoma
  • Alveolar variant
    • Classic grade I cytologic features
    • Rounded groups of cells
  • Solid variant
    • Classic grade I cytologic features
    • Groups or trabeculae >2 cells thick infiltrate between collagen bundles
  • Signet ring variant
    • Architectural and cytologic features of lobular carcinoma
    • >20% signet ring differentiation
      • Mucin positive vacuoles

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

Original posting, last update:: 5/1/06, 12/13/14

Supplemental studies

Immunohistology

  • 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
  • E-cadherin is reported to be negative in the pleomorphic variant and positive in the tubulo-lobular variant

  • 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 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
  • Broad spectrum antikeratin stains may be particularly useful for the identification of lobular carcinoma in lymph nodes

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

Infiltrating Ductal Carcinoma Infiltrating Lobular Carcinoma
Infiltration in cords of varying thickness Single file infltration
May form ductal structures No duct formation
E-cadherin positive E-cadherin negative
The utility of E-cadherin in borderline cases is currently uncertain

 

Tubulolobular Carcinoma Infiltrating Lobular Carcinoma
Contains a tubular component Uniform single file pattern
E-cadherin positive E-cadherin negative
Some consider tubulolobular carcinoma to be a variant of lobular carcinoma

 

Early stromal invasion in lobular carcinoma can be difficult to distinguish from LCIS involving sclerosing adenosis
LCIS in Sclerosing Adenosis Infiltrating Lobular Carcinoma
Circumscribed, nodular Infiltrating, not confined to nodule
Myoepithelial cells present Myoepithelial cells absent in infiltrating areas

 

Lymphocytes and histiocytes in breast stroma and lymph nodes can be difficult to distinguish from lobular carcinoma
Inflammation Infiltrating Lobular Carcinoma
No molding of nuclei Molding of nuclei
Single file pattern unusual Single file pattern common
No mucin positive signet ring cells Mucin positive signet ring cells may be present
Keratin negative Keratin positive

 

Lymphoma may be diffcult to distinguish from alveolar and solid variants of lobular carcinoma
Lymphoma Infiltrating Lobular Carcinoma
No molding of nuclei Molding of nuclei
Lymphoid markers positive Keratin positive

 

Mucinous Carcinoma vs. Signet Ring Carcinoma

  • Mucinous carcinomas are characterized by cells floating in pools of mucin
  • Signet ring carcinomas are characterized by cells with intracellular mucin that indents the nucleus
  • Signet ring cells can be found in otherwise mucinous carcinomas
    • If at least 20% of cells are signet ring, designate as signet ring carcinoma
      • Prognosis is that of usual infiltrating carcinoma of identical grade
      • Signet ring carcinoma is usually a variant pattern of lobular carcinoma
    • If <20% of cells are signet ring, designate as mucinous carcinoma with signet ring cells
      • Prognosis may not be worse than pure mucinous carcinoma

 

Signet Ring Carcinoma Secretory Carcinoma
One or few vacuoles that indent nucleus Abundant granular to clear cytoplasm
May be nuclear grade I or II Low nuclear grade
Often associated with classic lobular carcinoma pattern No association with lobular carcinoma
No predilection for young patients Most cases <30 years
May show aggressive behavior Excellent prognosis
Signet ring carcinoma is usually a variant pattern of lobular carcinoma

 

Breast vs. other origin in carcinoma of unknown primary

Clinical

  • The most important prognostic indicators are nodal status, grade and size
    • See Grading/Staging/Report link at left for guidelines on reporting prognostic factors
  • Classic lobular carcinoma is reported to have better prognosis than infiltrating ductal carcinoma
    • May reflect higher grade of many ductal carcinomas
    • Classic lobular carcinoma is nearly always grade I
  • In most, but not all studies, infiltrating lobular carcinoma implies a significantly increased risk of developing carcinoma in the contralateral breast
  • The clinical differences between infiltrating lobular and ductal carcinomas do not translate into any therapeutic importance
  • Behavior of pleomorphic lobular is worse than classical lobular carcinoma
    • Not entirely clear if this is independent of overall grade and marker status
  • Behavior of tubulo-lobular is roughly that of grade I infiltrating ductal carcinoma

Grading / Staging / Report

Grading

  • Although classic lobular carcinoma by definition is scored as 3 for lack of tubule formation, cases will receive scores of 1 for nuclear pleomorphism and mitotic count will usually be low, resulting in an overall score of grade I

  • 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

  • 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.
  • 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.
  • Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002 May;40(5):403-39.
  • Wheeler DT, Tai LH, Bratthauer GL, Waldner DL, Tavassoli FA. Tubulolobular carcinoma of the breast: an analysis of 27 cases of a tumor with a hybrid morphology and immunoprofile. Am J Surg Pathol. 2004 Dec;28(12):1587-93.
  • Green I, McCormick B, Cranor M, Rosen PP. A comparative study of pure tubular and tubulolobular carcinoma of the breast. Am J Surg Pathol. 1997 Jun;21(6):653-7.
  • Fisher ER, Gregorio RM, Redmond C, Fisher B. Tubulolobular invasive breast cancer: a variant of lobular invasive cancer. Hum Pathol. 1977 Nov;8(6):679-83.
  • Middleton LP, Palacios DM, Bryant BR, Krebs P, Otis CN, Merino MJ. Pleomorphic lobular carcinoma: morphology, immunohistochemistry, and molecular analysis. Am J Surg Pathol. 2000 Dec;24(12):1650-6.
  • Bentz JS, Yassa N, Clayton F. Pleomorphic lobular carcinoma of the breast: clinicopathologic features of 12 cases. Mod Pathol. 1998 Sep;11(9):814-22.
  • Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol. 1992 Oct;23(10):1167-71.
  • Eusebi V, Magalhaes F, Azzopardi JG. Pleomorphic lobular carcinoma of the breast: an aggressive tumor showing apocrine differentiation. Hum Pathol. 1992 Jun;23(6):655-62.
  • DiCostanzo D, Rosen PP, Gareen I, Franklin S, Lesser M. Prognosis in infiltrating lobular carcinoma. An analysis of "classical" and variant tumors. Am J Surg Pathol. 1990 Jan;14(1):12-23.
  • Sneige N, Wang J, Baker BA, Krishnamurthy S, Middleton LP. Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases. Mod Pathol. 2002 Oct;15(10):1044-50.
  • Dixon JM, Anderson TJ, Page DL, Lee D, Duffy SW. Infiltrating lobular carcinoma of the breast. Histopathology. 1982 Mar;6(2):149-61.
  • Fechner RE. Histologic variants of infiltrating lobular carcinoma of the breast. Hum Pathol. 1975 May;6(3):373-8.
  • Martinez V, Azzopardi JG. Invasive lobular carcinoma of the breast: incidence and variants. Histopathology. 1979 Nov;3(6):467-88.
  • Shousha S, Backhous CM, Alaghband-Zadeh J, Burn I. Alveolar variant of invasive lobular carcinoma of the breast. A tumor rich in estrogen receptors. Am J Clin Pathol. 1986 Jan;85(1):1-5.
  • DiCostanzo D, Rosen PP, Gareen I, Franklin S, Lesser M. Prognosis in infiltrating lobular carcinoma. An analysis of "classical" and variant tumors. Am J Surg Pathol. 1990 Jan;14(1):12-23.
  • 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.
  • 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.
  • Nonaka D, Chiriboga L, Soslow RA. Expression of pax8 as a useful marker in distinguishing ovarian carcinomas from mammary carcinomas. Am J Surg Pathol. 2008 Oct;32(10):1566-71.
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