Pseudoangiomatous stromal hyperplasia (PASH) of the breast with foci of morphologic malignancy: a case of PASH with malignant transformation?

Pseudoangiomatous stromal hyperplasia (PASH) is a benign proliferation of the hormonally responsive, specialized mammary stroma characterized by slit-like pseudovascular spaces lined by bland spindle cells. It is usually an incidental microscopic finding but in some cases it may present as a slowly growing mass. A malignant counterpart for this lesion has not been reported. We describe a case of PASH with foci of malignant histologic features presenting as a slowly growing mass in a 30-year-old woman. The previously reported variants of PASH and the other mammary stromal lesions related to PASH are also discussed. This is perhaps the first case of PASH with foci of malignant histologic features reported in the literature and represents a rare sarcoma derived from specialized hormonally responsive mammary stroma.     

Gynecomastia in type-1 neurofibromatosis with features of pseudoangiomatous stromal hyperplasia with giant cells. Report of two cases

We describe the histological finding in two cases of gynecomastia in patients with von Recklinghausen's disease. The histological and immunohistochemical features of the two cases were reviewed and compared with those of five cases of gynecomastia in men without clinical evidence of neurofibromatosis. In both patients bearing von Recklinghausen's disease, the breast stroma showed features consistent with pseudoangiomatous stromal hyperplasia (PASH). It was characterised by anastomosing empty spaces lined by spindle and multinucleated giant cells which were positive with CD34 and anti-vimentin antisera and negative with anti-FVIII and CD31 antisera. In two of five of the control cases without neurofibromatosis, the mammary stroma showed focal areas with features of PASH, but no multinucleated giant cells were present in any case. PASH with giant cells should be recognised as a feature of gynecomastia in von Recklinghausen's disease. The presence of multinucleated giant cells is very unusual and, although more cases have to be studied, these cells seem to be a feature of PASH occurring in patients with von Recklinghausen's disease.     

Columnar cell lesions and pseudoangiomatous hyperplasia like stroma: is there an epithelial-stromal interaction?

The significance of association between cancer and its microenvironment has been increasingly recognized. It has been shown in animal models that interaction between neoplastic epithelial cells and adjacent stroma can modulate tumor behavior. Carcinoma associated stromal cells can transform normal epithelial cells into neoplastic cells. In breast, columnar cell lesions are non-obligate precursors of low grade ductal carcinoma in situ. Columnar cell lesions can be seen intimately associated with PASH-like-stroma, a lesion we termed as CCPLS. Our aim is to investigate epithelial-stromal interactions in CCPLS and compare them to PASH without columnar cell lesions in breast core needle biopsies. Normal terminal duct lobular unit (TDLU) epithelium was seen in association with columnar cell lesions as well as PASH. Eight (8) cases of each category were examined by a panel of immunostains: CD117 (C-kit), CD34, CD105, bFGF, AR, ER-beta, MIB-1. We observed a markedly decreased expression of c-kit in columnar cell lesions compared to TDLU-epithelium. CD105 showed a quantitative increase in activated vessels in CCPLS compared to PASH. A subset of CCPLS and PASH were androgen receptor positive. A strong nuclear positivity for ER-beta is observed in the epithelium and stroma of all CCPLS cases. We conclude that (1) activated blood vessels predominate in CCPLS; (2) A molecular alteration is signified by c-kit loss in columnar cell lesions; (3) ER-beta and androgen receptor positivity indicate CCPLS are hormonally responsive lesions. Our study suggests an intimate vascular and hormone dependent epithelial-stromal interaction exists in CCPLS lesions.     

Pseudoangiomatous stromal hyperplasia of the breast-cytological features of two cases and review of literature

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a lesion characterized on histology by the presence of anastomosing slit like spaces embedded in a hyalinized fibrous stroma. Till date, the cytological features of PASH have been described in only 12 cases, of which two cases were diagnosed on aspiration cytology as suspicious for carcinoma and in one case, for phyllodes tumor. We describe the FNAC findings of two of our cases of PASH. The first case was diagnosed as a phyllodes tumor and the other case as a benign proliferative breast disease, possibly a fibroadenoma. A review of the published literature on cytology of PASH shows the morphological variations that can exist in the cytology smears of this lesion. FNAC findings of PASH are non-specific, and the role of FNAC in PASH is to confirm the benign nature of the lesion, rather than provide a definitive pre-surgical diagnosis.     

Fine-needle aspiration cytology of pseudoangiomatous stromal hyperplasia of the breast

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon lesion usually found in premenopausal women. Histologically, it is characterized by complex, anatomosing, empty slit-like spaces in a dense collagenous stroma. These pseudoangiomatous spaces are lined by monomorphic spindle cells of myofibroblastic differentiation. Cytological features of PASH are rarely discussed and reported, and may pose diagnostic challenge to surgical pathologists. Two cases of PASH are reported with emphasis on the FNAC features and cytologic differentiation from other benign fibroepithelial lesions.     

Pseudoangiomatous stromal hyperplasia with giant cells in the female breast. No association with neurofibromatosis?

A simultaneous finding of pseudoangiomatous stromal hyperplasia (PASH) and stromal multinucleated giant cells (MGC) in mammary tissue was previously observed in patients with type-1 neurofibromatosis, indicating that it can represent a morphologic marker for this syndrome. Here, we present PASH with MGC occurring in the left breast of a 39-years-old woman who does not have neurofibromatosis. This case, along with two additional ones reported previously, indicates that PASH with MGC in the female breast may not be associated with neurofibromatosis.     

Rapidly growing nodular pseudoangiomatous stromal hyperplasia of the breast in an 18-year-old girl

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a rare benign proliferation of mesenchymal stromal cells with irregular slit-like formations resembling angiomatous structures. In the majority of cases this lesion is a focal microscopic finding in breast biopsies performed for benign or malignant diseases. It may present in a pure diffuse or nodular form. The exact etiology and pathogenesis of this tumor-like lesion is still unknown, but a proliferative response of myofibroblasts to hormonal stimuli has been postulated. A large 12 x 9 x 3.5 cm rapidly growing nodular form of PASH of the breast in an 18-year-old woman is here described with clinical and histological findings. A possible hormonal etiology was indicated by elevated progesterone (three-fold) and decreased estrogen serum levels. Different diagnostic lesions, such as giant fibroadenoma and low-grade angiosarcoma, are discussed. To the authors' knowledge this is only the fourth case of nodular PASH of the breast reported in the English literature.     

Unilateral gynecomastia and pseudoangiomatous stromal hyperplasia in neurofibromatosis: case report and review of the literature

In this article, we describe unilateral gynecomastia and pseudoangiomatous stromal hyperplasia (PASH) in a case of type-1 neurofibromatosis (NF-1). It is important to distinguish PASH from fibroadenoma clinically, and from true blood capillaries and angiosarcoma histologically. In the present case, giant multinucleated cells lined the pseudovascular spaces, which was markedly different from that of conventional breast PASH. The origin of PASH has been reported to be either the fibroblast or the myofibroblast phenotype and may be affected by endocrine signaling because many cases have been reported in premenopausal women, and cases are often estrogen (ER) and progesterone receptor (PR) positive. However, previous reports have identified PASH in NF-1 in juvenile males only, and the cases were negative for α-SMA, ER and PR. The cause and prognosis of PASH in NF-1 may be distinguished from that of conventional PASH, and mast cells, histiocytes and CD54 may play roles.     

Pseudoangiomatous hyperplasia of mammary stroma: a case of pure type after removal of fibroadenoma

A case of pure pseudoangiomatous hyperplasia of the mammary stroma after removal of a fibroadenoma is described. The lesion, which was found in the right breast of a 40-year-old woman, was a well-circumscribed non-encapsulated, rubbery, lobulated mass measuring 40x40x35 mm. Histologically, it consisted predominantly of a proliferation of spindle cells with interanastomosing vascular-like arrangements in the interlobular or interductal stroma. Neither cytological atypia nor mitotic figures were observed. The stroma contained abundant collagen with focal hyalinization. Focally, epithelial elements showed mild ductal hyperplasia. There was no fibroadenoma. Immunohistochemically, the spindle cells were positive for vimentin, CD34, alpha-smooth muscle actin, muscle actin, CD34, calponin, and progesterone receptors. Ultrastructurally, many spindle cells had thin elongated cytoplasmic processes, which enveloped pseudovascular spaces containing a few collagenous fibrils, indicating fibroblastic cells. This lesion should be distinguished from other mammary fibrous and vascular lesions with which it may be confused.     

Aspiration biopsy of nodular pseudoangiomatous stromal hyperplasia of the breast: clinicopathologic correlates in 10 cases

Nodular pseudoangiomatous stromal hyperplasia (PASH) of the breast is rare and often indistinguishable from fibroadenoma, clinically and on aspiration biopsy smears. We report our observations in 10 patients with PASH, evaluated by fine-needle aspiration (FNA) biopsy and core biopsy. We retrospectively reviewed the clinical, radiographic, cytologic, and histologic findings in 10 cases of pure nodular PASH. Ten patients with a presumed clinical and radiologic diagnosis of fibroadenoma underwent aspiration biopsy. The aspiration smears were diagnosed as fibroadenoma (4 cases), cellular fibroadenoma (1 case), schwannoma versus neurofibroma (1 case), fibrocystic change (3 cases; 2 with atypia), and "not specific for a lesion" (1 case). A diagnosis of PASH was not suspected in any case. A discrepant or imprecise cytologic diagnosis and/or the presence of dissociated spindle or epithelial cells, or cellular stromal fragments prompted a surgical excision in 7 of 10 patients (70%). The remaining 3 patients exhibited cytologic features of fibroadenoma and were diagnosed as such; however, surgical excision was recommended. Three patients underwent a subsequent core biopsy, with a diagnosis of PASH being made in 1 patient. FNA biopsy could not discriminate PASH from fibroadenoma in 4 of 10 patients (40%) or suggest a diagnosis of PASH in any case. On retrospective review, the finding of plump, spindle-shaped mesenchymal cells may be a cytologic clue to suggest a diagnosis of PASH.     

Rapidly-growing nodular pseudoangiomatous stromal hyperplasia of the breast: case report

Pseudoangiomatous stromal hyperplasia is a benign proliferative lesion of the mammary stroma that rarely presents as a localized mass. Pseudoangiomatous stromal hyperplasia is characterized by a dense, collagenous proliferation of the mammary stroma, associated with capillary-like spaces. Pseudoangiomatous stromal hyperplasia can be mistaken with fibroadenoma on radiological examination or with low-grade angiosarcoma on histological examination. Its main importance is its distinction from angiosarcoma. The presented case was a 40-year-old woman who was admitted with a rapidly growing breast tumor. Physical examination revealed an elastic-firm, well-defined, mobile and painless mass in her right breast. Mammograms revealed a 6.7 x 3.7 cm, lobulated, well-circumscribed mass in her right breast but no calcification. Sonographic examination showed a well-defined and homogenous mass, not including any cyst. Based on these findings, a provisional diagnosis of fibroadenoma was made. Considering the rapid growth history of the mass, tumor excision was performed. The excised tumor was well demarcated and had a smooth external surface. Histological examination revealed the tumor to be composed of markedly increased fibrous stroma and scattered epithelial components (cystic dilatation of the ducts, blunt duct adenosis). The fibrous stroma contained numerous anastomosing slit-like spaces. Isolated spindle cells appeared intermittently at the margins of the spaces resembled endothelial cells. Immunohistochemical staining showed that the spindle cells were positive for CD34 and negative for Factor VIII-related antigen. The lesion was diagnosed as nodular pseudoangiomatous stromal hyperplasia.     

Diagnosis of pseudoangiomatous stromal hyperplasia of the breast: ultrasonography findings and different biopsy methods

Purpose

Pseudoangiomatous stromal hyperplasia (PASH) of the breast is a rare, benign condition that can be mistaken as a fibroadenoma on an ultrasound examination or as a low-grade angiosarcoma on a histological examination. The objective of this study was to evaluate the ultrasound features and to present biopsy methods to correctly identify PASH.

Patients and Methods

We retrospectively reviewed the data of 55 women who were diagnosed with PASH of the breast. Ultrasound features were evaluated according to the Breast Imaging Reporting and Data System (BI-RADS; American College of Radiology). The diagnostic ability of different biopsy methods such as core needle biopsy, vacuum-assisted biopsy and excisional biopsy were analyzed with the final histopathological results of surgical specimens.

Results

PASH presented as a circumscribed solid mass, with hypoechoic texture with or without heterogeneity, and a parallel orientation. The features of small, internal cysts or vascular channels and no calcifications can be used to differentiate the lesions from fibroadenomas. A core needle biopsy misdiagnosed PASH in 13 cases out of 28 cases and vacuum-assisted biopsy correctly identified PASH in all 3 cases.

Conclusion

Ultrasound features of PASH should be noted when performing a biopsy. For inconclusive cases of PASH, an excisional biopsy followed by an initial core biopsy should be performed.     

Aggressive giant fibroepithelial lesion with unusual vascular stroma--a case report.

The stroma of fibroadenoma and phyllodes tumor usually consists of fibroblastic proliferation. Rarely the stroma contains bundles of smooth muscle. Pseudoangiomatous hyperplasia of the mammary stroma has been described in fibroadenomas. However, true benign vascular stroma has not been reported. We report a case of a 34-year-old Chinese woman who presented with a large mass occupying the entire left breast. Left mastectomy was performed and showed a large, well-circumscribed, lobulated, rubbery-firm tumor measuring 13 x 10 x 6 cm. Microscopic examination revealed a fibroepithelial tumor formed by an organoid pattern of ductal structures with a very striking stromal appearance composed of extensive vascular proliferation and that demonstrated strong immunoreactivity for CD31, CD34, and Factor VIII. Ultrastructural examination revealed intercellular junctions, basal lamina, pinocytotic vesicles, and Weibel-Palade bodies in the cells lining the vascular spaces, confirming their endothelial nature. These findings rule out the diagnosis of pseudoangiomatous hyperplasia. The patient developed local recurrence a year later, and the resection showed malignant phyllodes tumor with ductal carcinoma in situ.The extensive vascular stroma noted in the primary tumor may have played a role in the malignant transformation of the epithelial and stromal components in this tumor.     

Mouse strain-specific patterns of mammary epithelial ductal side branching are elicited by stromal factors.

Variations in mammary ductal side branching patterns are known to occur between different strains of mice and this is related to the rate of spontaneous mammary cancers, which are increased in those strains which show highly side-branched mammary architecture. The cause of the variation in ductal side branching between mouse strains is unknown, but epithelial, stromal, and endocrine factors have been implicated. To define the mammary elements responsible for controlling strain-specific ductal side branching patterns, we formed recombined mammary glands from epithelial and stroma elements taken from highly side-branched 129 and poorly side-branched C57BL/6J mammary glands and transplanted them to Rag1(-/-) hosts on the inbred C57BL/6J background. When 129 epithelium was recombined with C57BL/6J stroma the poorly side-branched C57BL/6J pattern was observed. C57BL/6J epithelium recombined with 129 stroma resulted in development of the highly side- branched pattern, as did 129 epithelium recombined with 129 stroma. All transplants used the same C57BL/6J endocrine background, demonstrating that strain differences in the mammary stroma are responsible for the strain-specific ductal side branching patterns and that strain differences in epithelium or endocrine background play no part. Genes currently known to influence side branching by means of the stroma include activin/inhibin, epidermal growth factor receptor (EGFR), Wnt-2, Wnt-5a, and Wnt-6. Of these, Wnt-5a mRNA expression was decreased in 129 mammary glands compared with C57BL/6J mammary glands, but in F2 129:C57BL/6J animals Wnt-5a mRNA expression level did not correlate with the highly variable side branching patterns observed. These experiments exclude variation in the expression level of known candidate genes as the mechanism responsible. Regardless of underlying mechanism, transplantation without regard to the genetic background of the stromal donor, whether inbred or mixed, will compromise experiments with side branching and associated gene expression endpoints.     

Expression of CD34 and bcl-2 in phyllodes tumours, fibroadenomas and spindle cell lesions of the breast

AIMS: Strong expression of CD34 and bcl-2 has been described in solitary fibrous tumours. It has been proposed that these lesions arise from long-lived mesenchymal cells. We tested the hypothesis that spindle cell lesions of the breast arise from similar mesenchymal cells in the mammary stroma. METHODS and RESULTS: Sections of phyllodes tumours (26), fibroadenomas (15), myofibroblastomas (two), pseudoangiomatous hyperplasia (five) and myoid hamartoma (one) were stained immunohistochemically for CD34 and bcl-2. Conventional mammary carcinoma is known to be CD34-negative: we therefore stained 11 spindle cell carcinomas and one adenosquamous carcinoma. The mammary stroma, particularly around lobules, stained for CD34. All the lesions (except the carcinomas) showed spindle cell staining for CD34. There was more staining in fibroadenomas than in phyllodes tumours (especially malignant tumours). The staining in phyllodes tumours was typically patchy. In some there was increased or decreased staining adjacent to the epithelium. There were occasional spindle cells positive for bcl-2 in the normal perilobular stroma. bcl-2 was frequently expressed in spindle cells in fibroadenomas, phyllodes tumours and pseudoangiomatous hyperplasia, and rarely in the other lesions. CONCLUSIONS: The combined expression of CD34 and bcl-2 suggests that fibroadenomas, phyllodes tumours and pseudoangiomatous hyperplasia may arise from long-lived bcl-2-positive mesenchymal cells in the breast in a manner similar to that proposed for solitary fibrous tumours. The absence of CD34 staining in spindle cell carcinomas is of potential diagnostic value in the distinction from malignant phyllodes tumours in difficult cases.     

Morphological characteristics of mucinous cancer of the breast containing endocrine cells

It was established that mucus-forming mammary gland carcinoma containing endocrine cells may have a structure of an ordinary colloid mammary gland carcinoma or carcinoid carcinoma with mucus formation. The presence of amyloid in the stroma of colloid carcinoma containing endocrine cells may serve as an additional sign of the endocrine cell differentiation. Simultaneous observation in the tumour cells of both mucous inclusions and endocrine granules may be regarded as a proof of an origin of epithelial and endocrine cells of the mammary gland from a pluripotent stem cell.     

Benign spindle cell tumors of the mammary stroma: diagnostic criteria, classification, and histogenesis

Purely benign mesenchymal spindle cell neoplasms of the breast are currently labeled under various terms in the literature (benign spindle cell tumor, fibroma, spindle cell lipoma, myofibroblastoma, solitary fibrous tumor, myogenic stromal tumor). The lack of strict diagnostic criteria to clearly indicate such mesenchymal neoplasms is the main reason which generated the risk of terming the same lesion under different names or, conversely, of collecting different types under the same term. Although such neoplasms exhibit morphological and immunophenotypical heterogeneity, they actually represent variations of the same tumor entity, likely arising from the uncommitted vimentin+/CD34+ fibroblasts of the mammary stroma, capable of multidirectional mesenchymal differentiation. To cover the entire spectrum of such lesions, the term "benign spindle cell tumors (BSCTs) of the mammary stroma" is advocated. BSCTs can be subtyped into four main groups by light microscopy (LM) and immunocytochemistry (ICC): fibroblastic, myofibroblastic, fibrohistiocytic, and mixed forms. A simple and practical approach to a nosologically correct diagnosis and a list of differential diagnoses are presented. The awareness of the diversity of morphological and immunophenotypical features of BSCTs of the mammary stroma, including uncommon variants, is helpful to avoid confusion with other monomorphic bland-looking benign and malignant spindle cell tumors and tumor-like lesions of the breast.     

Stroma formation in epithelial malignant tumors]

The mechanism of stroma-formation and rearrangement of the stroma was studied on 221 cases of cancer of the lung, stomach and mammary gland using histological, histochemical and electron-microscopy methods of investigation. It was established that multiplying epithelial elements of teh tumour induced proliferation of histiogenic and vascular fibroblasts, activating them. Active fibroblasts play a double role: they either produce fibres and interstitial matter of the tumorous stroma, or participate in desintegration of preceding and newly formed collagenous structures. The processes of stroma-formation comply with the conventional schemes of normal fibrillogenesis and rearrangement of the interstitial tissue. It was shown that fibroblasts of the tumour stroma was capable of phagocytosis of a mature collagen. It is supposed that in the course of the tumorous growth correlation between the parenchyma and stroma is maintained, the leading role being played by the epithelium.