Definition

• A low grade breast carcinoma at least 90% of appears to be composed of well differentiated tubules

Diagnostic Criteria

• Stellate infiltrating configuration
  • Fibrous arms radiate out
  • Frequently infiltrates fat without a fibrous reaction
• 90% composed of small, minimally branched, oval to round duct-like structures with gaping lumens
  • Ducts frequently have pointed ends ("prows")
  • Ducts lined by a single row of cells and are widely patent
  • Apical snouts common
  • Bridging by small columns of cells is OK
  • Sheet-like stratification not seen
  • Low grade cribriform carcinoma has same behavior so may constitute more than 10%
    • Report mixtures of these two simply as the predominant type
• Nuclear grade I in at least 90% of cells
  • Slightly enlarged cells
  • Uniform nuclei, inconspicuous nucleoli, uniform chromatin
  • Pleomorphism minimal or absent
  • Mitotic figures unusual
  • Remaining 10% must not show nuclear grade III
    • Behavior may be that of the high grade component
    • Report such tumors as mixtures of two types
• 95% are less than 2.0 cm diameter, most are less than 1 cm
• Basement membrane absent by PAS and laminin stains and by EM
• Myoepithelial cells absent on immunohistochemical stains
• (Tubular 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: May 1, 2006
Updates: February 13, 2009

• 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 short strands of cells
• Tubulolobular carcinoma has a similar pattern but with longer 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

• 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

• 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

Differential Diagnosis

• Sclerosing adenosis
• Microglandular adenosis
• Tubular adenosis
• Radial scar
• Grade I infiltrating ductal carcinoma
• Tubulolobular carcinoma
• Cribriform carcinoma
• Low grade adenosquamous carcinoma

Tubular Carcinoma	Sclerosing Adenosis
Stellate, infiltrating	Circumscribed, nodular
Patent ducts, gaping lumens	Many ducts have obliterated lumens
Minimal branching	Frequent branching
Single layer of cells	Sometimes more than one layer of cells
Cells polarized to lumen	Cells smaller, streaming
Myoepithelial cell absent	Myoepithelial cells present

Tubular Carcinoma	Microglandular Adenosis
Stellate, infiltrating	Nodular or diffuse
Round to oval ducts with pointed ends and gaping lumens	Uniform small round ducts with small lumens
Frequent apical snouts	No apical snouts
Empty lumens	Eosinophilic secretion present in at least some lumens
Larger cells, polarized to lumen	Cells smaller, flatter
Round nuclei	Nuclei may be flat, parallel to base
EMA positive	EMA negative
Basement membrane absent	Basement membrane variable

Both have rounded non-branching ducts with a single layer of cells, lacking myoepithelial cells

Tubular Carcinoma	Tubular Adenosis
Stellate, infiltrating	Diffuse
Frequent apical snouts	No apical snouts
Ducts with frequent pointed ends	Infrequent pointed ends
Empty lumens	Eosinophilic secretion present in at least some lumens
Stroma desmoplastic	Stroma usually hypocellular or fat
No myoepithelial cells	Myoepithelial cells

Tubular Carcinoma	Radial Scar
Single layer of cells	Often multiple cell layers
No myoepithelial cells	Myoepithelial cells present
Frequent infiltration of fat by naked tubules	No bare infiltration of fat
No epithelial hyperplasia	May show epithelial hyperplasia

Both have a stellate configuration with radiating fibrous arms and fibroelastotic stroma

Tubular Carcinoma	Grade I Infiltrating Ductal Carcinoma, NOS
Stellate infiltration	Irregular infiltration
90% tubules	May have >10% ribbons or cords
Infrequent branching	Frequent budding and branching
Single layer of cells	May show stratification
Uniform chromatin	Slightly irregular chromatin
Nucleoli inconspicuous	Nucleoli may be prominent

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

Tubular Carcinoma vs Cribriform Carcinoma

• Low grade cribriform carcinoma and tubular carcinoma both have nearly 100% survival
• We report mixtures of these two types simply as the predominant type
  • 90% pure architectural pattern rule does not apply

Tubular Carcinoma	Low Grade Adenosquamous Carcinoma
Uniform, gaping tubules	Irregular, frequently compressed lumens
Tubules frequently have pointed ends	Tubules frequently have long comma-shaped tails
No squamous differentiation	At least focal squamous differentiation
No myoepithelial component	Myoepithelial cells prominently present around tubules

Both are low grade cytologically and clinically

Clinical

• Long term survival reported to be 95-100%
  • Probably close to 100% if strictly defined (90% tubular)
  • 100% survival if less than 1 cm
• 10% of large cases reported to have lymph node metastases at time of diagnosis
  • At least some of these cases may not have met the strict definition of tubular carcinoma
  • No further spread if nodes removed
• Grade I infiltrating ductal carcinoma has nearly the same prognosis
  • Distinction in difficult cases may not be critical
• 10-20% of patients have another carcinoma (ipsilateral or contralateral) at time of diagnosis

Grading / Staging / Report

Grading

• Tubular carcinoma is by definition low grade

• 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

• 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

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

• Infiltrating ductal carcinoma
• Infiltrating lobular carcinoma
  • Usual type
  • Pleomorphic
  • Alveolar
  • Signet ring
  • Solid
• Carcinomas of low malignant potential
  • Adenoid cystic
  • Cribriform
  • Low grade adenosquamous
  • Medullary
  • Mucinous
  • Secretory
  • Tubular
• Other types and patterns
  • Apocrine
  • Glycogen rich clear cell
  • Histiocytoid
  • Inflammatory
  • Invasive micropapillary
  • Invasive papillary
  • Lipid rich
  • Metaplastic
  • Neuroendocrine
    • Low grade
    • Not otherwise specified
    • High grade (small cell)
  • Oncocytic
  • Osteoclast-like giant cells, carcinoma with
  • Paget disease
  • Tubulolobular
  • Undifferentiated large cell

Bibliography

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• de Moraes Schenka NG, Schenka AA, de Souza Queiroz L, de Almeida Matsura M, Alvarenga M, Vassallo J. p63 and CD10: reliable markers in discriminating benign sclerosing lesions from tubular carcinoma of the breast? Appl Immunohistochem Mol Morphol. 2006 Mar;14(1):71-7.
• 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.