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Breast Pathology
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Case 3 -
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Invasive Ductal Carcinoma Nst, Grade 3, Associated with Microglandular Adenosis with Atypia
Fernando Schmitt, Porto University and IPATIMUP, Porto, Portugal
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Clinical History
74 year old woman, with no previous history of breast disease, presented with breast
lumps. US and mammography were inconclusive. A core-biopsy was performed.
Case 3 - Figure 1
Core biopsy sampling composed of two fragments of breast tissue with glandular proliferation. |
Case 3 - Figure 2
Round small glands lined by a single layer of cuboidal cells infiltrating fatty fibrous stroma. |
Case 3 - Figure 3
Glands showing variation in size and shape, lined by a pseudostratified epithelium with some tufts and micropapillae. |
Case 3 - Figure 7
Low-power view of areas of coalescent growth of atypical cells. |
Case 3 - Figure 8
Area of solid (Grade 3) invasive ductal carcinoma. |
Case 3 - Figure 9
High magnification of invasive ductal carcinoma showing numerous mitosis, solid growth and high nuclear grade. |
Histological and Immunohistochemical Findings
The core-biopsy was composed of two fragments of tissue. Histological analysis revealed
an epithelial glandular proliferation, which was rather infiltrative and haphazardly distributed in a
fibrous stroma, with focal extension into the adjacent fat tissue. The glands were predominantly round,
small and lined by a single layer of cuboidal cells. The nuclei were rounded, with inconspicuous
nucleoli and the cytoplasm was amphophilic. Intra-luminal eosinophilic secretion was present in some
glands. In some areas, the glands displayed a greater variation in size and shape and the single layer
was replaced by a pseudostratified epithelium, with some tufts and micropapillae. Cells comprising the
proliferate epithelium displayed irregular, hyperchromatic and enlarged nuclei, leading to a high
nuclear-to-cytoplasmic ratio. Myoepithelial cells were not present as demonstrated by P63 immunostaining
and S100 was strongly positive. With these findings our diagnosis was Microglandular adenosis (MGA) with
aypia and we recommended surgical excision of the lesion.
The surgical specimen showed similar lesion associated with a coalescent growth of
atypical cells, with numerous mitosis and high nuclear grade that was characterised as an invasive ductal
carcinoma of no special type, grade 3. The tumour cells were negative for ER, PR and HER2 and expressed
CK8/18, CK5/6 and displayed strong positivity for S100 protein.
Differential Diagnoses
Tubular carcinoma, sclerosing adenosis, acinic-cell carcinoma, adenoid cystic
carcinoma.
Final Diagnosis
Invasive Ductal Carcinoma Nst, Grade 3, Associated with Microglandular Adenosis with Atypia
Discussion
Microglandular adenosis (MGA) is a rare breast lesion, with no specific clinical and
radiological features. Pre and post-menopausal women are affected. It ranges from microscopic findings
to large palpable masses [1] . Histologically, MGA is an infiltrative proliferation of small glands in
fibrous of fatty mammary stroma. Most often, the distribution seems disorderly. The glands are lined by
a single layer of flat or cuboidal cells with single, round nuclei and inconspicuous nucleoli. The
cytoplasm tends to be clear or amphophilic, and may be vacuolated or granular. Luminal colloid-like
eosinophilic secretions are frequently present, which are typically PAS positive and diastase resistant.
Unlike other forms of adenosis, MGA is not composed of a dual population and lacks a myoepithelial cell
layer.
Although originally believed to be a hyperplastic lesion, a spectrum of lesions ranging
from typical MGA to atypical MGA (AMGA) and invasive carcinomas arising therein has been described
[2,
3,
4,
5,
6,
7,
8,
9].
AMGA is characterised by increasing architectural complexity, with variation in size and shape of
glands. The single layer of lining epithelium is replaced by stratified cells which show mild to
moderate cytological atypia. Mitotic activity and apoptotic figures can be identified. Invasive
carcinomas arising in the context of MGA show heterogeneous morphology, including metaplastic carcinomas,
salivary gland analogues acinic cell like and adenoid cystic subtipes, among others
[4,
5,
7]
.
MGA has a typical immunophenotype, the great majority being positive for S100 and negative for
oestrogen receptor (ER), progesterone receptor and HER2 expression (triple-negative phenotype)
[4,
8]
.
Invasive carcinomas arising in association with MGA, although displaying distinct morphological features,
are often of high histological grade and tend to share a similar immunophenotype and express basal-like
markers
[4,
8]
. In fact, it has been suggested that the unifying feature of invasive cancers arising in
the context of MGA is the lack of hormone receptors and HER2 expression (i.e. triple negative phenotype)
[4] .
Recent comparative genomic hybridisation analyses have identified concordant chromosomal copy number
changes across the spectrum (MGA, atypical MGA, associated DCIS and invasive carcinomas), providing
molecular evidence that MGA is, at least in some cases, a clonal lesion and a non-obligate precursor of
invasive breast cancer
[8,
9]
. In addition, given that the term microglandular adenosis implies a
hyperplastic process, it has been suggested that "microglandular adenoma", a term that better reflects
the biology of these lesions, would perhaps be more adequate [8] .
Taking together the data above described and the increasingly information available on the molecular
features of breast cancer and its precursors, a revised model of breast cancer evolution based on the
molecular characteristics of distinct subtypes of in situ and invasive
breast cancers has been recently proposed [10] . In this model, breast cancer development occurs
following two main pathways defined by activation of ER and ER-regulated genes (Figure 4). The
ER-positive arm encompasses most of the precursor lesions and a range of invasive lesions which may
progress from low (i.e. luminal A tumours) to high grade (i.e. luminal B tumours) due to the acquisition
of genetic instability and accumulation of stochastic genetic events. The ER-negative arm includes
ER-negative DCIS and invasive tumours (i.e., HER2, basal-like, claudin-low and molecular apocrine) and
has MGA as an early non-obligate precursor.
From a clinical point of view it remains to be determined how often MGA progress to triple-negative
tumours and how many tumours routinely identified originate from MGA. Due the rarity of these lesions it
is challenging to determine the rate of progression. However, based on the molecular data described and
on the observational studies on MGA
[5,
6,
7]
, we have basis for recommending complete excision of all MGAs
and AMGAs with clear margins and thorough examination of samples with MGA and/or AMGA to rule out an
invasive carcinoma.
Conclusion(s):
Our results provide additional evidence to support he contention that MGA is, at
least in some cases, a clonal lesion with genetic aberrations and is a non-obligate direct precursor of a
subgroup of triple-negative breast cancers. Based on these molecular data described and on the
observational studies we recommend complete excision of all MGAs and AMGAs with clear margins and
thorough examination of samples with MGA and/or AMGA to rule out an invasive carcinoma.
References
- Rosen, P., ed. Rosen's Breast Pathology, Second Edition. 2001, Lippincott Williams & Wilkins: Philadelphia.
- Acs, G., et al., Microglandular adenosis with transition into adenoid cystic carcinoma of the breast. Am J Surg Pathol, 2003. 27:1052-60.
- Kay, S., Microglandular adenosis of the female mammary gland: study of a case with ultrastructural observations. Hum Pathol, 1985: 637-41.
- Khalifeh, I.M., et al., Clinical, histopathologic, and immunohistochemical features of microglandular adenosis and transition into in situ and invasive carcinoma. Am J Surg Pathol, 2008. 32:544-52.
- Koenig, C., et al., Carcinoma Arising in Microglandular Adenosis: An Immunohistochemical Analysis of 20 Intraepithelial and Invasive Neoplasms. Int J Surg Pathol, 2000. 8:303-315.
- Rosen, P.P., Microglandular adenosis. A benign lesion simulating invasive mammary carcinoma. Am J Surg Pathol, 1983. 7:137-44.
- Rosenblum, M.K., R. Purrazzella, and P.P. Rosen, Is microglandular adenosis a precancerous disease? A study of carcinoma arising therein. Am J Surg Pathol, 1986. 10: 237-45.
- Geyer, F.C., et al., Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma. Histopathology, 2009. 55:732-43.
- Shin, S.J., et al., Molecular Evidence for Progression of Microglandular Adenosis (MGA) to Invasive Carcinoma. Am J Surg Pathol, 2008.33: 496-504, 2009.
- Lopez-Garcia, M.A., et al., Breast cancer precursors revisited: molecular features and progression pathways. Histopathology 2010. 57:171-192.
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