Primary neuroendocrine carcinoma of the breast: A case report of liver and lymph node metastases after eight years from diagnosis.

Primary neuroendocrine carcinoma of the breast (NECB) is one of the rarest subtypes of breast tumor, and for this reason, there are no data from prospective clinical trials on its optimal management. Its incidence is <0.1% of all breast cancers and <1% of all neuroendocrine tumors. The diagnosis of NECB requires the expression of neuroendocrine markers (chromogranin, synaptophysin, NSE) and the lack of simultaneous neuroendocrine carcinoma in extramammary sites. We present a case of a poorly differentiated neuroendocrine carcinoma (PD-NEC) metastasized in liver and lymph node after eight years. Mammography, ultrasound imaging, CT, and pathology findings are described.

Management of a periductal stromal tumor in a young woman: Our breast unit experience.

Periductal stromal tumor (PDST) is a rare biphasic tumor of the breast that exhibits low-grade malignancy and intermediate behavior. It is characterized by proliferation of atypical spindle cells surrounding benign mammary ducts and infiltrating adjacent adipose tissue. PDST is distinguished from phyllodes tumor by its lack of leaf-like architecture; however, it is still unclear whether PDST is a separate entity or a certain spectrum of phyllodes tumor. Phyllodes tumors constitute a group of rare epithelial lesions of the breast which mainly develops at around 40-50 years. The histologic characteristics to be considered are many and often heterogeneous in the same lesion which makes interpretation in needle biopsy material difficult. Most phyllodes tumors have a benign nature, with a high rate of postsurgical recurrence. In the malignant form, metastases are described by distant hematogenous route; its indolent behavior implies a tight surgical management with precise excision of the lesion even if there is not, however, a unanimous consent on the parameters of accuracy of the margins.

Self-healing CD30- T-clonal proliferation of the tongue: report of an extremely rare case.

BACKGROUND: The etiology of traumatic ulcerative granulomas with stromal eosinophilia (TUGSE) is not clear, traumatic irritation having advocated as the most likely cause. TUGSEs are typically self-limiting slow-healing lesions of the oral mucosa with unclear pathogenesis, commonly manifesting as a rapidly developing, long-lasting ulcer. CASE PRESENTATION: Here we report a controversial case of a self-healing lesion of the tongue in a 57 year-old woman. A clonal T-cell proliferation and CD30 negative immunohistochemical (IHC) profile could be documented. DISCUSSION AND CONCLUSION: In view of the very peculiar clinical and histological features, a retrospective diagnosis of a TUGSE with scarce eosinophilic infiltrate (possibly in regression), displaying CD30- T-clonal proliferation was eventually rendered. The patient did not report signs of recurrence after a 3-year follow-up period.

Posterior mediastinal myelolipoma resected by video-assisted thoracic surgery.

Myelolipoma (ML) is a benign tumour composed of haematopoietic and mature adipose tissue commonly found in adrenal glands. Prognosis is usually good with an indolent clinical course. The occurrence of an ML in the extra-adrenal site is very rare. Herein, we report a very interesting and unusual case of ML located in the posterior mediastinum successfully resected by video-assisted thoracic surgery. The clinical and histological features are largely discussed.

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target.

The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138(+) cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138(+) cells. Gln-free incubation or treatment with the glutaminolytic enzyme l-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138(+) cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM.

Can we define a role for perisentinel lymph-nodes on breast cancer disease?

BACKGROUND: The development of sentinel lymph node biopsy in breast cancer disease and the increasing of using adjuvant systemic therapy provide a rational reduction of axillary dissection in patients with Sentinel Lymph Nodes free from breast cancer cells. The aim of our study was to assess the state of the perisentinel lymph nodes removed and how these nodes can provide further information about the status of the axillary lymph nodes. MATERIALS AND METHODS: We have analysed data about 319 patients undergoing surgery for benign and malignant breast disease from January 2007 to July 2010; 134 cases were subjected to the sentinel lymph node biopsy; 29 cases of these patients had the presence of perisentinel lymph nodes at histological examination. Before the intervention, we have used colloidal albumin marked with 99mtc to select the sentinel lymph node; during the intervention, we identified by probe the ipercaptant lymph node, consequently we removed and sent it to histological extemporaneous definitive examination. RESULTS: In 134 Sentinel Lymph Nodes examined, 15 resulted positive for breast cancer cells at extemporaneous examination. In these cases, we decided to proceed with an axillary dissection in the same operative session, with the discovery of axillary lymph nodes metastases in 3 cases on 15 (20%). The positive predictive value of sentinel lymph node in case of positivity was 0.2. 8 cases (6,7% of the lymph nodes sentinel biopsy made) were negative to extemporaneous examination and positive to definitive histological examination for presence of micrometastasis. In 8 axillary dissection, 3 patients were positive for the presence of metastasis. We have analysed with the test "t-student" these data divided on age and the value of Ki-67. Then we calculated the predictive positive and negative value (patients with negative sentinel lymph node: Mean age (+/- sd) =61.93 +/- 13.8 years, ki-67=10.87 +/- 5.78; patients with positive sentinel lymph node: Age mean (+/- sd) = 64 +/- 12 36 years, ki-67=14.08 +/- 8.005). The study showed no statistically significant differences between the positive and negative sentinel lymphnodes about the age (p=0.58) and the Ki-67 (p=0.184). In the 29 cases in which the sentinel lymph node was negative at extemporaneous histological examination and in which were removed the perisentinel lymph nodes, resulted negative at definitive histological examination, the negative predictive value was equal to 1. CONCLUSIONS: The method of sentinel lymph node has demonstrated to be a reproducible, reliable and safe technique. The positivity of sentinel lymph node at final examination (micrometastasis, cells isolated) in case of extemporaneous examination negative for breast cancer cells, determines specifical considerations on surgical indication to axillary dissection. We think that in selected cases (age, biological characteristic of cancer) in which perisentinel lymph nodes were removed and free from breast cancer cells, may not be indicated in case of sentinel node positivity the axillary dissection.

Flat epithelial atypia and atypical ductal hyperplasia: carcinoma underestimation rate.

This study was carried out to determine the underestimation rate of carcinoma upon surgical biopsy after a diagnosis of flat epithelial atypia and atypical ductal hyperplasia and 11-gauge vacuum-assisted breast biopsy. A retrospective review was conducted of 476 vacuum-assisted breast biopsy performed from May 2005 to January 2007 and a total of 70 cases of atypia were identified. Fifty cases (71%) were categorized as pure atypical ductal hyperplasia, 18 (26%) as pure flat epithelial atypia and two (3%) as concomitant flat epithelial atypia and atypical ductal hyperplasia. Each group were compared with the subsequent open surgical specimens. Surgical biopsy was performed in 44 patients with atypical ductal hyperplasia, 15 patients with flat epithelial atypia, and two patients with flat epithelial atypia and atypical ductal hyperplasia. Five cases of atypical ductal hyperplasia were upgraded to ductal carcinoma in situ, three cases of flat epithelial atypia yielded one ductal carcinoma in situ and two cases of invasive ductal carcinoma, and one case of flat epithelial atypia/atypical ductal hyperplasia had invasive ductal carcinoma. The overall rate of malignancy was 16% for atypical ductal hyperplasia (including flat epithelial atypia/atypical ductal hyperplasia patients) and 20% for flat epithelial atypia. The presence of flat epithelial atypia and atypical ductal hyperplasia at biopsy requires careful consideration, and surgical excision should be suggested.

Gastric metastasis from breast carcinoma. Report of three cases, diagnostic-therapeutic critical close examination and literature review.

Gastric metastases of breast cancer represent a not so rare event in patients affected. In fact, it occurs in 0.3% of cases. Although the introduction of new adjuvant therapies has given rise to an increase in disease free survival and overall survival rates, it has also led to more frequent occurrences of breast cancer metastatic lesions localized in bone, lung/pleura and liver, but above all in the stomach. The authors present three cases of patients suffering from breast cancer with secondary gastric neoplastic lesions from lobular and infiltrating ductal breast cancer. Lobular breast cancer is the histological type mostly involved in disseminated disease, with an incidence of 85% of cases. A review of the literature reveals that authors address the clinical and diagnostic problems of differentiating between a breast cancer metastasis to the stomach and a primary gastric cancer using recent diagnostic strategies to make an early diagnosis. Today practitioners have specific tests to detect early gastric cancer metastases of breast cancer such as endoscopic ultrasound, which provides a better endoscopic definition of the lesions, and immunohistochemical markers, able to distinguish the primary lobular histological type from ductal cancer. Besides, an early diagnosis associated with the latest adjuvant systemic therapies and hormonal treatment, alone or in combination, may grant affected patients a remission with a survival rate of 10-28 months, and a reasonable quality of life. At present the surgical approach should be reserved for selected cases and/or complications.

Bovine pestivirus is a new alternative virus for multiple myeloma oncolytic virotherapy.

BACKGROUND: The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients' antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46. METHODS: We treated several human myeloma cell lines and non-myeloma cell lines with BVDV to evaluate the expression of CD46 and to study the effect on cell viability by flow cytometry. The possible synergistic effect of bortezomib in combination with BVDV was also tested. Moreover, we infected the bone marrow mononuclear cells obtained from myeloma patients and we checked the BVDV effect on different cell populations, defined by CD138, CD14, CD3, CD19, and CD56 expression evaluated by flow cytometry. Finally, the in vivo BVDV effect was tested in NOD-SCID mice injected subcutaneously with myeloma cell lines. RESULTS: Human myeloma cells were selectively sensitive to BVDV treatment with an increase of cell death and, consequently, of apoptotic markers. Consistently, bone marrow mononuclear cells isolated from myeloma patients treated with BVDV, showed a significant selective decrease of the percentage of viable CD138+ cells. Interestingly, bortezomib pre-treatment significantly increased the cytotoxic effect of BVDV in myeloma cell lines with a synergistic effect. Finally, the in vitro data were confirmed in an in vivo myeloma mouse model showing that BVDV treatment significantly reduced the tumoral burden compared to the vehicle. CONCLUSIONS: Overall, our data indicate, for the first time, a direct oncolytic effect of the BVDV in human myeloma cells suggesting its possible use as novel alternative anti-myeloma virotherapy strategy.

Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.

Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.

Use of axillary ultrasonography in breast cancer: a useful tool to reduce sentinel node procedures.

AIM OF THE STUDY: The lymph node sentinel method is today used for staging the axillary lymph node stations. Ultrasonography is widely available and inexpensive method to study axillary status. METHODS: One hundred fourteen patients were studied consecutively using axillary ultrasonography and ultrasound guided fine needle aspiration of the lymph node. We used ATL Ultramark 9 with 5-7.5 MHz multiple frequency linear probe or Aloka SSDD-1400 with 7.5 MHz linear probe. RESULTS: One hundred fourteen patients were examined; six were excluded because of definitive histological diagnosis of non-infiltrating carcinoma. 106 had monofocal carcinomas, 2 had bifocal carcinoma in 104/108 ultrasonography was carried out successfully. The axillary cytological examination was positive in 18 cases (17.3%) who were subjected to axillary examination. 86 patients were subjected to sentinel lymph node biopsy: positive 13 cases (6 micrometastases). 31 cases/104 (29.8%) showed positive axilla. Sensitivity of ultrasonography was 58%, 100%specificity. Predictive positive value 100%, Negative value 84.9% for an accuracy of 87.5%. DISCUSSION: Ultrasonography is useful in all cases eligible to sentinel lymph node examination; the minimum cost of the procedure and of the human resources is amply rewarded by the direct indication for surgical axillary dissection in case of a positive result (17.3% in our experience).

Bone Marrow CX3CL1/Fractalkine is a New Player of the Pro-Angiogenic Microenvironment in Multiple Myeloma Patients.

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138⁺ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14⁺CD16⁺ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis.

Neurofibromatosis type I and multiple myeloma coexistence: A possible link?

The association between Neurofibromatosis type I (NF1) and multiple myeloma (MM), a plasma cell, dyscrasia is very rare. Here we put to the attention of the scientific community two new cases. The first one is a patient with active MM whereas the second with smoldering MM. Both patients present typical features of NF1 but skeletal alterations were present only in the second case including dysplasia, marked scoliosis and osteoporosis. MM osteolytic lesions were absent in both patients. In addition to the clinical diagnosis of NF1, a molecular testing for NF1 gene mutations has been performed finding that patient one was heterozygous for the c.6855C>A (Tyr2285Ter) mutation, while patient two was heterozygous for the c.7838dupC (Lys2614GlufsTer20) mutation. The two mutations were diagnosed both in genomic DNA from peripheral blood and from MM cells. The potential link between NF1 mutation and the increased risk of MM is discussed in the report.

A Rare Case of Systemic AL Amyloidosis with Muscle Involvement: A Misleading Diagnosis.

Muscle involvement in AL amyloidosis is a rare condition, and the diagnosis of amyloid myopathy is often delayed and underdiagnosed. Amyloid myopathy may be the initial manifestation and may precede the diagnosis of systemic AL amyloidosis. Here, we report the case of a 73-year-old man who was referred to our center for a monoclonal gammopathy of undetermined significance (MGUS) diagnosed since 1999. He reported a progressive weakness of proximal muscles of the legs with onset six months previously. Muscle biopsy showed mild histopathology featuring alterations of nonspecific type with a mixed myopathic and neurogenic involvement, and the diagnostic turning point was the demonstration of characteristic green birefringence under cross-polarized light following Congo red staining of perimysial vessels. Transmission electron microscopy (TEM) confirmed amyloid fibrils around perimysial vessels associated with collagen fibrils. A stepwise approach to diagnosis and staging of this disorder is critical and involves confirmation of amyloid deposition, identification of the fibril type, assessment of underlying amyloidogenic disorder, and evaluation of the extent and severity of amyloidotic organ involvement.