Columnar Cell Lesions. Columnar Cell Lesions and Flat Epithelial Atypia

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1 Columnar Cell Lesions and Stuart J. Schnitt, M.D. Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA, USA Columnar Cell Lesions Lesions characterized by columnar epithelial cells lining TDLUs have long been recognized Renewed interest; encountered with increasing frequency in biopsies performed because of mammographic microcalcifications Lack of standardized terminology and paucity of information on natural history/clinical significance has created difficulties in pathologic dx and clinical management Proposed Simplified Terminology for Columnar Cell Lesions Schnitt and Vincent-Salomon, 2003 Columnar cell change Columnar cell hyperplasia Columnar cell change with atypia Columnar cell hyperplasia with atypia (FEA) Even More Simplified Terminology for Columnar Cell Lesions Columnar cell change Columnar cell hyperplasia Flat epithelial atypia Histologic Features of Columnar Cell Lesions and Page 1 1

2 Columnar Cell Change TDLUs with variably dilated acini Lined by 1-2 layers of columnar epithelial cells uniform ovoid to elongated nuclei oriented perpendicular to basement membrane nucleoli absent or inconspicuous Apical snouts Luminal secretions Calcifications Synonyms: CAL, BDA, HUL, ELUCA, columnar metaplasia Columnar Cell Hyperplasia TDLUs with variably dilated acini Cellular stratification more than 2 cell layers; no complex architectural patterns uniform ovoid to elongated nuclei oriented perpendicular to basement membrane nucleoli absent or inconspicuous Apical snouts, often exaggerated Luminal secretions, often prominent Calcifications, may be psammomatous Page 2 2

3 IARC Press, 2003 Variably distended TDLUs Native epithelial cells replaced by one to several layers of a monotonous, atypical cuboidal to columnar cell population with apical snouts and occasional cellular tufts and mounds Many spaces contain secretory or flocculent material that often contains microcalcifications Other Names Used to Describe Similar/Identical Lesions Atypical cystic duct Atypical cystic lobules Atypical lobules type A Clinging carcinoma (monomorphic type) Columnar alterations with prominent apical snouts and secretions (CAPSS) with atypia Columnar cell change with atypia Columnar cell hyperplasia with atypia DIN, flat monomorphic type Hypersecretory hyperplasia with atypia Pretubular hyperplasia Small ectatic ducts lined by atypical ductal cells with apocrine snouts Page 3 3

4 HG DCIS, NOT FEA! Histologic Hallmarks of Low-grade (monomorphic type) cytologic atypia Nuclei usually round rather than elongated; loss of polarization Flat growth pattern (relative term) Features do not fulfill combined architectural and cytologic criteria for diagnosis of ADH or DCIS Immunophenotype of Columnar Cell Lesions and FEA LMW-CK positive (8,18,19) ER/PR positive Low proliferation rate CK5/6 negative Page 4 4

5 ER Ki67 CCC FEA FEA Genetic Alterations FEA is a clonal proliferation Genetic changes relatively few in number; have been identified on multiple chromosomes Moinfar (LOH): most common losses on 3p and 11q; losses also on 2p, 16q, 17q Simpson (CGH): losses on 16q, 17p, X; gains on 15q, 16p, 19 Genetic alterations similar to those of associated DCIS and invasive ca Similar genetic alterations also observed in some CCC and CCH Apocrine metaplasia Differential Diagnosis of Microcysts Columnar Cell Change/Hyperplasia FEA ADH LG-DCIS vs Apocrine Metaplasia FEA Apocrine Metaplasia Apical snouts yes yes Granular eosinophilic cytoplasm no yes Hobnail cells yes no Psammomatous yes no calcifications ER expression yes no bcl-2 expression yes no Apocrine Metaplasia Page 5 5

6 Columnar Cell Change Columnar Cell Hyperplasia vs Non-Atypical Columnar Cell Lesions Can Pathologists Reproducibly Distinguish Columnar Cell Lesions That Are Not Atypical From FEA? (O Malley, Mod Pathol 2006) 8 pathologists (including 1 reference pathologist) Training tutorial Written criteria Representative images Test set of 30 cases Each scored as either FEA or not atypical by each of the 8 observers Inter-Observer Agreement (FEA vs Not Atypical) Overall agreement among 8 pathologists: 91.8% Multi-rater kappa value: 0.83 ( excellent agreement ) Are there objective markers to help distinguish non-atypical columnar cell lesions from FEA? Carlo, USCAP Abstract #95, 2003 High molecular weight cytokeratin (using antibodies 34ßE12, CK5/6) Expressed in usual ductal hyperplasias but not in atypical ductal hyperplasias?role in distinguishing nonatypical columnar cell lesions from FEA? UDH CCC ADH FEA Page 6 6

7 vs ADH or DCIS Low-grade cytologic atypia Complex architectural patterns FEA NO ADH/DCIS Differential Diagnosis of Microcysts ADH Apocrine CYTOLOGY metaplasia Columnar Cell Change/Hyperplasia FEA ARCHITECTURE LG-DCIS Page 7 7

8 Clinical Significance Observational studies Clinical follow-up studies Often Seen in Association with: Tubular carcinoma ADH DCIS Lobular neoplasia (ALH/LCIS) ER Page 8 8

9 DCIS and Lobular Neoplasia (Brogi, 2001) Atypical cystic lobules found in: 18/30 biopsies with LCIS (60%) 11/24 biopsies with ALH (46%) Clinical Follow-Up Studies Page 9 9

10 10 Follow-up Studies of Columnar Cell Change ALA associated with 1.3x risk of breast cancer (but at least some also had UDH) (Page, 1986) BDA associated with 2x risk of breast cancer (Shaaban, 2002) Lack of ER expression in ELUCA associated with increased breast cancer risk (O.R. 1.85) (McLaren, 2005) Follow-up Studies of Clinging Carcinoma (monomorphic type)/fea Eusebi (1994) EORTC (2001) de Mascarel (2006) Number of patients Type of study Retrospective review of breast biopsies originally considered benign Prospective, randomized clinical trial Retrospective review of cases originally considered clinging carcinoma of the monomorphic type Treatment Diagnostic biopsy; no attempt at excision Excision Alone or Excision and Radiation Therapy Surgical biopsy alone (n=70) Surgical biopsy and Radiation Therapy (n=45) Follow-up 19.2 years (mean) 5.4 years (median) 13.3 years (median) # (%) with local 1 (4%) 0 3 (2.6%) recurrence # (%) with subsequent invasive breast cancer (2.6%) Follow-up Studies of Clinging Carcinoma (monomorphic type)/fea Follow-up Studies of Clinging Carcinoma (monomorphic type)/fea Eusebi (1994) EORTC (2001) de Mascarel (2006) Number of patients Type of study Retrospective review of breast biopsies originally considered benign Prospective, randomized clinical trial Retrospective review of cases originally considered clinging carcinoma of the monomorphic type Treatment Diagnostic biopsy; no attempt at excision Excision Alone or Excision and Radiation Therapy Surgical biopsy alone (n=70) Surgical biopsy and Radiation Therapy (n=45) Follow-up 19.2 years (mean) 5.4 years (median) 13.3 years (median) # (%) with local 1 (4%) 0 3 (2.6%) recurrence # (%) with subsequent invasive breast cancer (2.6%) Eusebi (1994) EORTC (2001) de Mascarel (2006) Number of patients Type of study Retrospective review of breast biopsies originally considered benign Prospective, randomized clinical trial Retrospective review of cases originally considered clinging carcinoma of the monomorphic type Treatment Diagnostic biopsy; no attempt at excision Excision Alone or Excision and Radiation Therapy Surgical biopsy alone (n=70) Surgical biopsy and Radiation Therapy (n=45) Follow-up 19.2 years (mean) 5.4 years (median) 13.3 years (median) # (%) with local 1 (4%) 0 3 (2.6%) recurrence # (%) with subsequent invasive breast cancer (2.6%) Columnar Cell Change Practical Considerations Found on excision: No further treatment Found on CNB: No excision necessary No additional levels obtained Page 10

11 Columnar Cell Hyperplasia Found on excision: No further treatment Found on CNB: No excision necessary No additional levels obtained as an Isolated Lesion Found on CNB: Recommend excision ( worse lesion in about 25-30% of cases) Found on excision: Multiple levels to look for architectural changes diagnostic of ADH or DCIS Submit all tissue ADH in Background of Flat Epithelial Atypia Associated with DCIS Unanswered Questions Manage as ADH in other settings Should this lesion be taken into consideration in: Determining DCIS size/extent? Margin evaluation? Why Bother Recognizing/Reporting If We Don t Know What It Means? ADH DCIS Tubular carcinoma Lobular neoplasia Conclusions Columnar cell lesions and flat epithelial atypia are being encountered with increasing frequency due to the increasing use of mammographic screening Lack of standardized terminology and paucity of information on natural history has created difficulties in pathologic dx and clinical management Page 11 11

12 Conclusions Flat epithelial atypia likely represents a precursor to or early stage of LG-DCIS Clinical significance uncertain Risk of progression to invasive cancer appears to be very low when present as an isolated lesion (but data limited) Page 12 12