Marco Mele

Contribution of Na+,HCO3−‐cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7)

Genome‐wide association studies recently linked the locus for Na+,HCO3−‐cotransporter NBCn1 (SLC4A7) to breast cancer susceptibility, yet functional insights have been lacking. To determine whether NBCn1, by transporting HCO3− into cells, may dispose of acid produced during high metabolic activity, we studied the expression of NBCn1 and the functional impact of Na+,HCO3−‐cotransport in human breast cancer. We found that the plasmalemmal density of NBCn1 was 20–30% higher in primary breast carcinomas and metastases compared to matched normal breast tissue. The increase in NBCn1 density was similar in magnitude to that observed for Na+/H+‐exchanger NHE1 (SLC9A1), a transporter previously implicated in cell migration, proliferation and malignancy. In primary breast carcinomas, the apparent molecular weight for NBCn1 was increased compared to normal tissue. Using pH‐sensitive fluorophores, we showed that Na+,HCO3−‐cotransport is the predominant mechanism of acid extrusion and is inhibited 34 ± 9% by 200 μM 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid in human primary breast carcinomas. At intracellular pH (pHi) levels >6.6, CO2/HCO3−‐dependent mechanisms accounted for >90% of total net acid extrusion. Na+/H+‐exchange activity was prominent only at lower pHi‐values. Furthermore, steady‐state pHi was 0.35 ± 0.06 units lower in the absence than in the presence of CO2/HCO3−. In conclusion, expression of NBCn1 is upregulated in human primary breast carcinomas and metastases compared to normal breast tissue. Na+,HCO3−‐cotransport is a major determinant of pHi in breast cancer and the modest DIDS‐sensitivity is consistent with NBCn1 being predominantly responsible. Hence, our results suggest a major pathophysiological role for NBCn1 that may be clinically relevant.

Myofibroblastoma of the breast: Case report and literature review.

Myofibroblastoma of the breast is a rare benign mesenchymal tumor. The literature describes relatively few cases of this type of tumor. We report on a new case of myofibroblastoma in a 65-year old man successfully managed at our institution. The purpose of this case report is to highlight characteristics and differential diagnosis of this rare neoplasm.

Primary breast sarcoma: A retrospective study over 35 years from a single institution

Abstract Aim: The aim of this study was to contribute to the collected knowledge of prognostic factors in primary breast sarcomas (PBS) to the benefit of possible future prospective studies and therapeutic guidelines. Method: All patients with pathologically verified PBS in the period of 1979–2014 were extracted from a hospital-based database at Aarhus University Hospital. All records were reviewed for patient and tumor characteristics. Primary endpoints were overall survival, disease-free survival (DFS) and disease-specific survival (DSS). Adjustments were made for age, tumor location, surgical strategy, size, histological classification, prior radiation and grade. Prognostic factors were determined by the use of Cox proportional hazard ratio. Results: In total 42 patients were identified. Surgical resection was the main method of treatment. Nineteen (45%) patients were initially selected for lumpectomy, of these 68% needed at least one re-excision to attain wide margins. In total 55% experienced recurrence, loco regional in 43%. Five-years overall survival was 49%, five-year DFS was 48% and five-year DSS was 40%. Significant prognostic factors were size and grade. A trend towards better survival in those with superficial tumors was observed as well as an increased incidence in radiation-induced angiosarcoma (AS) of the breast, however, prognosis was no different from non-radiation-induced AS. Conclusion: Prognostic factors in PBS patients were size and grade with a trend towards better survival in those with superficial tumors. There was no difference in survival between radiation-induced and spontaneous breast sarcomas. High rate of local recurrence suggests the need for aggressive surgical approach or the routine addition of postoperative radiotherapy in those selected for breast conserving surgery (BCS).

Melanocyte Colonization and Pigmentation of Breast Carcinoma: Pathological and Clinical Aspects

Introduction. Melanocyte colonization of breast carcinoma by nonneoplastic melanocytes of epidermal origin is a rare and serious condition first described in 1977. We report on the exceptional clinical and pathological features of this migration phenomenon in a 74-year-old patient. Discussion. The pathogenesis by which melanocyte migration takes place is not known, but a breached basement membrane is considered essential. Conclusion. Histological examination and additional staining of skin are essential to differentiate breast cancer melanosis from malignant melanoma.

Breast carcinosarcoma: Clinical and pathological features

Carcinosarcoma of the breast is an extremely rare and highly aggressive breast tumor.It has two distinct malignant cell lines involving epithelial (carcinomatous) and mesenchymal (sarcomatous) components. The literature on the topic is sparse. We report a rare case of carcinosarcoma of the breast containing a small fraction of a pancytokeratin positive sarcomatous-appearing cell population i.e. a metaplastic cell population. The patient was treated with a multidisciplinary approach.

Validity of Danish Breast Cancer Group (DBCG) registry data used in the predictors of breast cancer recurrence (ProBeCaRe) premenopausal breast cancer cohort study

Abstract Background: Validation studies of the Danish Breast Cancer Group (DBCG) registry show good agreement with medical records for adjuvant treatment data, but inconsistent recurrence information. No studies have validated changes in menopausal status or endocrine therapy during follow-up. In a longitudinal study, we validated DBCG data using medical records as the gold standard. Material and methods: From a cohort of 5959 premenopausal women diagnosed during 2002–2010 with stage I–III breast cancer, we selected 151 patients – 77 estrogen-receptor-positive and 74 estrogen-receptor-negative – from three hospitals. We assessed the validity of DBCG registry data on patient, tumor, and treatment factors, and follow-up information on menopausal transition, changes in endocrine therapy, and recurrence. We computed positive predictive values (PPVs) with 95% confidence intervals (95%CI). Results: Agreement was near perfect for tumor size, lymph node involvement, receptor status, surgery type, and receipt of radiotherapy, chemotherapy, or tamoxifen treatment. The PPV for a change in endocrine therapy in the DBCG was 96% (95%CI = 83, 100). The PPV for menopausal transition was 61% (95%CI = 42, 77). The PPV for DBCG-recorded recurrence was 100%. However, of 19 patients who had a recurrence documented in their medical record, 13 had the recurrence registered in DBCG. Conclusions: DBCG data are valid for most epidemiological studies of breast cancer treatment. Data on menopausal transition may be less valid, though this interpretation depends on the suitability of medical records for making this assessment. Although recurrence is missing for some, this would not bias most ratio measures of association.

Recurrence of Hyperparathyroid Hypercalcemia in a Patient With the HRPT-2 Mutation and a Previous Parathyroid Carcinoma in Hyperparathyroidism-Jaw Tumor Syndrome

Introduction Cancer in the parathyroid gland is rare, but parathyroid cancer is occasionally seen in relation to genetic abnormalities. Due to a limited amount of evidence, the optimal handling of these cases is not clear. Furthermore, the presence of a malignant parathyroid tumor is rarely known at the time of the initial operation; therefore, re-operations are often necessary. The aim of this study was to present the case of a patient with a previously diagnosed jaw tumor and parathyroid carcinoma that presents as a recurrence of hyperparathyroid hypercalcemia. Case Presentation A 41-year-old patient who was already diagnosed with a parathyroid carcinoma and a jaw tumor caused by a CDC73 mutation, presented with biochemical evidence of increasing parathyroid hormone (PTH) and calcium levels after a previous total parathyroidectomy. The patient’s ionized calcium increased to 1.55 mmol/L and PTH increased to 16.0 pmol/L. A previous genetic analysis revealed a mutation in the CDC73 gene. There was no family history of hyperparathyroidism. We performed a sestamibi scintigraphy and an 11-C methionine (MET) positron emission tomography (PET) scan that showed a recurrence on the left side of the trachea. The patient underwent a third neck operation for the removal of a tumor on the left side of the trachea. The pathology report revealed that the tumor was a lymph node metastasis from the previous parathyroid carcinoma. The patient is currently enrolled in our follow-up regime. Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a rare autosomal dominant disorder characterized by a parathyroid adenoma or carcinoma, fibro-osseous lesions (ossifying fibroma) of the mandible and maxilla, and renal cysts and tumors. This autosomal dominant familial cancer syndrome has been reported with a variable and incomplete penetrance, and up to 10% of gene carriers do not show any clinical manifestations. Here we present a patient’s case and discuss the literature related to this condition. Conclusions The recurrence of hyperparathyroid hypercalcemia in HTP-JT syndrome after an initial total parathyroidectomy is a well-known condition necessitating careful management, an evaluation of any underlying genetic abnormality, and a family examination. A surgical treatment and surveillance of calcium and PTH measurements are necessary to prevent a recurrence.

Apocrine carcinoma arising in a complex fibroadenoma: A case report

A carcinoma arising in a fibroadenoma is a rare event, which often entails a diagnostic challenge. The most common type is the lobular carcinoma and secondary a ductal carcinoma. We present an extremely rare case of malignant development of an invasive apocrine carcinoma in a complex fibroadenoma and underline the importance for clinicians to recognize the possibility of benign and malignant co-existence especially in older women.