Indmedica Home | About Indmedica | Medical Jobs | Advertise On Indmedica
Search Indmedica Web
Indmedica - India's premier medical portal

Indian Journal for the Practising Doctor

Lobular Carcinoma of Breast - A Pathologic Study
(25-year Experience)

Author(s): Shah P, Shah A, Sofi GN, Sheikh S

Vol. 5, No. 5 (2008-11 - 2008-12)

ISSN: 0973-516X

Shah P, Shah A, Sofi GN, Sheikh S

Dr. Parveen Shah, MD, (Additional Professor), Dr. Azra Shah, MD, (Professor and Head), Dr. G N Sofi, MD, (Associate Professor) and Dr. Sheema Sheikh, MD, (Senior Resident), Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Kashmir (India).

Correspondence: Dr. Parveen Shah, Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences, P. Box: 27, Srinagar-190 011 (India)
Tel. (Res.): 0194-2463811, Cell: 9419011841, e-mail: shahparveenK (at) yahoo.co.in

Abstract

17 cases of lobular carcinoma of breast diagnosed over a period of 25 years in the Department of Pathology at the Sher-i-Kashmir Institute of Medical sciences (SKIMS), Srinagar, are presented in this paper which focuses on the histopathology and molecular pathology of tumour. The studied patients included 15 females and 2 males with an age range of 50-70 years. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in the cytogenetic profiles.

Key words: Lobular neoplasia, Lobular carcinoma, terminal duct.

Introduction

Lobular neoplasia of the breast represents a group of related malignancies with histological presentations ranging from risk lesions, atypical lobular hyperplasia and lobular carcinoma in situ (LCIS) to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma.

The classical form of infiltrating lobular carcinoma was recognized by Foote and Stewart1 and the definition reviewed later by Wheeler and Enterline2. Other variants have since been recognized3. These are solid lobular carcinomas and mixed lobular carcinoma described by Fechner4, alveolar lobular by Martinez and Azzopardi5, and tubul-lobular carcinoma which was first recognized by Fisher and co-workers6. Lobular neoplasia represents a broad range of noninvasive (in-situ) proliferations of lobular cells in the breast7.

The historic view that lobular carcinomas emanate from the lobules and ductal carcinomas from the ducts was challenged long ago by the seminal studies of Wellings8, which demonstrated that most breast cancers arise from the same locality – the terminal duct lobular unit (TDLU). A great deal of data now indicates that differences which characterize breast cancer morphology are manifestations of their differing molecular profiles9.

Material and Methods

This study includes all cases of lobular carcinoma of breast diagnosed over a period of 25 years (from January 1983 to July 2008) at the Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar. Out of a total of 670 cases of breast carcinoma, 17 cases of lobular carcinoma were diagnosed. The gross morphological and histological features were examined in detail.

The number of microscopic slides stained with Haematoxylin and Eosin (H&E) that were available for review ranged from 4 to 10, with a minimum of three slides from the tumour area. Clinical assessment, pathology and molecular markers were the focus of this study.

Results

  • Incidence: The lobular carcinoma of the breast accounted for 2.53% of the total resected cases of breast carcinoma. There were 2 cases (0.3%) of male lobular breast carcinoma – a rare entity.
  • Sex: With 15 female and 2 male patients in this series, the female-male ratio was 15:2.
  • Age: The mean age of the patients was 58 (range 50 to 70 years); the respective mean ages for females and males were 56 and 60 years.
  • Clinical: All the patients presented with the discovery of a painless breast lump of 1 to 3 year duration. In 10 cases, the tumour was located in the left breast and in the remaining 7 cases in the right breast. In two patients with lobular carcinoma in-situ, the tumour was multicentric and in one of these cases, bilateral. In all the cases, surgical treatment had been given in the form of partial, sub-total or total mastectomy.
  • Gross pathology: Grossly, the tumours varied from being a well-circumscribed schirrous mass to a poorly-defined area of induration. The tumour was generally firm, ranging in size from 1.5 to 4.5cms. The cut-section of the tumour was grayish-white with foci of necrosis seen in eight cases.
  • Histologic examination: In the classical invasive lobular carcinoma (12 cases), the cells were small and uniform growing singly in the Indian file fashion (Fig. 1) with bland nuclei and eccentrically-placed cytoplasm in a plasmacytoid manner. Some cases showed an occasional intracytoplasmic vacuole which was visible in a few cases on H&E staining, but was more distinct on histochemical staining with the Periodic-acid Schiff and the Alcian blue stains. The stroma was dense and fibrous with periductal elastosis. In one case of an ‘alveolar variant’, the tumour cells were in small aggregates. In another case of a ‘solid variant’, the cells were of uniform lobular type, seen in diffuse sheets with no intervening stroma. In the ‘mixed lobular carcinoma’ (one case), the infiltrative pattern was of the classical lobular type showing atypia and pleomorphism. The cells were larger with more cytoplasm than the classical type. There were two cases of ‘lobular carcinoma in-situ’ with one case showing a focus of early invasion. Lobular carcinoma in-situ was characterized by a solid proliferation of cells with small, uniform, round to oval nuclei and minimal nuclear atypia. These cells were evenly spaced, with distinct cell borders, and showed loss of cohesion. Mitoses were uncommon and necrosis was not seen. Cells remained within the terminal duct lobular unit or involved adjacent ducts by pagetoid spread (Fig. 2).
  • Cytologic study: FNAC was performed in 14 cases. The diagnosis of infiltrating carcinoma was given in 12 cases. In two cases, material aspirated was insufficient with few scattered dysplastic cells only.
  • Immunohistochemical studies: Estrogen receptor (ER), progesterone receptor (PR), and HER-2 study was done in 12 cases. All the cases were ER and PR positive and HER-2 negative. Discussion

The term lobular neoplasia includes a continuum of disease10 from risk indicators for malignant disease (ie atypical lobular hyperplasia, ALH) to lesions that are fully malignant.

The epidemiology of lobular carcinoma is of interest. Lobular carcinoma represents only 1% of the tumours11. The incidence in our study is in conformity with another similar study giving an incidence of 0.32%12. Other reports from the country have shown a higher incidence of 1.08%13 and 5%14. Two of the cases in our study were multifocal and two cases of lobular carcinoma in-situ also were detected. In both of them, multiple tumour foci were observed in the same breast and in one of them, the tumour was bilateral. One of the characteristic features of the ‘in-situ’ lobular neoplasia is its propensity to exist in multiple foci within the same or both breasts15. The risk of malignancy applies to both breasts, the risk appears greater in the ipsilateral than in the contralateral breast16.

Lobular carcinoma is a very uncommon form of male breast cancer because of the absence of lobules in the normal male breast. There are only case reports in literature about the lobular male breast cancer.

The defining pathological features shared by classical examples of lobular lesions are populations of small aberrant cells with small nuclei, individual ‘private’ acini and a lack of cohesion between cells17. The classical lobular carcinoma cases in our series shared similar histological features with the tumour cells showing frequent intracytoplasmic vacuolation and infiltrating in a diffuse manner forming cords between collagen bundles, thus giving the characteristic ‘Indian file pattern’. The intracytoplasmic structures may be visible on H&E staining but are more easily visualized by immunocytochemical staining for epithelial membrane antigen or histochemical staining with Periodic-acid Schiff and Alcian blue18. The other histological variants seen in our study were in conformity with reports from other studies19.

The hallmark molecular feature of lobular malignancies of both in-situ and invasive form is ‘loss of down-regulation of E-cadherin’20. This is manifest in routine practice by immuno-negativity for the molecule E-cadherin – an adhesion molecule localized at the zonula adherens of epithelial cells which enhances cellular cohesion by homotypic interactions21. However, caution needs to be exercised in using this as a definitive test since ductal carcinoma can also be E-cadherin negative, either wholly or partly, and still show clear ductal morphology22.

The rest of the molecular profile of classic lobular neoplasms is distinctive, though not entirely unique. They are typically epidermal growth factor receptor 1 and HER2-negative, and the antibody 34bE12 (cytokeratins 1,5,10 and 14)23 and ER and PR positive17. The limited molecular profile available in our cases matches with these studies. It should be noted, however, that some ductal carcinomas share this profile24 and that pleomorphic lobular carcinomas can be ER-, PR- and HER 2+.

More recent studies have suggested that there are a number of other specific and distinctive molecular changes, seen in lobular carcinomas, most notably amplication of the fibroblast growth factor receptor 1 (FGFR 1)- gene at a complex locus 8P 11.225.

This change is not lobular-specific as it occurs in other low grade breast tumours typically those that are ER+26. This amplification identifies the receptor as a novel potential therapeutic target25.

Conclusion

Lobular carcinoma is a diverse group of diseases presenting a challenge to the cancer biologist to identify the molecular basis of the heterogeneity, to the pathologist to assess correctly the wide range of morphologies, and to the clinician to manage the disease in the context of greatly differing biologies. The morphological and cytogenetic diversity implies a spectrum of neoplasms verified by common features of loss of E-cadherin fraction and a close relationship to low-grade ductal carcinomas. More research is required to understand the longterm pathogenic implications and genetics behind the well-recognized high risk of bilateral disease. For invasive carcinomas, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against the fibroblast growth factor receptor17.

Fig. 1:Photomicrograph showing classical 'Indian file arrangement' of lobular carcinoma cells. Also visible are small clusters of neoplastic cells (H&E x 100).

Photomicrograph

Larger image here

Fig. 2:Photomicrograph of lobular carcinoma in-situ showing the acini filled with monotonous proliferation of cells that distend and distort the acini.

Photomicrograph

Larger image here

References

  1. Foote FW Jr, Stewart FW. A histologic classification of carcinoma in the breast. Surgery 1946;19:74-99.
  2. Wheeler JE, Enterline HT. Lobular carcinoma of the breast in-situ and infiltrating. Pathol Ann 1976;11:161-188.
  3. Lee BJ, Hauser H, Pack GT. Gelatinous carcinoma of the Breast. Surg. Gynecol Obstet 1934;59:841-850.
  4. Fechner RE. Histological variants of infiltrating lobular carcinoma of the breast. Hum Pathol 1975;6:373-378.
  5. Martinez V, Azzopardi J. Invasive carcinoma of the breast. Incidence and variants. Histopathol 1979;3:467-488.
  6. Fisher ER, Gregorio R C, Redmond C, Fisher B. Tubulolobular invasive breast cancer. A variant of lobular invasive cancer. Hum Pathol 1977;8:679-681.
  7. Mastracci TI, Boulos FI, Andrulis IL and Lam WL. Review – genomics and premalignant breast lesions: Clues to the development and progression of lobular breast cancer. Breast Cancer Res 2007;9:215.
  8. Wellings SR, Jensen HM, Marcum RG.; Atlas of subgross pathology of the human breast with special reference to possible cancerous lesions. J Natl Cancer Inst 1975;55:231-273.
  9. Hanby AM. Aspects of molecular phenotype and its correlations with breast cancer behaviour and taxonomy. Br J Cancer 2005;92:613-617.
  10. Pritt B, Ashikaga T, Oppenheimer RG, Weaver DL. Influence of breast cancer histology on the relationship between ultrasound and pathology tumour size measurements. Mod Pathol 2004;17:905-910.
  11. Salvadori B, Saccozzi R. Manzari A et al. Prognosis of breast cancer in males: An analysis of 170 cases. Eur J Cancer 1994;30A:930-935.
  12. Gupta JC, Munjal S, Raman A, Gandagule VN, Panda PK. Breast lumps in Jabalpur area. Ind J Surg 1983;45:268-273.
  13. Tyagi SP, Khan MH, Haque A, Gahlaut YVS. Carcinoma breast: Its incidence and histomorphological variants at Aligarh. Ind J Surg 1980;42:597-607.
  14. Joshi K, Mehtani VG, Mehrotra GC. The pathologic profile of invasive breast cancer. Factors intrinsic to the tumour. Ind Jr Cancer 1983;20:15-22.
  15. Rosen PP, Kosloff C, Lieberman PH, Adair F, Braun DW Jr. Lobular carcinoma in-situ of the breast. Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 1978;2:225-251.
  16. Page DL, Schuyler PA, Dupoint WD, Jensen RA, Plummer WD Jr, Simpson JF. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: A retrospective cohort study. Lancet 2003;361:125-129.
  17. Hanby AM and Hughes TA. Review. In-situ and invasive lobular neoplasia of the breast. Histopathol 2008;52:58-66.
  18. Quiney C, Raitt N, Bell J, Ellis IO. Intracytoplasmic lumina: A useful diagnostic feature of adenocarcinoma. Histopathol 1991;19:83-87.
  19. Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer II. Histological type, relationship with survival in a large study with long term follow-up. Histopathol 1992;20:479-489.
  20. Moll R, Miltz M, Frixen U, Birchmeier W. Differential loss of E-Cadherin expression in infiltrating ductal and lobular breast carcinomas. Am J Pathol 1993;142:987-993.
  21. Takeichi M. Cadherin cell adhesion receptors as a morphogenic regulator. Science 1991;251:1451-1455.
  22. Gillet CE, Miles DW, Ryder K et al. Retention of the expression of E-Cadherin and catenins is associated with shorter survival in grade III ductal carcinoma of the breast. J Pathol 2001;193:433-441.
  23. Bratthauer GL, Moinfar F, Stamatakos MD et al. Combined E-Cardherin and high molecular weight cytokeratin immunoprofile differentiates lobular, ductal and hybrid mammary intraepithelial neoplasias. Hum Pathol 2002;33:620-627.
  24. Tan DSP, Potts HWW, Leong ACK et al. The biological and prognostic significance of cell polarity and E-Cadherin in grade I infiltrating ductal carcinoma of the breast. J Pathol 1999;189:20-27.
  25. Reis-Filho JS, Simpson PT, Turner NC et al. FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res 2006;12:6652-6662.
  26. Elbauomy Elsheikh S, Green AR, Lambros MB et al. FGFR1 amplication in breast carcinomas: A chromogenic in-situ hybridization analysis. Breast Cancer Res 2007;9:R23.
Access free medical resources from Wiley-Blackwell now!

About Indmedica - Conditions of Usage - Advertise On Indmedica - Contact Us

Copyright © 2005 Indmedica