Bonita K.B. Law

Hamartoma of the breast: a clinicopathological review

Aims: To review 25 cases of breast hamartoma and discuss the pathological criteria, and the usefulness of imaging modalities, fine needle aspiration cytology (FNAC), and needle core biopsy in the diagnosis. Methods: The hamartomas were assessed for interlobular fibrotic stroma, stromal adipose tissue content, pseudo-angiomatous stromal hyperplasia, and epithelial changes (hyperplasia, adenosis or apocrine metaplasia, and cyst formation). All imagings, previous FNACs, and biopsies were also reviewed. Results: Imaging (mammography, ultrasound, and magnetic resonance imaging) was performed in 18 cases, and mostly showed encapsulated masses with a heterogeneous appearance. Microscopically, all hamartomas demonstrated good demarcation with fibrous tissue condensation. Adipose tissue was noted in all cases (5–90%; mean, 31%), and interlobular fibrosis in 21 cases. Benign epithelial hyperplasia occurred in 10 cases, and pseudo-angiomatous stromal hyperplasia or cystic ducts in eight cases each. Apocrine metaplasia, calcification, stromal giant cells, and adenosis occurred in four cases or less. Two cases showed coexisting ductal carcinoma in situ limited to within the hamartoma. Needle core biopsies (four cases) and FNAC (14 cases) were largely insufficient, inconclusive, or non-specific. Conclusions: Hamartomas do not possess specific diagnostic histological features. The role of FNAC and needle core biopsy in making the diagnosis is limited, and requires clinical and radiological correlation to avoid underdiagnosis.

Granulomatous mastitis: a clinicopathological review of 26 cases

Aims: Twenty‐six cases of granulomatous mastitis were examined to determine the common histological and clinical features and the possible association with micro‐organisms. Methods: A retrospective review of the clinical and histological features of these cases was undertaken, including granuloma, inflammatory cell infiltrate, multinucleated giant cells, necrosis and lymphocytic lobulitis, as well as special stains for micro‐organisms including Mycobacterium, other bacteria and fungus. PCR for Mycobacterium tuberculosis DNA was also performed in 19 cases. Results: Granulomas were present in all cases (100%) while multinucleated giant cells were seen in 17 cases (65%), background inflammatory cell infiltrate in 23 cases (88%), predominantly lymphocytes in 18 cases (69%), significant lymphocytic lobulitis in 13 of 19 cases (68%) and necrosis in three cases (11%). Special stains and cultures for micro‐organisms were all negative. Clinically, four cases (15%) were associated with duct ectasia, eight (31%) with abscess, and there was no such association in 14 cases (54%). Of the 19 cases with PCR for tuberculosis, one case showed Mycobacterium DNA in the sample, raising the possibility of occult tuberculosis infection. Conclusions: Granulomatous mastitis is a heterogeneous group of diseases with a diverse clinical picture and association. Most idiopathic cases are not associated with specific micro‐organisms.

Fine needle aspiration cytology of granulomatous mastitis

Aims: Granulomatous mastitis (GM) is an uncommon breast lesion that mimics carcinoma. The fine needle aspiration cytological (FNAC) features of GM have rarely been discussed in the literature. These features are reported in eight histologically confirmed cases of GM. Methods: A retrospective study was undertaken in which a diagnosis of GM had been made on histopathology, and the FNAC slides were reviewed and assessed for the presence of granulomas, necrosis, multinucleated giant cells, and inflammatory background cells. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis was performed on the histological material to exclude tuberculosis. Results: All cases were confirmed histologically and PCR for mycobacterial DNA was negative. In the FNACs, varying numbers of granulomas composed of epithelioid histiocytes were present in four cases. The same four cases showed giant cells of either foreign body or Langhan’s type. No necrosis was noted. Six cases showed many histiocytes, some plump and others epithelioid, in the background. The number of epithelioid histiocytes corresponded to the presence of granulomas. Neutrophils were the predominant background inflammatory cells in most cases (six). Conclusions: The cytological diagnosis of GM is difficult because the features overlap with other aetiologies, including tuberculosis. Specific features are absent. The absence of necrosis and a predominantly neutrophilic infiltrate in the background favour a diagnosis of GM. This diagnosis should also be considered when abundant epithelioid histiocytes are seen in smears, even in the absence of granulomas. However, the definitive diagnosis of GM depends on histology from fine needle biopsies and negative microbiological investigations.

Increased p53 Protein Expression in Malignant Mammary Phyllodes Tumors

The authors reviewed 143 cases (87 benign, 37 borderline, and 19 malignant) of mammary phyllodes tumors (PTs) and used immunohistochemistry to detect p53 protein product semi-quantitatively as negative, weak, moderate and strong (scored 0 to 3). For all PTs, an increasing trend of tumor size and malignancy was detected with increasing age. For p53 staining, 60 cases (42%) were negative, 55 (38%) stained weakly, 28 (13%) stained moderately, and 10 (7%) stained strongly. Of the 87 benign PTs, 41 (47%) were negative, 37 (43%) stained weakly, and 9 (10%) stained moderately. For the 37 borderline PTs, 16 (43%) were negative, 14 (38%) stained weakly, 6 (16%) stained moderately, and 1 (3%) stained strongly. Of the 19 malignant PTs, 3 (16%) were negative, 4 (21%) stained weakly, 3 (16%) stained moderately, and 9 (47%) stained strongly. The mean intensity score for p53 staining increased progressively from benign to borderline to malignant PT, with established statistical significance (P < .0001). This is significantly correlated with mitotic count but not stromal cellularity, pleomorphism, margin, and stromal overgrowth. When considering strong staining alone (score, 3), 47% of malignant, 3% of borderline, and none of the benign PTs were positive. The use of strong positive staining for diagnosing malignant PT gave positive and negative predictive values, specificity, and sensitivity of 90%, 92.5%, 99%, and 47%, respectively. Thus diffuse strong p53 protein staining can be used as a soft sign in assisting the diagnosis of malignant PT. Conversely, negative or weak staining of p53 protein in PT is of little discriminatory value. The role of p53 gene mutation in the malignant transformation of PT is unclear; but this may not be the sole mechanism as many malignant PT were p53 protein negative.

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (χ2=13.844, P=0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.

Hormonal Receptors Expression in Epithelial Cells of Mammary Phyllodes Tumors Correlates With Pathologic Grade of the Tumor A Multicenter Study of 143 Cases

We used immunohistochemical analysis to detect the presence of estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) protein expression in the epithelial and stromal cells of 143 phyllodes tumors (PTs). Expression of epithelial ER and PR proteins was common, occurring in 43% to 84% of PTs. Expression of epithelial AR protein and stromal ER, PR, and AR proteins was low (5% or less) in all tumors. An inverse relationship of epithelial ER and PR protein expression with degree of malignancy in PT was found (P < .05), and ER expression also correlated with mitotic count (P < .05). When considering PT with the expression of ER or PR proteins and the coexpression of both, the inverse relationship with tumor grade also was significant (P < .05). As the hormonal receptor protein expression shows a consistent decrease with increasing malignancy, we infer that the epithelium has a crucial role in the pathogenesis or progression of PT.

Tumour Angiogenesis and p53 Protein Expression in Mammary Phyllodes Tumors

We examined 186 phyllodes tumors (106 benign, 51 borderline, 29 malignant) for angiogenesis by assessing stromal microvessel density by the hot spot method and assessing p53 protein expression; we correlated these factors with stromal cellularity, margin status, nuclear pleomorphism, mitosis, and stromal overgrowth. Increased degree of malignancy in phyllodes tumors is associated with increased patient age and tumor size. Microvessel density and p53 protein expression also showed a similar increase with malignancy. Using a logistic regression model, microvessel density was shown to be useful in predicting malignancy in phyllodes tumors, independent of key criteria of stromal overgrowth, nuclear pleomorphism, and mitosis. Microvessel density showed correlation with stromal cellularity and margin status, suggesting an interrelationship between these parameters. P53 protein expression showed a positive correlation with microvessel density, suggesting possible overlap in the underlying mechanism of these two factors in the pathogenesis of phyllodes tumors. The numbers of recurrences and metastases are small in our series, and no significant difference was demonstrated in microvessel density and p53 protein expression compared with the primary. We conclude that microvessel density and p53 are useful as independent criteria in evaluating malignancy in phyllodes tumors.

Multinucleated stromal giant cells in mammary phyllodes tumours

Summary Mammary phyllodes tumour (PT) is an uncommon fibro‐epithelial neoplasm with a prominent stromal component. We report five cases of PT (one benign, three borderline, one malignant) with giant cells in the stroma. All occurred in adults and ranged from 1.8 to 4.0 cm in size. The overall cellularity, stromal cell pleomorphism and mitotic count was higher for the malignant and borderline than the benign PT. The giant cell number ranged from 18 to 35 cells per 10 high power fields, but there was no relationship between this number and the grade of the PT. Most giant cells were subepithelial, with multiple nuclei arranged in a linear or irregular pattern, and moderate amount of cytoplasm. The immunohistochemical profile of the giant cells was similar to the stromal cells. In all cases, both giant cells and stromal cells expressed vimentin strongly but not desmin; in two cases, both cell populations expressed actin weakly. The respective percentage of giant cells and stromal cells expressing MIB1 was also similar. This suggests that these giant cells do not represent a different, more active stromal population, despite the more bizarre appearance. In view of the small number of cases, the significance of such giant cells on the prognosis of PT remains uncertain.

MR imaging of primary breast fibromatosis

Abstract Fibromatosis of the breast is a very rare mesenchymal neoplasm. Most of the cases reported arise from the aponeurosis or muscular fascia of the chest wall or shoulder girdle, involving the pectoralis muscle in patients with history of previous surgery (Cancer 41 (1978) 1409). We report a case of pathologically proven primary fibromatosis of the breast in a young woman, in which the neoplasm arises de novo and is not attached to the chest wall. Mammographically, it appears as a high-density spiculated mass and sonographically, it is irregular and hypoechoic. MR imaging showed that it is hyperintense on both T1- and T2-weighted images and is contrast enhancing.