Follow-up of tissue genomics in BRCA1/2 carriers who underwent prophylactic surgeries.

PURPOSE: The genomic status of non-malignant tissues from carriers of pathogenic germline BRCA1/2 (gBRCA1/2) variants may reveal information towards individualized prophylaxis. We performed spatiotemporal tissue genotype comparisons in a real-life cohort of gBRCA1/2 carriers of Greek origin, who underwent multiple risk-reducing/prophylactic surgeries at various time points. METHODS: Fifty-three women (median age 36 years) within cancer families were observed for up to 37.5 years; 43 were cancer carriers and 10 were healthy carriers. Histology review and genotyping were performed for 187 paraffin tissues (average: 3.5 per carrier) including 46 carcinomas (40 breast) and 141 non-malignant breast and gynecological samples. RESULTS: High allelic imbalance (AI) and somatic pathogenic TP53 variants were present in cancer carriers only (p values < 0.0001). High AI was associated with gBRCA1/2 indels (p < 0.0001) and gBRCA2 alterations (p = 0.0109). Somatic (pathogenic) variants were infrequently shared between non-malignant tissues and matched carcinomas. Aberrations of gBRCA1 variant heterozygosity were noticed in tissues from cancer carriers only (13/43, 30.2%). These pertained to classic LOH (neoplastic lesions in 9/43 carriers, 20.9%) and under-representation of the germline variants (5 samples, 4 non-malignant, all in the breast). Both aberrations coexisted in matched samples in one case. Over time, germline variant heterozygosity prevailed in non-malignant tissues; intra-carrier genomic alterations were aggravated (21.1%), ameliorated (26.3%) or remained stable. CONCLUSION: This real-life case study supports the need to address tissue genotypes from prophylactic surgeries in combination with polygenic scores towards personalized prophylaxis. To this end, knowing the traditionally classified pathogenic potential of a gBRCA1/2 variant may not be enough.

Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center.

Germline mutations in the BRCA1 and BRCA2 genes are associated with hereditary predisposition to breast and ovarian cancer. Sensitive and accurate detection of BRCA1 and BRCA2 mutations is crucial for personalized clinical management of individuals affected by breast or ovarian cancer, and for the identification of at-risk healthy relatives. We performed molecular analysis of the BRCA1 and BRCA2 genes in 898 Greek families, using Sanger sequencing or Next Generation Sequencing for the detection of small insertion/deletion frameshift, nonsynonymous, truncating and splice-site alterations and MLPA for the detection of large genomic rearrangements. In total, a pathogenic mutation was identified in 12.9% of 898 families analyzed. Of the 116 mutations identified in total 9% were novel and 14.7% were large genomic rearrangements. Our results indicate that different types of mutational events in the BRCA1 and BRCA2 genes are responsible for the hereditary component of breast/ovarian cancer in the Greek population. Therefore the methodology used in the analysis of Greek patients must be able to detect both point and small frameshift mutations in addition to large genomic rearrangements across the entire coding region of the two genes.

Evaluation of the Prognostic Value of RANK, OPG, and RANKL mRNA Expression in Early Breast Cancer Patients Treated with Anthracycline-Based Adjuvant Chemotherapy.

BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription-polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis. CONCLUSIONS: Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts.

Hemangiopericytoma/solitary fibrous tumor of pectoralis major muscle mimicking a breast mass.

INTRODUCTION: Hemangiopericytoma (HPC)/solitary fibrous tumor (SFT) is a very uncommon tumor of uncertain malignant behavior. In 1942, Stout and Murray first characterized these neoplasms as "vascular tumors arising from Zimmerman's pericytes" and till now hemangiopericytomas and solitary fibrous tumors of the soft tissues are regarded as features of the same entity in the soft tissue fascicle. PRESENTATION OF CASE: We present a case of hemangiopericytoma/solitary fibrous tumor of the pectoralis major muscle in a 33-year-old female. She first noticed a painless mass in her right breast. Ultrasound of the breast revealed a large heterogeneously hypoechoic lesion within the pectoralis major muscle. Fine needle aspiration of the tumor did not produce any meaningful result. The lesion was completely removed by surgical resection. Histologically, the tumor had staghorn-like vasculature and immunohistochemistry for CD34 was positive, whereas desmin, smooth-muscle actin, S-100 protein, cytokeratins (AE1/AE3) and epithelial membrane antigen (EMA) were all negative. A diagnosis of hemangiopericytoma/solitary fibrous tumor was rendered. DISCUSSION: Tumors comprising the HPC/SFT spectrum represent a small subset of soft tissue sarcomas and are found virtually at any site in the body. Wide surgical resection can achieve favorable long-term survival. CONCLUSION: Due to the rarity and unpredictable biological potential of these tumors, long-term follow-up is mandatory even after radical resection, because recurrence or development of metastasis may be delayed many years.

Pure mucinous carcinoma with axillary lymph node metastasis in a male breast.

Pure mucinous carcinoma of the male breast is an extremely uncommon malignant breast neoplasm and usually occurs at advanced age. It is characterized by a higher degree of mucus production, a more benign behavior, a lower incidence of metastatic nodal involvement, and a subsequent higher survival rate. We describe such a case of a 59-year-old male, who displayed a gradually growing retroareolar tumor of the right breast. The tumor was well demarcated and had a soft consistency with a gelatinous appearance. Based on the preoperative clinical identification of right axillary lymphadenopathy, the patient eventually underwent right modified radical mastectomy and right axillary nodal dissection. Regarding histological findings, the neoplasm corresponded to a pure mucinous carcinoma with axillary lymph node metastasis. Although lymph node metastasis of pure mucinous carcinoma of the breast is rare, it is essential to perform careful clinical examination when the primary breast mass is suspicious for mucinous carcinoma, because the presence of axillary lymphadenopathy will subsequently define the proper choice of therapeutic strategy.

Breast tumour as the first manifestation of extramedullary relapse of Philadelphia positive (Ph+) acute lymphoblastic leukemia.

Extramedullary relapses of acute lymphoblastic leukemia (ALL) are rare and usually localized in the central nervous system. We describe such an uncommon case of extramedullary relapse of ALL in the breast of a 44 year old female. The patient, who had been diagnosed with precursor B cell, Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) 5 years before and had been in complete molecular remission for the last 19 months, was admitted to the hospital for investigation of a hard, non-tender lump in her right breast. Mammography detected a dense, ill-defined mass, whereas on grey-scale and power Doppler sonography, the appearance of the lesion was consistent with malignancy. Histopathologic and immunohistochemical examination of the specimen demonstrated a similar immunophenotype (CD20+, CD10+, Tdt+, CD3-) as this of the onset ALL cell population in the bone marrow.

Late local recurrence of dermatofibrosarcoma protuberans in the skin of female breast.

Dermatofibrosarcoma protuberans (DFSP) of the breast is exceptionally obscure and late local recurrence of this entity on this site is even more uncommon. We describe such a case in a 48-year-old woman, who at the age of 35 had a DFSP excised from her right breast. Thirteen years later, she developed an ovoid mass in her right breast over the postsurgical scar area. Wide local excision of the tumor with generous tissue margin was performed and microscopic and immunohistochemical findings established the diagnosis of recurrent DFSP. No further treatment was administered and she remains well 18 months later, without tumor recurrence. We report an exceptionally rare case of local recurrence of DFSP in the female breast and discuss in detail the diagnostic and therapeutic implications of this pathology.

Axillary silicone lymphadenopathy secondary to augmentation mammaplasty.

We report a case involving a 45-year-old woman, who presented with an axillary mass 10 years after bilateral cosmetic augmentation mammaplasty. A lump was detected in the left axilla, and subsequent mammography and magnetic resonance imaging demonstrated intracapsular rupture of the left breast prosthesis. An excisional biopsy of the left axillary lesion and replacement of the ruptured implant was performed. Histological analysis showed that the axillary lump was lymph nodes containing large amounts of silicone. Silicone lymphadenopathy is an obscure complication of procedures involving the use of silicone. It is thought to occur following the transit of silicone droplets from breast implants to lymph nodes by macrophages and should always be considered as a differential diagnosis in patients in whom silicone prostheses are present.

Pulmonary sarcoidosis simulating metastatic breast cancer.

The clinical appearance and imaging findings of sarcoidosis and breast carcinoma may sometimes mimic one another, making the differential diagnosis between these two diseases difficult in some cases. A 69-year-old woman displayed an irregular shaped lesion in her left breast. Preoperative localization modalities detected a breast mass with malignant characters. The patient also was found to have pulmonary findings for metastatic disease on chest computed tomography. These features were proven upon biopsy to be consistent with sarcoidosis. The patient underwent breast surgery, adjuvant chemoradiotherapy and hormonal therapy, while corticosteroids were administered for pulmonary sarcoidosis. The patient is well 12 months later, without recurrence. An unfortunate consequence of the presence of both entities in the same patient is the risk of misguided differential diagnosis and incorrect therapeutic strategy. This patient shows the importance of confirming a clinical diagnosis of sarcoidosis with appropriate biopsies and histological examination, prior to initiation of breast cancer therapy.

Axillary lymph node metastases as the sole clinical site of occult breast carcinoma.

Patients without evidence of breast disease, who present with axillary lymph node metastases, consistent with breast origin, comprise a diagnostic and therapeutic dilemma. We describe such a case of a 47-year-old female, who complained of swelling and pain of the left axilla, but no breast mass was palpable. Although histology identified a metastatic adenocarcinoma in the lymph nodes, numerous tests failed to detect the primary tumor. Immunohistochemistry showed that the resected lymph nodes were positive for both estrogen and progesterone receptors, CEA and Gross Cystic Disease Fluid Protein 15 (GCDFP-15), suggesting the breast as the site of the primary tumor. Left modified radical mastectomy was performed. Pathology revealed an invasive ductal carcinoma, 12 mm in size. The patient received adjuvant chemotherapy and radiation therapy. She is currently being treated with tamoxifen and is well without evidence of disease 2 years after surgery.