Abstract
We herein report a case of the breast fibroadenoma with foci of so-called immature variant of the conventional ductal hyperplasia. This type of usual ductal hyperplasia is histologically characterised by encircling intraductal proliferation of large cells with pale to amphophilic cytoplasm and large nuclei which vary in shape and in staining quality of the chromatin. We showed here, using the cytokeratin immunohistochemistry, that the proliferating cells were not of immature but rather mature immunohistochemical phenotype. Because of the presented discordance between immature histology and mature immunohistological profile we suggest that this rare type of usual ductal hyperplasia should be called “immature-like”.
Introduction
Breast fibroadenoma (FA) is common benign tumour that is histologically composed of the simultaneous proliferation of both stromal and epithelial components. Although it may occur in women of any age, it is most frequently seen during the second and third decades of life. The epithelial component of fibroadenoma may harbour any type of pathohistological alteration described in the epithelium of the normal breast [4,6].
Here, we describe the case of fibroadenoma with foci of unreported type of usual ductal hyperplasia (UDH), called immature ductal hyperplasia.
Case report
A 30-year-old woman presented with non-palpable, painless nodule in her left breast detected by breast ultrasound examination. The physical examination of the breast tissue including overlaying skin and the nipple-areola complex was without abnormalities. There were no palpable axillary or supraclavicular lymph nodes. Breast ultrasound depicted solid, oval, homogeneous hypoechogenic zone of 1.5 cm in diameter, without acoustic enhancement. Mammography showed dense breast tissue without visible nodule. Fine needle cytology showed epithelial proliferation with atypia, with consequent advice for the excisional biopsy.
The lumpectomy was performed. On gross examination the tumour was a well-defined, grey-white nodule sharply demarcated from surrounding tissue, measuring 1.5 cm in greatest diameter.
Tissue was fixed in neutral buffered formalin and embedded in paraffin for routine histological examination. Slides were stained with hematoxylin and eosin with additional immunohistochemical analysis using CKß12, CK 8/18, CK5/6, CK14, SMA, p63, and e-cadherin antibodies.
Histologically the nodule was composed of proliferating fibrocollagenous stroma of low cellularity and epithelial component of proliferating branching ducts lined with ductal and myoepithelial cells (Fig. 1). In a few terminal ducts the proliferation of large cells with pale, amphophilic cytoplasm was observed. These cells had large nucleus with one or two small acidofilic nucleoli, with slight variation in nuclear shape and orientation. In ducts with more pronounced epithelial hyperplasia and luminal obliteration, the cells showed focal signs of maturation with the formation of smaller, more conventional hyperplastic cells. In other ducts the hyperplastic cells showed subluminal growth with preservation of the flattened luminal cells, simulating the pagetoid growth of malignant cells (Fig. 2). Similar findings were observed in the few ducts in the surrounding breast tissue.
Immunohistochemically the proliferating cells showed strong positive reaction with CK8/18 antibody, while the CK5/6 and CK14 antibodies showed focal positive reaction only in the luminal, terminally differentiated hyperplastic cells (Fig. 3 and Fig. 4). The staining with CKß12 was faint and focally observed in the population of subluminal proliferating cells. These proliferating cells were immunohistochemically also e-cadherin positive and SMA, p63 negative.
The histological diagnosis was consistent with fibroadenoma with foci of immature-like ductal hyperplasia.
Discussion
The epithelial component of FA can display variety of pathohistological changes, ranging from epithelial metaplasia to invasive carcinoma. Among these changes the hyperplasia is the most common. In the large series of 396 cases of FA, Kuijper et al. have found epithelial hyperplasia in 43,9% of cases. The most frequent form of hyperplasia was moderate UDH (26,8%), followed by mild UDH (11,6%) and florid UDH (5,3%), with only one case showing the features of atypical ductal hyperplasia [4]. In juvenile type of FA stromal hypercellularity is accompanied with UDH which is often of micropapillary type [6].
We presented here the typical fibroadenoma with foci of morphologically peculiar type of UDH. The principal cytological finding in UDH is variability of nuclear distribution, shape and chromatin texture of hyperplastic cells. In classical forms these cytological findings are coupled with architectural characteristics such as irregular or crescent-shaped ductal fenestrations, streaming arrangement of cells and the maturation of the cells in central parts of hyperplastic ducts [3]. These architectural and cytological features of UDH were not so obvious in presented case. The large size of the cells and their nuclei, along with their encircling growth under the preserved mature luminal cells suggested the presence of atypia. However, the slight variation in shape of hyperplastic cells, variation of nuclear shape and orientation, along with the focal signs of maturation and the lack of cellular discohesion favoured benign hyperplastic process. Immunohistochemically, preserved e-cadherin staining in proliferating cells ruled out the colonization of terminal ducts by lobular neoplasia, while the negative immunoreaction with p63 and SMA antibody excluded the possibility of myoepithelial proliferation. Interestingly, the proliferating cells showed no immunoreaction with CK 5/6 and CK 14 antibodies, while the reaction with CKß12 was only focally observed. These high molecular weight cytokeratins (HMW-CKs) usually show an intense positive reaction in proliferating cells of UDH.
The detailed description of this type of intraductal proliferation is provided by Koerner, who named it immature hyperplasia. The author stated that the large size of the cells with the peculiar proliferation which undermines the pre-existing luminal ductal and acinar cells may in some pathologists cause concern that this type of proliferation represents a form of atypical ductal hyperplasia or even ductal carcinoma in situ. Despite some atypical features coupled with the lack of immunoreaction with CK 5/6, Koerner showed that these proliferating cells continue to exhibit many of the features of UDH, but in the subtle form [3]. Some of these features like slight variation in nuclear shape and orientation, and focally observed maturation were also present here.
The similar terminology is used for the similar cytological change in the uterine cervix. The cases of cervical squamous metaplasia with immature looking, more cellular squamous cells which show some degree of nuclear atypia and crowding, sometimes with increased mitotic activity, are designated as the cases of atypical immature squamous metaplasia [2].
Apart from the above mentioned description by Koerner we could not find any additional report of this finding in the English written literature. This notion may be explained not only by the rarity of this type of hyperplasia but also by the possibility that it could be reported under different terminology. Mies and Rosen in the study of 49 cases of juvenile fibroadenoma with severe epithelial hyperplasia described four patterns of epithelial proliferation: ductal-laciform, cystic-papillary, ductal-solid and lobular-terminal ductal. They have found that all patterns have some atypical cytological features. While the description and illustrations of the ductal-laciform and the cystic-papillary type of hyperplasia mainly correspond to the florid and micropapillary (gynecomastoid) types of UDH, those of the ductal-solid and lobular-terminal ductal types are morphologically identical to our findings. In the ductal-solid type of hyperplasia the authors described dilated duct-like structures filled with a uniform population of large round to ovoid cells, while in the lobular-terminal type the same type of cells extended into terminal ducts and lobules in pagetoid fashion. The authors stated that the cellular atypia was most pronounced in these two particular types of hyperplasia, suggesting that it may produce considerable diagnostic difficulty in pathohistological interpretation [5].
In the breast, the cellular heterogeneity of UDH is also visible on immunohistochemistry with the mixture of CK5/14 + basal (progenitor) cells, CK5/14 and CK8/18 + intermediate cells, and CK8/18 + differentiated glandular cells [1]. Regarding this, in a case of immature hyperplasia one should expect that proliferating cells predominately express basal (immature) cytokeratins. However, the immature looking proliferating cells in our case were strongly positive for luminal (mature) CK8/18 cytokeratins, while the mosaic immunohistochemical pattern for CK5/6 and CK14 antibodies, typical for the UDH, was only seen in the central parts of involved ducts showing epithelial maturation. Koerner also stated that proliferating cells failed to stain with CK5/6 in his cases of immature hyperplasia [3]. Because of this discordance between immature histology and mature immunophenotype we think that such cases should be rather called “immature-like” instead of the immature hyperplasia cases.
In conclusion, we presented here the case of immature-like hyperplasia occurring in FA. This type of hyperplasia is characterized by the less pronounced histological features of UDH, coupled with some atypical cytological and immunohistochemical features. The larger group of such cases with long follow-up should be collected to reveal the true biologic potential of this morphologically peculiar type of the breast ductal hyperplasia.