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Surgical Pathology Criteria
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Tubulolobular Carcinoma of the Breast

Definition

  • Infiltrating carcinoma exhibiting both ductal and lobular differentiation

Alternate/Historical Names

  • Tubulo-lobular carcinoma

Diagnostic Criteria

  • Must have classic grade I cytologic features
  • Intimately mixed tubular and linear architecture
    • Overall infiltrative pattern is that of lobular carcinoma
    • Considered by some to be a variant of lobular carcinoma
  • E-cadherin positive
  • (Tubulolobular carcinoma is not really tubular)

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

    Original posting: August 4, 2007
    Updates: February 13, 2009

Tubulolobular Carcinoma Is Not Really Tubular

  • Serial sections with 3-D reconstruction shows the actual structure is not tubular
    • No continuous and/or branching tubules
  • Pattern is better described as a necklace formed by a string of beads
    • Oval to spherical cavitated blebs with tapering ends
    • Connected by moderately long strands of cells
  • Tubular carcinoma has a similar pattern but with short connecting strands of cells
  • These findings explain the observed pattern that always appears to be cross-sections or oblique sections of tubules, but never longitudinal sections
  • See Marchio et al. 2006 for the full story

Supplemental studies

Immunohistology

E-cadherin is consistently (and definitionally) positive in tubulolobular carcinoma

  • 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 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 cases

Genetic analysis

    • Her2neu status can be determined by either immunohistology or by FISH
      • The other technique can be used for borderline cases

Differential Diagnosis

Tubular Carcinoma Tubulolobular Carcinoma
90% pure tubular pattern Mixed tubular and lobular patterns
Stellate infiltrating architecture Linear infiltrative pattern, frequently concentric
Both are typically E-cadherin positive

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

Breast vs. other origin in carcinoma of unknown primary

Clinical

  • Behavior of tubulolobular is roughly that of grade I infiltrating ductal carcinoma
  • Rare, constitutes approximately 1% of breast carcinomas

Grading / Staging / Report

Grading

  • Tubulolobular carcinoma is by definition nuclear 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.
  • Esposito NN, Chivukula M, Dabbs DJ. The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study. Mod Pathol. 2007 Jan;20(1):130-8. Epub 2006 Nov 24.
  • Kuroda H, Tamaru J, Takeuchi I, Ohnisi K, Sakamoto G, Adachi A, Kaneko K, Itoyama S. Expression of E-cadherin, alpha-catenin, and beta-catenin in tubulolobular carcinoma of the breast. Virchows Arch. 2006 Apr;448(4):500-5.
  • Marchiò C, Sapino A, Arisio R, Bussolati G. A new vision of tubular and tubulo-lobular carcinomas of the breast, as revealed by 3-D modelling. Histopathology. 2006 Apr;48(5):556-62.
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