Myeloid nuclear differentiation antigen: an aid in differentiating lymphoplasmacytic lymphoma and splenic marginal zone lymphoma in bone marrow biopsies at presentation.

The differential diagnosis between lymphoplasmacytic lymphoma (LPL) and marginal zone B-cell lymphoma, particularly splenic type (SMZL), can be challenging on onset of bone marrow biopsy (BMB) since morphology and phenotype are not specific and clinical features can overlap or be mildly developed at diagnosis. The LPL-specific L265P mutation in the MYD88 gene is not available in all laboratories, and genetic aberrancies identified in SMZL (del7q, mutations of NOTCH2 and KLF2) are seldom searched in routine practice. The study aim is to investigate the potential role of myeloid nuclear differentiation antigen (MNDA) expression in this specific differential diagnosis. We report MNDA reactivity in 559 patients with small B-cell lymphoma including bone marrow biopsies from 90 LPL and 91 SMZL cases. MYD88 p.Leu265Pro mutation status was assessed and confirmed as positive in 24 of 90 LPL cases, which served as the test set. MNDA staining was negative in 23 of 24 LPL cases in the test set (96%). In the 157 remaining cases (66 LPL, 91 SMZL), which served as the validation set, the MYD88 p.Leu265Pro mutation was unavailable and MNDA was more frequently expressed in SMZL (p < 0.00001). In addition, immunohistochemical features more consistent with SMZL (i.e., presence of CD23+ follicular dendritic cell meshworks, polytypic plasma cells, DBA44 reactivity) were more often present in MNDA-positive cases (statistically significant for 2 such parameters). On the widest case series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset of BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable.

The diagnostic role of Next Generation Sequencing in uncovering isolated splenomegaly: A case report.

Many diseases can induce splenomegaly, however, about 5% of splenomegalies are idiopathic. When there is no underlying treatable cause, and the splenomegaly significantly affects the quality of life, splenectomy is the best therapeutic choice. A 67-year-old woman had idiopathic and asymptomatic splenomegaly. The increase in splenomegaly resulted in hypersplenism with cytopenia and symptoms related to abdominal discomfort. The patient underwent splenectomy which led to clinical improvement. A histological examination showed the presence of hematopoietic tissue. Peripheral blood Next Generation Sequencing with the myeloid panel SOPHiA Genetics showed the following mutations: ASXL1, SRSF2, KRAS and TET2. Three out of these four mutations were also found in the splenic tissue. Next Generation Sequencing could be useful in the diagnosis of splenomegalies associated with myeloproliferative neoplasms otherwise defined as idiopathic, in order to address a therapeutic strategy.

Diagnostic accuracy of positron emission tomography/computed tomography-driven biopsy for the diagnosis of lymphoma.

INTRODUCTION: Biopsy of affected tissue is required for lymphoma diagnosis and to plan treatment. Open incisional biopsy is traditionally the method of choice. Nevertheless, it requires hospitalization, availability of an operating room, and sometimes general anesthesia, and it is associated with several drawbacks. Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) can be potentially used to drive biopsy to the most metabolically active area within a lymph node or extranodal masses. METHODS: A study of diagnostic accuracy was conducted to assess the performance of a PET-driven needle biopsy in patients with suspect active lymphoma. RESULTS: Overall, 99 procedures have been performed: three (3.0%) were interrupted because of pain but were successfully repeated in two cases. Median SUVmax of target lesions was 10.7. In 84/96 cases, the tissue was considered adequate to formulate a diagnosis (diagnostic yield of 87.5%) and to guide the following clinical decision. The target specimen was a lymph node in 60 cases and an extranodal site in 36. No serious adverse events occurred. The sensitivity of this procedure was 96%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 75%. CONCLUSION: Patients can benefit from a minimally invasive procedure which allows a timely and accurate diagnosis of lymphoma at onset or relapse.

Two Different Extranodal Lymphomas in an HIV+ Patient: A Case Report and Review of the Literature.

Human immune deficiency virus- (HIV-) infected individuals present a higher risk of developing malignancies. Herein, we are presenting an unusual case of an untreated HIV+ patient, who developed two distinct lymphoproliferative disorders in a period of 4 years: a primary cutaneous T-cell lymphoma (PCTCL) and a diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), the latter developed while commencing combined antiretroviral therapy (cART). The two lymphomas also showed peculiar features: PCTCL are rarely described in HIV+ setting and particularly at such a low clinical stage, and the DLBCL showed uncommon cytology, non-GCB phenotype, EBER negativity, and absence of c-MYC translocation, all atypical features in this clinical context. This report not only confirms the increased risk of lymphoma for HIV+ patients and HIV infection being one of the major risk factors for lymphoid disorders but draws the attention on the possible occurrence of unusual features, suggesting that HIV serology should always be investigated in the clinical suspicion of lymphoma.

Saprochaete clavata infections in patients undergoing treatment for haematological malignancies: A report of a monocentric outbreak and review of the literature.

Saprochaete clavata is a rare cause of fungaemia with deep organ involvement in patients with haematological malignancies with reported mortality rates of 60%-80%. We describe four cases of S clavata infection in a haematology unit over several months that were treated with voriconazole-based regimens. We also review the literature on factors that could contribute to earlier recognition and effective treatment of S clavata. We included all cases of culture-positive S clavata from sterile sites with associated signs of infection in patients undergoing treatment for a haematological malignancy. Isolates were identified by MALDI-TOF MS, and spectrum profiles were used to prepare clustering analysis of isolates. Susceptibility testing was performed using a commercial microtitre methods. Saprochaete clavata was isolated from the bloodstream in three cases and bronchial alveolar lavage (BAL) fluid in one case. Clustering analysis suggested strains of S clavata were clonal without evidence of divergence although a common source was not identified. Susceptibility testing yielded elevated MICs to fluconazole (8 mg/L) and echinocandins (>1-8 mg/L). All patients were treated with voriconazole-based regimens resulting in survival of 3/4 patients, who continued chemotherapy for their underlying malignancy without evidence of relapse. Saprochaete clavata is a rare but aggressive cause of breakthrough yeast infection in patients undergoing treatment for haematological malignancies, particularly patients with a prior history of echinocandin treatment. Timely initiation of appropriate treatment, aided by more rapid identification in microbiology laboratory, can reduce the risk of deep organ dissemination and patient death.

Sclerosing Angiomatoid Nodular Transformation of the Adrenal Gland: A Case Report of a Novel Histopathological Entity.

The finding of an indeterminate adrenal mass at radiological investigations is a challenge for physicians. Complex diagnostic work-up, periodic follow-up, or surgical intervention are therefore needed to rule out malignant lesions. Tertiary care hospitals are provided with 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET) and 18F-dihydroxyphenylalanine (18F-DOPA) PET, which aid in the characterization of indeterminate adrenal masses. Nevertheless, the histopathological examination may be required to exclude malignancy or rare etiologies. A 54-year-old woman presented to our clinic 6 months after a cerebral hemorrhage. She was hypertensive and had recently discovered a left adrenal mass of 15 mm during an abdominal ultrasound. Contrast-enhanced CT, following adrenal protocol, revealed a 14-mm adrenal mass without characteristics suggestive of an adrenal adenoma. Tumor markers were negative. Functional tests excluded hormone hypersecretion. An 18F-DOPA PET was negative. An 18F-FDG PET showed mild uptake of both the adrenal glands, with a more circumscribed pattern in the left one (maximum standardized uptake value = 4). As the clinical diagnosis was still indeterminate, we performed laparoscopic left adrenalectomy. The histopathological examination described a sclerosing angiomatoid nodular transformation (SANT) of the adrenal gland, a benign lesion already described as a rare occurrence only in the spleen. IgG4 levels were reduced. In conclusion, this is a report of a SANT of the adrenal gland, a novel entity that should be taken into consideration in the differential diagnosis of indeterminate adrenal masses at CT scan.

Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia.

BACKGROUND: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM-ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin. CASE PRESENTATION: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response. CONCLUSIONS: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation.

Two cases of primary vitreoretinal lymphoma: a diagnostic challenge : The supporting role of multimodal imaging in the diagnosis of primary vitreoretinal lymphoma.

PURPOSE: To report two cases of primary vitreoretinal lymphoma (PVRL), which presented as intermediate and posterior uveitis. METHODS: Combined clinical assessment, multimodal imaging with spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, brain magnetic resonance imaging and vitreous and retinal biopsy. Case 1 was a 48-year-old woman who complained of visual loss in her right eye secondary to a diffuse vitreous opacification and multiple chorioretinal lesions. Case 2, a 74-year-old man, presented with low vision in his right eye due to a wide chorioretinal lesion at the posterior pole, vitreous opacification and posterior uveitis in both eyes. RESULTS: Diffuse large B cell lymphoma was histologically diagnosed in the cerebellum in the first case and in chorioretinal tissue in the second patient. Atypical lymphoid cells were detected and allowed to make a diagnosis of primary central nervous system lymphoma in case 1 and PVRL in case 2. CONCLUSION: PVRL often masquerades ad intermediate or posterior uveitis. The management of the patients needed a team of pathologists, haematologists and ophthalmologists to achieve the correct diagnosis and choose the more appropriate therapy. Some peculiar characteristics on multimodal imaging, even in atypical cases of PVRL, should raise suspicious for PVRL and lead to a diagnostic vitrectomy and/or retinal biopsy.

Disappearance of Bone Marrow Fibrosis in a Patient with Chronic Myeloid Leukemia Treated with Dasatinib.

We report a case of a chronic myeloid leukemia patient showing progressive bone marrow fibrosis and anemia during imatinib therapy. Given the loss of major molecular response, we switched treatment to dasatinib 100 mg daily, observing a reduction in BCR-ABL transcript, a significant improvement of anemia, and a gradual disappearance of fibrosis. After 7 years of dasatinib therapy the patient maintains a complete cytogenetic response and a deep molecular response; the last bone biopsy confirmed the absence of fibrosis.

Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas.

Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541-52. ©2017 AACR.

Reproducibility of SOX-11 detection in decalcified bone marrow tissue in mantle cell lymphoma patients.

Mantle cell lymphoma (MCL) usually harbors the t(11;14)(q13;q32) with overexpression of CCND1 mRNA and transcription of the cyclin D1 nuclear protein. Regardless of CCND1 status, most MCLs also express the SOX11 nuclear protein, which is thus helpful in the diagnosis of the rare CCND1-negative MCLs. Recently, SOX11 has been reported to be often negative in MCLs clinically resembling marginal zone lymphoma and recently defined as "leukemic non-nodal" MCL in the incoming revision of the WHO classification of lymphoid tumors, for which the bone marrow biopsy is commonly the first diagnostic approach. Due to the less aggressive clinical behavior of the latter MCLs, the reliable determination of the SOX11 antigen in decalcified tissue is mandatory. To this end, since little data are available in the literature, four commercially available anti-SOX11 antibodies (two polyclonal and two monoclonal) were tested on 21 positive staging bone marrow (BM) biopsies from cyclin D1/SOX11-positive MCL patients (17 fixed in B5, 4 in 10% buffered formalin) and on 9 positive BM biopsies from leukemic non-nodal MCL patients. The results were compared for specificity, sensitivity, staining strength and degree of an additional staining on myeloid precursors, also evaluating possible impact of the different fixatives used. Non-mantle cell lymphomas were also tested to address specificity. All reagents showed high sensitivity but the monoclonal code CMC38221001 provided the highest specificity and the lowest degree of non-lymphoid staining on myeloid cells. Formalin fixation generally improved the performance of most antibodies when compared to B5 fixation.

Successful surgical resection of solitary plasmacytoma of the liver mimicking hepatocellular carcinoma. A case report.

Solitary extramedullary plasmacitomas (SEMP) of the liver are very rare. We report the case of an elderly woman with a huge symptomatic SEMP of the liver mimicking hepatocellular carcinoma (HCC). The patient was a 89-year-old woman who presented with severe abdominal pain and a huge solid mass in the right hypochondrium. The laboratory data on admission revealed normal liver function tests. A multiphasic computed tomography (CT) showed a huge solid mass of the left hemiliver, hypoattenuating on noncontrast images, dishomogeneously hyperenhancing in the late arterial phase, with washout in the portal venous and equilibrium phases. A 18F-FDG positron emission tomography (18F-FDG PET)-CT scan documented a marked FDG uptake within the lesion, without evidence of extrahepatic metastases. We considered the clinical and radiologic findings consistent with the diagnosis of high-grade HCC with areas of intratumoral necrosis preluding to possible tumour rupture. Surgical resection was ultimately considered feasible with a reasonable risk and the patient underwent left hepatectomy with diaphragmatic resection. Pathological examination exhibited an extramedullary plasmacytoma. At immunohistochemical analysis neoplastic cells were positive for CD45, CD38, IRF4, HTPD52, kappa-chain, but negative for lambda- chain; Mib-1 proliferation index was 50%. Subsequent clinical evaluation excluded any sign of multiple myeloma, so that a diagnosis of truly localized SEMP of the liver was finally established. To our knowledge, this is the first case of a solitary extramedullary plasmacitoma of the liver undergoing successful radical liver resection. The patient is alive and well 5 years after surgery without evidence of local recurrence and of systemic disease. KEY WORDS: Extramedullary plasmacytoma, Hepatocellular carcinoma, Liver, Liver resection, Multiple myeloma.

Extramedullary Plasmacytoma of the Maxilla Simulating a Maxillary Radicular Cyst: Quick Diagnosis and Management.

Plasma cell tumors are lymphoid neoplastic proliferations of B cells. Multiple myeloma is the disseminated type of this disorder, while localized forms of plasma cell neoplasms are solitary plasmacytoma of bone that is observed as centrally localized in bones, and extramedullar plasmacytoma (EMP) that develops in soft tissues. EMP of the head and neck region is a rare malignant tumor comprising approximately 3% of all plasma cell tumors, and approximately 0.4% of all head and neck malignancies; among them, plasmacytoma of the maxilla is extremely rare. The authors present a case of a patient affected by an EMP of the maxilla simulating a maxillary radicular cyst comparing our results with the recent literature. EMP entity requires a meticulous overview of the patient by the specialist and overall the control of any signs or symptoms of systemic diseases, a fact that would mark a dramatic change in the treatment and prognosis for the patient.

Unique presentation of a plasmablastic lymphoma superficially involving the entire large bowel.

Plasmablastic lymphoma (PBL) is an uncommon, aggressive B-cell lymphoma mostly occurring in the oral cavity of human immunodeficiency virus (HIV) positive patients, but also described in extraoral sites and in HIV negative patients. One of the relatively common extraoral sites of PBL is the gastrointestinal (GI) tract. Few cases of PBL have been reported in association with inflammatory bowel disease (IBD). Here, we describe the unique presentation of a PBL involving the large bowel superficially along its entire length and without forming a tumor mass in an HIV negative patient with a recent diagnosis of ulcerative colitis.