Angiosarcoma and atypical vascular lesions of the breast: diagnostic and prognostic role of MYC gene amplification and protein expression.

MYC amplification has been reported as a prominent feature of secondary angiosarcomas (SAS). The differential diagnosis between atypical vascular lesion (AVL) and low-grade angiosarcoma (AS) can be occasionally very difficult or even impossible, and MYC amplification status has been pointed as an important diagnostic tool to distinguish cutaneous vascular lesions of the breast. We assessed MYC amplification and protein expression status by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC), respectively, in 49 patients diagnosed with breast AS, and 30 patients diagnosed with post-radiation AVL of the breast. Clinical and pathological features, and follow-up data were collected, and survival analyses were performed. Among 37 patients with SAS, twenty patients had tumors with high-level MYC amplification and protein overexpression (54 %). None of primary angiosarcomas (PAS) or AVL cases showed MYC amplification or protein expression. Concordance between MYC amplification (FISH) and protein expression (IHC) was 100 % in AVL, PAS, and SAS. Survival analysis of the SAS patients demonstrates that those with MYC amplification had a significantly worse overall survival compared to cases without MYC amplification (P = 0.035). There was a non-significant trend toward a poor disease-free survival between cases with and without MYC amplification (P = 0.155). Our findings show that MYC amplification is a highly specific but poorly sensitive marker for SAS and, therefore, a negative result does not exclude the diagnosis of angiosarcoma. MYC amplification was associated with adverse prognosis, suggesting a prognostic role of MYC amplification status on SAS of the breast.

Clinicopathological and immunohistochemical study of 30 cases of post-radiation atypical vascular lesion of the breast.

Atypical vascular lesions (AVL) that occur in the field of prior radiation therapy for breast carcinoma are placed within the differential diagnosis with low grade angiosarcoma and other benign vascular lesions. Although considered a benign entity, the exact biological behavior of AVLs is not fully established because of the small number of cases reported in the literature. We aim to further characterize these lesions clinically and histopathologically, and to study their behavior. We report a series of 30 patients with AVL of the breast occurring after radiation exposure, diagnosed and treated at the European Institute of Oncology, Italy. Immunohistochemical study was performed in all cases, using CD31, D2-40, CD105, and Ki-67 antibodies. Twenty-seven patients were treated with standard doses of conventional adjuvant radiation therapy for the prior breast carcinoma. Three patients were treated with intraoperative radiotherapy with electrons. The post-radiation latency interval from breast carcinoma to AVL was 48.5 months (ranged from 1 to 146 months). Most of the lesions were classified as lymphatic type (78.6 %) based on D2-40 positivity. No extension into subcutaneous tissue or significant atypia was noted in all cases. Despite the fact that the AVL of our series have shown benign behavior in 93.3 %, one patient developed local recurrence of AVL, and two cases progressed to angiosarcoma at the previous AVL site. Further studies should be conducted to better understand the clinical behavior and to propose additional histopathologic diagnostic criteria to distinguish AVL from low grade angiosarcoma and those AVL with increased risk for malignant progression. Concerning current treatments of AVL, we recommend complete excision with free surgical margins and close follow up.

Histological and immunohistochemical identification of atypical ductal mammary hyperplasia as a preneoplastic marker in dogs.

This study describes and evaluates the morphological and molecular relationship between canine mammary ductal hyperplasias with atypia and canine mammary neoplasias. Ductal hyperplasia was identified in association with malignant neoplasia in 56 of the 115 cases (48,8%), and although ductal hyperplasia without atypia was the type most frequently noted in the cases, most examples of hyperplasia with atypia were associated with mammary tumors. Estrogen receptor, E-cadherin, and cytokeratins 1, 5, 10 and 14 (CK34bE12) expression was quite lower than in normal mammary tissue, and HER2 overexpression was absent in all proliferative cells of ductal hyperplasia. The Ki-67 expression, epidermal growth factor receptor and progesterone receptor expression appeared higher in those hyperplastic lesions analyzed than in normal mammary glands. These findings suggest that canine mammary atypical hyperplasia may play an important role in the process of malignant neoplastic transformation, with molecular alterations that are similar to precursor lesions reported in humans.

Transforming growth factor-beta and breast cancer risk in women with mammary epithelial hyperplasia.

BACKGROUND: Transforming growth factors-beta (TGF-betas) regulate mammary epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta-RII) is related to cell proliferation and tumor progression. Breast epithelial hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and the risk of subsequent invasive breast cancer. METHODS: We conducted a nested case-control study of women with biopsy-confirmed EHLA who did not have a history of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54) who subsequently developed invasive breast cancer were matched with control patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of breast biopsy specimens of all 169 patients with EHLA were studied by immunohistochemical analysis with antibodies against TGF-beta-RII. All P values are two-sided. RESULTS: Women with breast EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectively (P for trend =.008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a heterogeneous pattern of TGF-beta-RII expression in their normal breast lobular units and either greater than 75%, 25%-75%, or less than 25% positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively (P for trend =.003). These risks are relative to women with a homogeneous pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA. CONCLUSION: This study indicates that loss of TGF-beta-RII expression in epithelial cells of EHLA is associated with increased risk of invasive breast cancer.

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion.

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS). This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded. Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands. Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinterpretation as invasive mammary carcinoma.

A case-control study of risk factors for breast cancer in Brazil, 1978-1987.

BACKGROUND: There are still controversies regarding the role of many risk factors assessed for breast cancer worldwide. In Brazil, it represents a major cause of death among women but yet few analytical studies have been published to date. METHODS: The association of selected factors with breast cancer was assessed in a case-control study of 300 women, aged 25-75 years, treated at the Federal University Hospital, Belo Horizonte, Brazil, from 1978 to 1987. In all, 300 cases with diagnosed breast carcinoma were compared with 600 controls matched on age and date of diagnosis. Socio-economic, demographic and reproductive factors were analysed. RESULTS: Multiple logistic regression analysis showed the following factors to be independently associated with increased risk of breast cancer: a) monthly family income (odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.18-2.42); b) being a housewife (OR = 2.86, 95% CI: 1.83-4.47; c) parity of less than six deliveries and nulliparous women (OR = 5.06, 95% CI: 3.01-8.52 and OR = 2.42, CI: 1.64-3.59, respectively); d) history of breast cancer among first degree female relatives (OR = 9.35, 95% CI: 3.22-27.14); and e) oral contraceptive use (OR = 1.81, 95% CI: 1.15-2.85). Irregular menstrual cycle (OR = 0.44, 95% CI: 0.25-0.75) was associated with breast cancer as a protective effect. CONCLUSIONS: The study has confirmed most risk/protective factors previously demonstrated elsewhere in the world and provides clear documentation of breast cancer epidemiology in Brazil.

Reactive spindle cell nodules of the breast after core biopsy or fine-needle aspiration.

Reactive spindle cell nodules (RSCNs) arising postoperatively or after fine-needle aspiration (FNA) have been reported previously in the genitourinary tract and thyroid. We describe 18 cases of similar lesions in breast, associated with a history of core needle biopsy or FNA. The majority of the RSCNs (15 cases) were associated with papillary lesions or complex sclerosing lesions. The RSCNs were nonencapsulated and relatively nodular, measuring 1.5 to 9 mm. They were composed of spindle cells with mild to moderate nuclear pleomorphism and a low mitotic count. A network of small blood vessels, macrophages, and lymphocytes was present in all cases. Immunohistochemically, the spindle cells expressed smooth and specific muscle actins, supporting a myofibroblastic origin. The association of RSCNs with needle trauma to fibrosclerotic lesions, such as complex sclerosing lesions and papillary lesions that regularly have myofibroblasts, suggests an exuberant reparative cause. Recognition of this reactive process will avoid overdiagnosis of mammary spindle cell malignant neoplasm.

Inflammatory myofibroblastic tumour of the breast: report of a case with giant vacuolated cells.

Inflammatory myofibroblastic tumours (IMTs) or inflammatory pseudo-tumours are uncommon lesions of unknown aetiology. The majority of the cases are reported in the lungs of young patients. Extra-pulmonary anatomic locations include the abdomen and pelvis, but rare cases have been described in the breast. We describe an IMT in an 86-year-old female, presenting as a well-circumscribed palpable mass in the left breast. Histologically the remarkable feature was the presence of giant vacuolated cells intermixed with spindle cells and a prominent plasma cell infiltrate immersed in a fibrous hyalinized stroma. Immunohistochemical and electron microscopy studies demonstrated the myofibroblastic nature of the giant vacuolated cells and the spindle cells, and the polyclonal nature of the plasma cells. The morphologic and immunohistochemical findings supported the diagnosis of IMT. The biological behaviour of IMT in this age group is unknown and surgical excision with close mammographic follow-up is considered to be appropriate treatment for this lesion in the breast.

Androgen receptor CAG repeat lengths in ductal carcinoma in situ of breast, longest in apocrine variety.

CAG repeat number in the androgen receptor (AR) has been associated with decreased prostate cancer risk, and AR expression has been found in female breast cancer, often associated with apocrine differentiation. Because trinucleotide expansion can alter gene expression and protein function, we hypothesized that it might occur in breast neoplasms. We used a repeat expansion detection technique to determine CAG repeat lengths in DNA from breast biopsies. Three lesion types were microdissected: fibroadenoma (48 cases), ductal carcinoma in situ (DCIS, 24 cases), and invasive mammary carcinoma (18 cases). The maximum number of CAG repeats in either allele of each patient in these three groups was compared. Microsatellite repeat lengths in DCIS were longer than in fibroadenomas or invasive carcinomas (P= 0.017 comparing DCIS vs invasive carcinomas). Two cases of apocrine DCIS had very long repeat lengths, both exhibiting microsatellite lengths at the longest range of normal (32 and 33). Inherited differences in AR CAG length might influence the transition from DCIS to invasive breast cancer, perhaps by modulating function of AR in breast tissue. AR microsatellite polymorphisms could influence cellular differentiation in DCIS lesions, promoting formation of the apocrine subtype in the presence of longer CAG repeats.

Gastric acetylcholine and histamine content of normal and Trypanosoma cruzi-infected rats.

1. The consequences of acute Trypanosoma cruzi infection for acetylcholine and histamine levels in gastric wall and for mast cells of the stomach were studied in rats. 2. Intraperitoneal infection with 4,000 trypomastigotes/g of a Y strain of Trypanosoma cruzi led to a 4-fold decrease in gastric acetylcholine level and to a 57- and 15-fold increase in histamine content in the membranous and glandular regions of the rat stomach, respectively. 3. Infection of rats with Trypanosoma cruzi also induced a 2- and 4-fold increase in mast cell numbers in the membranous and glandular regions of the muscle layer of the gastric wall, respectively, and a ganglionic inflammatory reaction with predominance of mononuclear cells. 4. We conclude that in acutely Trypanosoma cruzi-infected rats, the reduction of acetylcholine content is due to gastric denervation and that the histamine increase might be secondary to gastric denervation and/or to an increase in the number of mast cells of the gastric wall.

[Central pontine and extrapontine myelinolysis: report of an autopsied case and review of the literature]. / Mielinólise pontina central e extra-pontina: apresentação de um caso autopsiado e revisão da literatura.

An autopsied case of central pontine and extrapontine myelinolysis in a 16-year-old diabetic girl is described. Due to dehydration she was treated vigorously with daily intravenous isotonic saline, from the first day of hospitalization. In the first three days the serum sodium level increased by more than 30 mEq/l when compared with the initial level. By the next days the serum sodium level, after a mild drop, rose again and was maintained above normal range for a further 12 days. On the sixth day of this new and sustained serum sodium increase, the patient presented progressive neurological manifestations that remained until her death, characterized by mutism, inability to eat, to move her head, trunk, and members and, in addition, retention of respiratory secretions. The neuropathological examination showed massive central pontine myelinolysis and similar myelinolytic lesions in the subcortical white matter of the temporal lobe, the right optic tract, the external and extreme capsules to the right, the main mammillary tract and the subcortical white matter of the left cerebellar hemisphere. The review of the literature on central pontine and extrapontine myelinolysis shows that the present case is the 30th of such condition. The clinical picture and the etiopathogenesis of central pontine and extrapontine myelinolysis are commented upon. It is suggested, as possible causative factors, the persistent and rapid correction of serum sodium concentration as well as its fluctuation in patients with hyponatremia and/or dehydration.

[Comparative study of the suture of pancreatic stump with absorbable and unabsorbable threads in rats]. / Estudo comparativo da sutura do coto pancreático com fios absorvível e inabsorvível em ratos.

The safety of suture and healing of pancreas after surgery with absorbable and unabsorbable suture was studied. One hundred and twenty female rats was underwent a segmentar pancreatic resection. The pancreatic suture was performed with catgut in Group I (n = 48), polygalactin in Group II (n = 48) and silk in Group III (n = 24). The animals were sacrificed at 5th, 10th, 20th and 30th days after surgery and analized at macroscopy: inflammatory signs, fistula, abscess and suture bearing in tissue. Microscopic findings were: suture bearing in tissue, inflammatory aspects against suture, necrosis, edema, neovascular modifications, fibrosis and the collagen's type. After comparing the results with Wilcoxon's two sample test, we concluded that pancreatic healing was not modified with differents sutures, and then pancreatic absorbable or unabsorbable suture was safe.

[Cutaneous melanoma: clinical versus anatomopathological diagnosis]. / Melanoma cutâneo: diagnóstico clínico x anatomopatológico.

In order to estimate the ability of physicians to make the clinical diagnosis of cutaneous malignant melanoma, a retrospective study was carried out. A comparison between clinical hypothesis and histopathological diagnosis was assessed. The rate of diagnostic accuracy was only 51%. There were problems in the differential diagnosis between malignant melanoma and other pigmented skin lesions. The majority of the cases of melanoma was recognized in advanced stages of tumor invasion. These data point out toward the need of improving the skills of the general physicians in the clinical recognition of the cutaneous melanoma and its precursor lesions.