Detecting Multiple Driver Mutations in a Patient with Essential Thrombocythemia.

BACKGROUND Three driver mutations have been identified in patients with essential thrombocythemia - JAK2 V617F, CALR, and MPL. Out of these, JAK2 V617F is mostly common. These mutations are thought to be mutually exclusive; therefore, the initial workup may not include the identification of all mutations separately. CASE REPORT We present a case of a 55-year-old woman who was referred to the hematology clinic for an elevated platelet count noted when she was hospitalized for a renal stone. The patient was asymptomatic. A workup was initiated for essential thrombocythemia, and she was tested for JAK2 V617F mutation using an allele-specific polymerase chain reaction (AS-PCR) test in peripheral blood, which came back positive. The variant allele frequency was 2%. She underwent a bone marrow biopsy, and next-generation sequencing (NGS) showed a CALR mutation. A 52 bp deletion-type mutation was detected in the CALR gene on exon 9, with a variant allele frequency of 7%. The NGS did not detect JAK2 mutation due to its low sensitivity. She was started on aspirin alone as she was less than 60 years old and had no history of thrombotic events. The patient has been following up with the hematology clinic for the last 2 years and has not had any thrombotic events. CONCLUSIONS We propose that in patients with a low JAK2 V617 allele variant, testing for other driver mutations should be performed. In our patient, JAK2 mutation could be clonal hematopoiesis of indeterminate potential; therefore, the dominant mutation (CALR) would determine the disease phenotype.

Syncope and Cardiac Arrhythmias Caused by a Paratracheal Mass.

Background: Syncope is a common complaint in clinical practice. The etiologies and mechanisms can be multiple and complex. Syncope caused by a mediastinal mass compressing the vagus nerve is rare. Case Report: We report the case of a patient who presented to the emergency department experiencing recurrent syncope. Imaging revealed a large, calcified mass in the right paratracheal region. After intracranial lesions, cardiac arrhythmias, and orthostatic hypotension were excluded, we suspected that the syncope was related to vagus nerve compression. The patient underwent surgical resection of a mediastinal mass and had complete resolution of syncopal episodes after surgery. Conclusion: This case outcome suggests that recurrent syncope could be the first symptom of an intrathoracic mass.

Lymphomas mimicking neuroinflammatory diseases - A diagnostic conundrum worth revisiting.

PURPOSE OF REVIEW: Central nervous system (CNS) lymphomas (CNSLs) have varied clinical presentations which can mimic neuroinflammatory disease, leading to a diagnostic dilemma for clinicians. RECENT FINDINGS: This report describes two patients who initially received a diagnosis of neuroinflammatory disorders but were refractory to treatment over a protracted time course. In both cases, biopsy revealed diffuse large B cell lymphoma (DLBCL) as the final diagnosis. SUMMARY: The analysis of these cases provides an opportunity for increased recognition of CNS lymphomas for earlier diagnosis and treatment. It also calls for increased clinical suspicion for CNSLs in such circumstances. And possibly the search for new biomarker development for identifying and tracking CNSLs.

Histiocytic Disorder Mimicking a Brain Tumor: A Report of 2 Rare Cases.

BACKGROUND Histiocytic disorders, a group of disorders with heterogeneous pathogenesis, morphology, and clinical presentation, include Rosai-Dorfman disease, Langerhans cell histiocytosis, and Erdheim-Chester disease. They can mimic primary or metastatic tumors, both clinically and radiologically, when involving the brain. Therefore, it is crucial to present and discuss cases of histiocytic disorder involving the central nervous system (CNS) to provide new information on disease presentation and diagnosis more. In this paper, we present 2 cases of histiocytic lesions involving the brain and mimicking primary brain tumors. CASE REPORT Case 1: A 65-year-old man presented with increasing memory loss, confusion, and depression. CT scans showed an isolated 2.9×2.0×0.6 cm intracranial hypothalamic lesion. Case 2: A 61-year-old woman presented with dizziness and confusion for 3 weeks and headaches for 1 day. MRI showed a single 5.0×4.0×3.3 cm extra-axial, dural-based, avidly enhancing, well-defined lesion along the left parietal convexity causing mass effect upon the underlying brain parenchyma, left atrial effacement, and minimal vasogenic edema. CONCLUSIONS Histiocytic disorders are relatively rare in the CNS compared with other locations and mimic more common entities in the brain, such as glioma or metastatic tumors. Despite its rarity, one should remain aware of the condition and consider it in the differential diagnosis. This article provides a brief review and adds pivotal data to the literature.

Bilateral Eagle Syndrome.

Significance StatementUnilateral Eagle Syndrome is relatively rare and highlights important concepts in anatomy and pathophysiology. Bilateral Eagle Syndrome is exponentially more rare and has only been mentioned several times in the literature. Understanding the impact this can have on the human body and the severity of symptoms and sequelae is valuable for several types of specialists that treat this disorder.

Primary Pulmonary Leiomyosarcoma in a Forty-Year-Old Woman.

Primary pulmonary leiomyosarcomas (PPLs) are rare aggressive malignancies originating from the smooth muscle cells of the pulmonary interstitium, bronchial tree, or blood vessels. Accounting for <0.5% of lung tumors, PPLs are often initially undetected or misdiagnosed as pulmonary emboli, cardiac neoplasms, or as other more common lung cancer subtypes. Due to their aggressive and often lethal clinical profile, the diagnostic delay of PPL can significantly affect patient outcomes and must be avoided. Here we describe a case of PPL in a 40-year-old woman.

Cystathionine Gamma-Lyase Is Increased in Testicular Seminomas, Embryonal, and Yolk Sac Tumors.

BACKGROUND: Testicular cancer constitutes 1.0% of male cancer and typically carries a good prognosis. As far as we are aware, the role for hydrogen sulfide in testicular cancer and the level of hydrogen sulfide-synthesizing enzyme have never been addressed. Here we examined cystathionine gamma-lyase (CSE) expression in several germ-cell testicular tumors. MATERIALS AND METHODS: Tissue microarrays were employed to examine CSE expression in 32 benign testicular samples, 88 testicular seminomas, 34 embryonal carcinomas, 4 mature teratomas, and 16 yolk sac tumors, and CSE expression was compared to that seen in benign testicular tissue. RESULTS: Compared to benign testicular tissue, CSE expression was increased in all three types of testicular neoplasm but not in mature teratomas. Highest CSE expression was identified in embryonal carcinomas, which often show a relatively aggressive clinical course. CONCLUSION: For the first time, we show that CSE is increased in several common testicular germ-cell tumor types.

Nicotinamide Phosphoribosyl Transferase Is Increased in Osteosarcomas and Chondrosarcomas Compared to Benign Bone and Cartilage.

BACKGROUND/AIM: Primary bone neoplasms include osteosarcomas (OS), chondrosarcomas (CS), and giant cell tumors (GCT). Nicotinamide phosphoribosyl transferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide synthesis and is increased in multiple tumor types. In malignancies, NAMPT expression often correlates positively with tumor grade, chemotherapy resistance, and metastatic potential. MATERIALS AND METHODS: Tissue microarray was used to examine NAMPT expression in benign bone and cartilage, GCTs, OS, and different CS grades. RESULTS: For the first time, we showed that NAMPT expression was increased in GCTs and OS compared to benign bone, and in CS compared to benign cartilage. Its expression also increased with higher CS grade. CONCLUSION: Our data indicate that NAMPT plays a role in bone sarcomas and GCTs, and its higher expression may contribute to increased tumor aggressiveness.

Cystathione ß-Synthase Is Increased in Thyroid Malignancies.

BACKGROUND: Cystathione ß-synthase (CBS) catalyzes the conversion of homocysteine and cysteine to hydrogen sulfide (H2S) and cystathione, via the trans-sulfuration pathway. CBS protein expression levels are increased in several different human malignancies, with increased protein expression correlating with parameters such as tumor stage, anaplasia, metastases, and chemotherapy resistance. MATERIALS AND METHODS: This study employed tissue microarrays to examine CBS expression in benign thyroid tissue, thyroid oncocytomas, thyroid follicular adenomas, and in follicular, papillary, anaplastic, and medullary thyroid carcinomas. RESULTS: CBS expression was increased in all thyroid carcinomas types compared to benign thyroid tissue, but not in thyroid follicular adenomas or oncocytomas. A similar pattern was observed for nicotinamide phosphoribosyltransferase (NAMPT) tissue microarray analysis comparing thyroid adenomas and follicular carcinomas. CONCLUSION: For the first time, we showed that an H2S-syntheszing enzyme plays a role in thyroid malignancies. Additionally, our data suggest that CBS and NAMPT immunohistochemistry may be useful in differentiating follicular adenomas from follicular carcinomas.

Ovarian Adenomatoid Tumor Coexisting with Mature Cystic Teratoma: A Rare Case Report.

Adenomatoid tumor of the ovary is rare, and so are collision tumors in this location. The most common histological combination of ovarian collision tumors is the coexistence of mature cystic teratoma with ovarian cystadenoma or cystadenocarcinoma. Presented herein is a rare case of ovarian adenomatoid tumor found incidentally and coexisting with mature cystic teratoma. A 44-year-old woman presented with a one-year history of intermittent right-sided pelvic pain. Ultrasound evaluation revealed a heterogeneous cystic mass in the right ovary, and a clinical diagnosis of teratoma was made. The patient subsequently underwent a right salpingo-oophorectomy. Pathological examination revealed a mature cystic teratoma and coexistent adenomatoid tumor. The two tumors were separate and no transitional features were recognized histologically. To our knowledge, no previous report of coexistence of these two tumors has been reported. Both tumors are benign and completely excised; therefore no adverse consequences are expected.

γδ T-Cell Acute Lymphoblastic Leukemia/Lymphoma: Discussion of Two Pediatric Cases and Its Distinction from Other Mature γδ T-Cell Malignancies.

Gamma delta (γδ) T-cell antigen receptor (TCR) expression and its related T-cell differentiation are not commonly reported in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Here we report two pediatric T-ALL cases and present their clinical features, histology, immunophenotypes, cytogenetics, and molecular diagnostic findings. The first patient is a two-year-old girl with leukocytosis, circulating lymphoblasts, and a cryptic insertion of a short-arm segment at 10p12 into the long-arm segment of 11q23 resulting in an MLL and AF10 fusion transcript, which may be the first reported in γδ T-ALL. She responded to the chemotherapy protocol poorly and had persistent diseases. Following an allogeneic bone marrow transplant, she went into remission. The second patient is an eleven-year-old boy with a normal white cell count, circulating blasts, and a normal karyotype, but without any immature cellular markers by flow cytometric analysis. He responded to the chemotherapy well and achieved a complete remission. These cases demonstrate the diverse phenotypic, cytogenetic, and molecular aspects of γδ T-ALL. Early T-precursor- (ETP-) ALL and their differential diagnosis from other mature γδ T-cell leukemia/lymphomas are also discussed.

Pediatric Pulmonary Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma: A Case Report and Review of the Literature.

Non-Hodgkin's lymphoma (NHL) is a common malignancy of childhood; however, a lung primary presentation is an uncommon finding, as is finding an association with the Epstein-Barr virus (EBV). We report the case of a 23-month-old female who developed EBV-associated diffuse large B-cell lymphoma (DLBCL) that was initially thought to be pneumonia. Extensive tissue necrosis, focal angioinvasion, and angiodestruction were observed. She was refractory to various therapy regimens, subsequently developed DLBCL in the central nervous system, and eventually expired. Although EBV+ DLBCL was initially considered to occur predominantly in elderly patients over 50 years of age, it is now increasingly recognized to occur in younger patients with primarily nodal involvement who have overall better prognoses. To our knowledge, this case is the first reported EBV+ DLBCL occurring in a patient below two years of age with lung involvement as the initial clinical presentation.

Disseminated Mycobacterium avium-Intracellulare Complex Infection Presenting With Disseminated Intravascular Coagulation in an AIDS Patient.

Disseminated Mycobacterium avium-intracellulare complex (MAC) infection is one of the relatively common opportunistic infections seen in severely immunocompromised AIDS patients. A constellation of clinical, laboratory, and pathological features involving multiple organ systems are often present in disseminated MAC infection but disseminated intravascular coagulation (DIC) has not been previously described in association with this condition. To our knowledge, this is the first reported case of DIC complicating disseminated MAC infection in an AIDS patient. In this article, we present the case of a 33-year-old AIDS patient with high viral load, CD4 lymphocyte count of 1/mm3, who presented with nonspecific symptoms, anemia, thrombocytopenia, and increased lactate dehydrogenase, alkaline phosphatase, and ferritin. She also had abnormal coagulation parameters and features compatible with chronic DIC. Bone marrow biopsy assisted in making the correct diagnosis. She also later grew MAC from blood and sputum cultures. There were no other factors identified after a complete workup to explain DIC in this patient. After commencement of appropriate MAC therapy, she initially had a good response with some improvement of her coagulation parameters. Few months later, however, probably attributable to poor medication compliance, her condition deteriorated with development of thromboembolism, full-fledged DIC, sepsis, and an eventual fatal outcome. This case illustrates the importance of including disseminated MAC in the differential diagnosis of DIC in an AIDS patient.

Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile.

BACKGROUND: T-cell lymphomas with anaplastic morphology typically comprise of anaplastic lymphoma kinase positive, anaplastic large cell lymphoma (ALK+ ALCL), ALK-negative ALCL (ALK- ALCL), and primary cutaneous ALCL (PC-ALCL). However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features. AIMS: To study the clinical features and histological spectrum of ALCL and emphasize the role of immunohistochemistry (IHC) in their diagnosis and categorization. SETTING AND DESIGN: Eight cases of ALCL diagnosed over a period of 4 years were selected for the study. MATERIALS AND METHODS: Histopathological review and IHC was performed on all cases. Two ALK+ ALCL cases were tested by fluorescent in situ hybridization (FISH) for t(2;5)(p23;q35). RESULTS: There were four cases of ALK+ ALCL and two each of ALK- ALCL and PC-ALCL. Histologically, all the subtypes showed pleomorphic and "hallmark" cells with strong CD30 expression and variable loss of T-cell antigens. One case of PC-ALCL was leukocyte common antigen (LCA) negative. Epithelial membrane antigen was positive in all the six systemic ALCL cases. Two cases tested for t(2;5)(p23;q35) by FISH were positive. CONCLUSIONS: Diagnosis of ALCL is based on recognizing the key morphological features, especially the presence of "hallmark" cells. IHC is essential for confirmation of diagnosis and excluding other malignancies with anaplastic morphology. The inclusion of CD30 in the initial IHC panel will help identify LCA negative cases and avoid misdiagnosis.

Nicotinamide Phosphoribosyl Transferase a Reliable Marker of Progression in Cervical Dysplasia.

BACKGROUND/AIM: Nicotinamide phosphoribosyl transferase (Nampt) catalyses the rate-limiting step of the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Nampt is highly expressed in several epithelial and mesenchymal neoplasms, where is promotes cell-cycle progression ans chemotherapy resistance. To our knowledge, alterations in Nampt expression have not been examined in cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC). MATERIALS AND METHODS: We performed immunohistochemical analysis for Nampt using tissue microarrays on 14 samples of benign cervical squamous epithelium and 15 CIN I, 15 CIN II, and 13 samples of CIN III. The SCCs included 5 low-grade, 67 intermediate-grade, and 81 high-grade tumors. RESULTS: Nampt levels increased with increased CIN grades were compared to benign cervical squamous epithelium. Similarly, Nampt levels increased with increasing SCC grade. CONCLUSION: Nampt expression is a reliable marker of progression in cervical dysplasia and SCC.

Anaplastic lymphoma kinase rearrangements in non-small-cell lung cancer: novel applications in diagnostics and treatment.

The ALK gene, first identified as an anaplastic large cell lymphoma driver mutation, is dysregulated in nearly 20 different human malignancies, including 3-7% of non-small-cell lung cancers (NSCLC). In NSCLC, ALK commonly fuses with the EML4, forming a constitutively active tyrosine kinase that drives oncogenic progression. Recently, several ALK-inhibiting drugs have been developed that are more effective than standard chemotherapeutic regimens in treating advanced ALK-positive NSCLC. For this reason, molecular diagnostic testing for dysregulated ALK expression is a necessary part of identifying optimal NSCLC treatment options. Here, we review the molecular pathology of ALK-positive NSCLC, ALK molecular diagnostic techniques, ALK-targeted NSCLC treatments, and drug resistance mechanisms to ALK-targeted therapies.

Increased Nicotinamide Phosphoribosyltransferase and Cystathionine-ß-Synthase in Renal Oncocytomas, Renal Urothelial Carcinoma, and Renal Clear Cell Carcinoma.

BACKGROUND: Renal oncocytomas (ROs), and clear cell (RCC) and urothelial carcinomas (UC), are common renal neoplasms. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of NAD+ synthesis and its expression is increased in several tumors. Nampt concomitantly regulates hydrogen sulfide (H2S)-synthesizing enzyme levels, including cystathionine-ß-synthase (CBS). MATERIALS AND METHODS: We used tissue microarrays to examine Nampt and the H2S-synthesizing enzyme CBS protein levels in benign kidney, RCC, UC and ROs. RESULTS: Compared to benign kidney, all three neoplasms showed increased Nampt and CBS protein levels, with the levels increasing in RCC at higher Fuhrman grades. CONCLUSION: H2S is known to ameliorate chronic renal failure but, as yet, no role for H2S in renal neoplasia has been demonstrated. Here, we showed, for the first time, that Nampt, CBS and, likely, H2S likely play a role in malignant and benign neoplastic renal disease.

Acute Promyelocytic Leukemia and Chronic Lymphocytic Leukemia: Concomitant Presentation of Two Molecularly Distinct Entities.

Acute myeloid leukemia (AML) developing in patients with chronic lymphocytic leukemia (CLL) is very uncommon and usually associated with prior treatment. Acute promyelocytic leukemia (APL) accounts for a very small proportion of treatment-associated AML. So far, there has been only one reported case of APL occurring post radiation for prostate cancer in a patient with CLL. We report herein the first case of APL and CLL presenting concomitantly in an untreated patient. Evaluation of peripheral blood and bone marrow aspirate with immunohistochemistry, flow cytometry, and FISH to confirm two morphologically, molecularly and genetically distinct leukemic populations characteristic of APL and CLL is required. APL is a hematologic emergency, and aggressive management is vital to a successful therapeutic outcome. Standard treatment is with All-trans retinoic acid (ATRA) and anthracycline-based regimen, whether the process is de novo or therapy-related. Due to increased incidence of secondary malignancies in CLL patients, active surveillance is necessary.

Histiocytic sarcoma as a secondary malignancy: pathobiology, diagnosis, and treatment.

Histiocytic sarcoma (HS) is an extremely rare non-Langerhans cell disorder with an aggressive course and limited treatment options. Recent advances in molecular/genetic sequencing have suggested a common clonal origin between various hematolymphoid disorders and cases of secondary HS. Deriving conclusions from previously reported cases of HS arising secondarily to certain hematolymphoid disorders, here we have tried to provide insight into the mechanisms influencing this evolution. We also discuss a clinical case of a 72-year-old man with a diagnosis of chronic myeloid leukemia (CML), presenting subsequently with a heterogeneous liver mass positive with a diagnosis of HS. The liver mass showed a retained BCR-ABL1 translocation suggesting clonality between the CML and HS. As seen in our case and other reported cases of HS derived secondarily, the concurrent expression of immunoglobulin heavy (IGH)-/light-chain rearrangements or cytogenetic markers common to the primary malignancy suggests an evolutionary mechanism involving lineage switching that could potentially be influenced by genetic or epigenetic cues which may occur at the level of a progenitor or the malignant cell itself.

ABSOLUTE PLATELET REFRACTORINESS ASSOCIATED WITH HLA ANTIBODIES: A CASE REPORT.

Refractoriness to platelet transfusion is a complex process that can be due to a diverse array of etiologies. We report a case of refractoriness in a patient with acute myelogenous leukemia (AML) and the diagnostic challenge associated with it. During the course of myeloablative therapy the patient demonstrated no response to multiple sequential platelet transfusions given to prevent the onset of bleeding complications in the setting of severe thrombocytopenia. Diagnostic evaluation revealed multiple potential underlying etiologies and contributing factors, with alloimmunity to HLA antigens determined to be the most probable cause after thorough laboratory investigation.