TLR2 Derangements Likely Play a Significant Role in the Inflammatory Response and Thrombosis in Patients with Ph(-) Classical Myeloproliferative Neoplasm.

We investigated the role of toll-like receptors (TLRs) in inflammatory pathways in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-)MPNs). TLR2 expression was increased in ET, PV, and MPN (grouped as (PV + (ET) + MF)), whereas TLR4 was elevated only in MPN. TLR3, 7, and 9 were not elevated. Cultured monocyte-derived dendritic cells and plasma assays in TLR2-elevated patients were found to secrete more cytokines than those from TLR2-normal patients. These facts suggest that TLR2 is the major inflammatory pathways in MPN. We also measured S100A9 and reactive oxygen species (ROS), revealing increased S100A9 in PV, MF, and MPN, while ROS were only increased in MF. These data suggests that MPNs initially involve TLR2, with minor contributions from TLR4, and with S100A9, leading to ROS formation, JAK2 mutation, and progression to MF or leukemia. Furthermore, patients with JAK2 mutations or leukocytosis exhibited higher TLR2 expression. In leukocyte-platelet interactions, cells from MPN patients displayed a stronger response to a TLR2 agonist than TLR4 agonist. A TLR2 inhibitor (but not a TLR4 inhibitor) attenuated this response. Thrombosis incidence was higher in TLR2-elevated patients (29%) than in TLR2-normal patients (19%). These findings suggest that TLR2 likely contributes to thrombosis in MPN.

Primary Neuroendocrine Carcinoma of the Breast Metastatic to the Bones, Which Chemotherapy?

The primary neuroendocrine carcinoma (NEC) of the breast is defined as immunohistochemical expression of neuroendocrine markers (chromogranin and synoptophysin) in more than 50% of the neoplastic cells according to World Health Organization (WHO) classification of tumors in 2003 (Tumours of the Breast and Female Genital Organs, 2003, Lyon: IARC Press). It accounts for less than 5% of all cancers arising from the breast (Tumours of the Breast and Female Genital Organs, 2003, Lyon, France: IARC Press). However, based on the study conducted by Wang et al., the primary NEC of breast comprises less than 0.1% of all mammary carcinomas (Frankf Z Pathol, 73, 1963, 24). Because of the rarity of the disease and absence of the prospective trials, there is no standard treatment for primary NEC of the breast. Herein, we report the case of a middle age woman with primary NEC with bone metastasis.

Predictors of plasma cell disorders among African American patients: a community practice perspective.

African Americans have two- to three-fold higher incidence of multiple myeloma and MGUS compared to other ethnic groups in the USA. Some physicians often perform diagnostic evaluations for plasma cell disorders (PCD) in African American patients on the basis of hematological abnormalities (thrombocytopenia, leucopenia, etc.) even in the absence of traditional triggers such as anemia, renal impairment, hypercalcemia, hyperglobulinemia, and lytic bone disease. Whether these nontraditional triggers have any significant association with PCD in African American population is not known. In addition, whether this approach could detect more asymptomatic PCD than black population prevalence is questionable. Moreover, the association between traditional triggers and PCD particularly in blacks has not been clearly delineated. Hence, we have carried out a retrospective study in an attempt to answer these questions. Two hundred fifty-four patients were eligible. Multiple myeloma workup based on parameters other than traditional triggers did not detect more asymptomatic PCD than what is expected of black population prevalence (p = 0.19). Of traditional triggers, the finding of only anemia or hyperglobulinemia seemed to be nonspecific in black population (p = 0.17 and 0.85, respectively). However, the presence of serum creatinine >2 mg/dL or corrected serum calcium >10.5 mg/dL or a combination of traditional triggers appeared to be strongly predictive of PCD (odds ratio of 6.9, 4.2, and 3, respectively). The number of trigger variables was positively correlated with the likelihood of PCD (p < 0.001). Light-chain-only PCD, renal disease, and abnormal free light chain ratio seemed to be higher in black patients than their white counterparts.

Axillary Lymphadenopathy as an Initial Presentation of Systemic Amyloidosis: A Case Report and Literature Review.

Amyloidosis rarely presents as localized lymphadenopathy. Various studies have elucidated the varied presentation and manifestations of this interesting disease. We reviewed the literature and found 36 cases of primary amyloidosis with lymph node enlargement as a presentation, and 17 of the 36 cases (47%) had systemic involvement on further work up. We describe a patient who presented with an isolated right axillary mass. Clinical examination and radiology were indicative of a lymph node enlargement with no evidence of malignancy in the breasts or lungs. Histopathological examination was indicative of amyloidosis. A further work up including serum, urine biochemistry, cardiac work up, bone marrow examination, and a kidney biopsy revealed systemic amyloidosis. Patient was treated with daratumumab and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) followed by a stem cell transplantation. Patient is in remission for 1 year, at the time of submission of this report. Therefore, we conclude (1) systemic amyloidosis presenting as an isolated lymph node enlargement is rare, (2) a structured systemic work up is imperative for early diagnosis and proper management of amyloidosis, when there is an index of suspicion, and (3) use of novel therapeutic options such as CD38 + antibody (daratumumab) and stem cell transplant have positive impact on disease outcomes.

Scalp Metastasis as the First Presentation of an Underlying Aggressive Pancreatic Cancer.

Pancreatic ductal adenocarcinoma, an extremely aggressive cancer, has high metastatic potential. Cutaneous metastasis is very uncommon, representing only <10% of all cases, presenting mostly around the umbilical region. Non-umbilical metastasis is even rarer, and the significance remains unknown. In this article, we describe a case of a 76-year-old gentleman who initially presented with an asymptomatic scalp lesion, which on biopsy revealed metastatic adenocarcinoma of pancreatic origin. Detailed workup revealed extremely high tumor burden with metastases involving muscles, subcutaneous tissues, bone, lung, spleen, liver, and colon. Cutaneous involvement in pancreatic cancer represents poor survival with widespread dissemination of the disease. The involvement of some sites and not others and the extreme degree of aggressiveness might reflect subgroups of this cancer with different molecular biology. Identifying these groups may have utility in determining prognosis and stratifying treatment for patients. This will hopefully translate into better diagnostic tests and therapies in the near future.

Paraneoplastic Pemphigus: An Indication for Treatment in Chronic Lymphocytic Leukemia.

Paraneoplastic disorders are rare multiorgan diseases associated with hematological malignancies such as chronic lymphocytic leukemia (CLL). Some of these paraneoplasms manifest as cutaneous lesions, appearing as a simple rash, ulcers or skin thickening. The pathogenesis for this process has been described as development of certain autoimmune reactions against cell wall antigens and proteins. An example is paraneoplastic pemphigus (PNP) which manifests as cutaneous bullae. Bullae may occur anytime during the course of the malignancy i.e. acute phase or remission. Diagnosis involves evaluation of clinical findings, serology and presence of characteristic histological findings. Its pathogenesis is described as development of auto-antibodies against cell junctional and basement membrane proteins. Presence of paraneoplasms has been associated with poorer prognosis and increased mortality in hematological malignancies including CLL. Currently, there are established indications for the treatment of CLL; however, presence of paraneoplasms as an indication for treatment is unclear. Patients with paraneoplasms who underwent expeditious treatment have exhibited better clinical outcomes. Herein we describe a case of a CLL patient in remission presenting with PNP and its response to treatment.

Cholangiocarcinoma Presenting as Humoral Hypercalcemia of Malignancy: A Case Report and Literature Review.

Humoral hypercalcemia of malignancy (HHM) is most commonly encountered in squamous cell carcinoma (SCC) of different organs, and It is characterized by elevated parathyroid hormone-related peptide (PTHrP) levels. It may be seen as a manifestation of cholangiocarcinoma (CCC) at presentation and later in the course of the disease. However, HHM due to intrahepatic cholangiocarcinoma is a rare association and is associated with a poor prognosis. We herein report a case of hypercalcemia presenting as the first manifestation of an underlying rare variant of intrahepatic cholangiocarcinoma. Our patient is a 57-year-old male who presented to the emergency room with severe symptoms of constipation and polyuria and was admitted to the hospital for symptomatic hypercalcemia. He was found to have a hypermetabolic 15 cm liver mass, abdominal lymph nodes on imaging, which was subsequently diagnosed as adenosquamous cholangiocarcinoma by liver biopsy. This necessitated an urgent inpatient treatment with gemcitabine/cisplatin combination chemotherapy to control the aggressive nature of the malignancy. However, he deteriorated and expired after three months of his diagnosis. Adenosquamous cholangiocarcinoma is a very rare variant of a liver tumor. It develops due to squamous metaplasia of an underlying cholangiocarcinoma and usually has aggressive clinicopathological features. HMM is a life-threatening, yet unrecognized, phenomenon of cholangiocarcinoma, which represents a poor prognostic marker. Prompt recognition of this complication is important for preventing serious complications associated with hypercalcemia and to improve the quality of life of these patients.

Case Reports on Metaplastic Squamous Cell Carcinoma of the Breast and Treatment Dilemma.

Metaplastic squamous cell carcinoma of the breast is a very rare form of breast cancer that consists of both glandular and nonglandular components mixed with epithelial and mesenchymal tissues. Worldwide, the incidence of this tumor is between 0.1 and 2%. Because of the rarity of this tumor and heterogeneous behavior of the tumor cells, it is difficult to establish the standard therapeutic approach. We report 2 cases of metaplastic squamous cell carcinoma of the breast in young patients with different responses to treatment strategies. The first case is a premenopausal female with metaplastic squamous cell carcinoma treated with surgery, chemotherapy, and radiotherapy, and the second case is perimenopausal metaplastic squamous cell carcinoma with sarcomatoid subtype and osteoid matrix production which progressed on chemotherapy and was treated with surgery and radiation.

Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia chromosome-negative myeloproliferative neoplasms.

Programmed Cell Death Receptor (PD-1) and its Ligand (PD-L1) pathway inhibitor therapy has been explored in the field of oncology treatment mainly for solid tumors. In hematologic malignancies, there is limited information except for Hodgkin's lymphoma, and there is even less information regarding myeloproliferative neoplasm (MPN). Therefore, we explored this by first measuring PD-1 and PD-L1 levels (percentage of positive cells) in 63 patients with Philadelphia chromosome-negative MPN (Ph(-) MPN), including 16 MF (12 PMF, 2 post-PV-MF, 2 post-ET-MF), 29 ET, and 18 PV. We found there was no significant difference in PD-1 or PD-L1 levels between the different MPN groups but that there was a significant difference when PV, ET and MF were grouped as MPN and compared with controls, of all immune cells including CD4+, CD8+, CD14+ and CD34+ progenitor cells. We further found a higher incidence of higher expression levels (more than 50% of cells with positive expression) of PD-1 and PD-L1 (20% and 26%, respectively) in the CD34+ cells; in contrast, we found a low incidence (0.08-1.8%) in the immune cells in MPN patients. PD-1 and PD-L1 levels were also measured by MFI methods, and we obtained similar results except the measurements by percentage appeared to be more sensitive than the MFI methods. We found no correlation between PD-1 and PD-L1 expression levels and clinical features including WBC, platelet counts, hemoglobin levels, presence or absence of the JAK2, MPL, or CALR gene mutation, or splenomegaly. Since MPN represents stem cell disorders, the presence of elevated expression of PD-1 and PD-L1 in these cells suggests that the exploration of PD-1 and PD-L1 pathway inhibitor therapy may be worthwhile in Ph(-) MPN.