Microglandular adenosis in association with invasive ductal carcinoma Sunil R Lakhani, M.D., FRCPath., FRCPA Molecular and Cellular Pathology, School of Medicine, The University of Queensland Mayne Medical School , Herston Rd, Herston QLD 4006, Australia

Clinical History: A 72 year old woman presented with a 27mm lump in her breast. Initial investigations suspicious for malignancy, lump excised. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Findings: The specimen submitted for pathology was a WLE plus axillary dissection and shaved margins. The main specimen shows widespread involvement by a proliferation composed of small round glands without an apparent myoepithelial cell layer. There was little pleomorphism and little mitotic activity. Some of the glands had eosinophilic secretions within the lumen. The glands were haphazardly arranged and diffusely infiltrating the breast parenchyma. In places, this proliferation showed more nuclear atypia and merged with an area of grade 1 invasive ductal carcinoma – NOS. There was no evidence of ductal carcinoma in situ (DCIS). The invasive carcinoma was completely excised by a minimal margin of 5mm. The small bland glandular proliferation however was present at multiple margins including the shave margins – inferior, superior, anterior and medial. None of 16 lymph nodes contained metastatic carcinoma. The invasive carcinoma was ER PgR Her2 Diagnosis: Microglandular adenosis in association with invasive ductal carcinoma Discussion: The lump was noted in right breast on self examination in July 2000. It was investigated by mammography on 27July; core biopsy diagnosis was infiltrating ductal carcinoma. She was admitted in August 2000 for surgery. Past History: Hypertension,? MI, thyroidectomy, cholecystectomy, previous smoker (20 years previously) Current status: Now nearly 6 yrs post surgery; serial mammograms every 6 months. Most recent follow up 13 April 2006 , lymphedema of right upper limb but clinically free of disease. Microglandular adenosis (MA) is a rare benign mammary lesion and usually an incidental finding although it can present as a palpable mass [1]. The term "microglandular adenosis" is believed to have been coined and illustrated by McDivitt et al [2]. These authors described such lesion and cautioned about the possibility of mistaking it for tubular carcinoma of the breast. They also thought it to be a rare form of sclerosing adenosis [3]. It was later descriubed in detail by Clement and Azzopardi [4]. It is a proliferation of small uniform and round glands lined by epithelial cells without apparent myoepithelial cells and with open lumina which infiltrate the adipose tissue or fibrous tissue haphazardly [2, 4]. The epithelial cells are cuboid with clear to eosinophilic cytoplasm. Nuclei are bland, mitotic figures uncommon and gland lumina usually have an eosinophilic secretion that can stain positively for PAS or mucicarmine. The epithelium is positive for S-100 in addition to cytokeratin and the glands are surrounded by a basement membrane that stains for collagen type IV and laminin. The epithelial layer lining the lumen of the glands lacks cytoplasmic protrusions/blebs (as in tubular carcinoma) and is surrounded by a thick multilayered basement membrane. There are abundant apical lysosomal granules and villus interdigitation between epithelial cells ultrastructurally [5, 6, 7]. Although it is thought that there is an absence of a myoepithelial cell layer around the glands of the lesion [8, 9], a contradictory study showed that luminal cells in nine cases of MA were surrounded by a cuff of muscle-specific actin-reactive cells, which also coexpressed cytokeratin and vimentin. The immunophenotype of these cells was consistent with myoepithelial differentiation, which was thought to be lacking in MA hitherto. This study suggested that myoepithelial cells are indeed present in MA subjacent to luminal epithelial cells which also helps to distinguish MA from tubular carcinoma [10]. Such lesions with expression of myoepithelial markers seem to be better categorized as tubular adenosis or they may be examples of adenomyoepitheliosis [11]. MA can mimic carcinoma both clinically and histologically [12]. Carcinoma arising in areas of MA has been reported, however clinical follow-up data are limited in these cases [5, 13, 14, 15, 16]. Despite being thought of as benign, a range of atypical glandular proliferations ("atypical MA"), which are suggestive of transition from MA to invasive carcinoma, have been reported [12, 13, 16]. These lesions have shown features of classical MA associated with architectural complexity and cytologic abnormality such as epithelial bridges and cellular expansion in luminal compartment together with presence of vesicular nuclei [12, 13]. MA was thoroughly admixed with carcinoma in a few reported cases, as well as transitional patterns of atypical MA, suggesting that carcinoma can arise in MA [13, 16]. However, other investigators have interpreted MA as an innocent lesion and expressed their doubt that MA can be precancerous [5]. There is no current molecular data regarding MA or atypical MA and their suggested biological malignant potential. Due to the lack of follow-up data, it seems prudent to treat and observe cases of atypical MA as a form of atypical hyperplasia. References: Rosen PP. Microglandular adenosis. A benign lesion simulating invasive mammary carcinoma. Am J Surg Pathol. 1983 Mar;7(2):137-44. McDivitt RW, Stewart FW, Berg JW: Tumours of the Breast. In Atlas of Tumour pathology, series 2, fascicle 2. Washington DC, Armed Forces Institute of Pathology, 1968, p91. McDivitt RW, Boyce W, Gersell D. Tubular carcinoma of the breast. Clinical and pathological observations concerning 135 cases. Am J Surg Pathol. 1982 Jul;6(5):401-11. Clement PB, Azzopardi JG. Microglandular adenosis of the breast - a lesion simulating tubular carcinoma. Histopathology. 1983 Mar;7(2):169-80. Tavassoli FA, Norris HJ. Microglandular adenosis of the breast. A clinicopathologic study of 11 cases with ultrastructural observations. Am J Surg Pathol. 1983 Dec;7(8):731-7. Kay S. Microglandular adenosis of the female mammary gland: study of a case with ultrastructural observations.Hum Pathol. 1985 Jun;16(6):637-41. Joshi MG, Lee AK, Pedersen CA, Schnitt S, Camus MG, Hughes KS. The role of immunocytochemical markers in the differential diagnosis of proliferative and neoplastic lesions of the breast. Mod Pathol. 1996 Jan;9(1):57-62. Tavassoli FA, Bratthauer GL. Immunohistochemical profile and differential diagnosis of microglandular adenosis. Mod Pathol. 1993 May;6(3):318-22. Eusebi V, Foschini MP, Betts CM, et al. Microglandular adenosis, apocrine adenosis, and tubular carcinoma of the breast: an immunohistochemical comparison. Am J Surg Pathol 1993; 17:99-109. Diaz NM, McDivitt RW, Wick MR. Microglandular adenosis of the breast. An immunohistochemical comparison with tubular carcinoma.Arch Pathol Lab Med. 1991 Jun;115(6):578-82.. Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology, Barnes Hospital. Lee KC, Chan JK, Gwi E. Tubular adenosis of the breast. A distinctive benign lesion mimicking invasive carcinoma. Am J Surg Pathol. 1996 Jan;20(1):46-54.Lee KC, Chan JK, Gwi E. Rosenblum MK, Purrazzella R, Rosen PP. Is microglandular adenosis a precancerous disease? A study of carcinoma arising therein. Am J Surg Pathol. 1986 Apr;10(4):237-45. James BA, Cranor ML, Rosen PP. Carcinoma of the breast arising in microglandular adenosis. Am J Clin Pathol. 1993;100:507-513. Rosemblum MK, Purrazzella R, Rosen PP. Is microglandular adenosis a precancerous disease? A study of carcinoma arising therein. Am J Surg Pathol. 1986; 10:237-245. Koenig C, Dadmanesh F, Bratthauer GL, Tavassoli FA. Carcinoma arising in microglandular adenosis: an immunohistochemical analysis of 20 intraepithelial and invasive neoplasms. Int J Surg Pathol. 2000;8:303-315. Acs G, Simpson J F., Bleiweiss IJ, Hugh J, Reynolds C, Olson S, Page DL. Microglandular Adenosis With Transition Into Adenoid Cystic Carcinoma of the Breast Am J Surg Pathol 2003; 27,1052-1060