Presumptive pulmonary toxocariasis in a patient affected by acute myeloid leukemia and Hodgkin lymphoma: case report and review of the literature in immunocompromised hosts.

Toxocariasis is a zoonosis transmitted by the nematode Toxocara spp. Immunocompromised hosts are more susceptible than general population to bacterial, viral, fungal and parasitic infections. In this population toxocariasis may present as exacerbation or reactivation and could have severe or atypical manifestations being a diagnostic challenge for healthcare providers. We report a case of a presumptive pulmonary toxocariasis during chemotherapy in a patient affected by acute myeloid leukaemia (AML) and Hodgkin lymphoma and we summarize current evidence of pulmonary involvement in immunocompromised population with Toxocara spp infection in a narrative review. The aim of this work is also to revise the current literature on pulmonary involvement during Toxocara spp infection in immunocompromised hosts to improve knowledge on clinical presentation, treatment and outcome. A 66 years old man who had undergone to a cytarabine and idarubicin chemotherapy induction scheme for AML, complained of febrile neutropenia and dry cought. At the chest computed tomography (CT) there were multiple nodular pulmonary lesions with subpleural consolidations. The lung biopsy revealed inflammatory infiltration with diffuse small granulomas with minor eosinophil component. The laboratory analysis showed high immunoglobulin E (IgE) count with normal peripherical eosinophils, among the extended parasitological analysis, Toxocara immunoblot assay resulted positive. In the most accepted hypothesis of a polmunary toxocariasis infection, the patient was treated with a combination of albendazole plus corticosteroids for four weeks, with a positive outcome. Infection complications during chemotherapy are not uncommon, however, this is the first reported case of pulmonary toxocariasis during cytarabine and idarubicin treatment in AML. The revised literature shows male gender and younger age as possible risk factors, nevertheless the majority of cases of seropositivity for Toxocara was reported in solid organ malignancies. In this case, the suspect was mainly based on laboratory total elevated IgE, confirmed by serological, anatomo-pathological and radiological findings. Hypereosinophilia is often not present in chronic infection. In conclusion, pulmonary toxocariasis should be ruled out in patients with pulmonary involvement and high IgE titre, with or without peripheral eosinophilia, especially in those with known immunocompromised status.

First-hit SETBP1 mutations cause a myeloproliferative disorder with bone marrow fibrosis.

ABSTRACT: SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.

Epstein-Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Radiologically guided percutaneous core needle biopsy of the spleen: a reliable and safe diagnostic procedure for neoplastic and reactive conditions.

RATIONALE: Percutaneous core needle biopsy (CNB) of the spleen is rarely performed, due to concerns about its complications and low diagnostic yield. However, this procedure represents a potentially useful diagnostic tool, especially in patients with splenomegaly and no definitive diagnosis after a clinical and radiological work-up. METHODS AND RESULTS: We report the data on a cohort of 45 radiologically guided percutaneous core needle biopsies of the spleen from 44 patients performed at two centres. Platelet count and prothrombin time were within normal limits in all patients at the time of the procedure. The biopsy was ultrasound-guided in all cases except one, which was guided by computed tomography. An 18G needle was used in 82% of the cases, followed by 16G (10.2%) and 20G (7.8%) needles. The biopsy provided sufficient material for histological examination (including immunohistochemical studies) in 41 cases (91.1%). Haematological malignancies were most commonly diagnosed (52.3%); diffuse large B cell lymphoma (DLBCL) was the most frequent, followed by splenic marginal zone lymphoma (SMZL). For the most recent cases of DLBCL, the CNB provided sufficient material for fluorescence in-situ hybridisation to assess the status of MYC, BCL2 and BCL6. This allowed the identification of a case of high-grade B cell lymphoma with MYC and BCL2 rearrangement. Major complications were not reported; minor complications occurred in three cases (6.7%). CONCLUSIONS: Our data demonstrate that radiologically guided percutaneous CNB should be considered as a valid diagnostic tool, as it provides quick and reliable histological diagnoses avoiding the complications and risks of splenectomy.

GATA1 downregulation in prefibrotic and fibrotic stages of primary myelofibrosis and in the myelofibrotic progression of other myeloproliferative neoplasms.

GATA binding protein 1 (GATA1) is a transcription factor essential for effective erythropoiesis and megakaryopoiesis. Two isoforms of GATA1 exist, derived from alternative splicing. "GATA1" is the full length and functionally active protein; "GATA1s" is the truncated isoform devoid of the activation domain, the function of which has not been fully elucidated. Reduced megakaryocytic expression of GATA1 has been linked to impaired hematopoiesis and bone marrow fibrosis in murine models and in vivo in patients affected by primary myelofibrosis (PMF). However, data is limited regarding GATA1 expression in other myeloproliferative neoplasms (MPN) such as pre-fibrotic PMF (pre-PMF), polycythemia vera (PV) and essential thrombocythemia (ET) and in their respective fibrotic progression. To assess whether an immunohistologic approach can be of help in separating different MPN, we have performed a comprehensive immunohistochemical evaluation of GATA1 expression in megakaryocytes within a cohort of BCR-ABL1 negative MPN. In order to highlight any potential differences between the two isoforms we tested two clones, one staining the sum of GATA1 and GATA1s ("clone 1"), the other staining GATA1 full length alone ("clone 2"). At the chronic phase, a significant reduction preferentially of GATA1 full length was seen in pre-fibrotic PMF, particularly compared to ET and PV; no significant differences were observed between PV and ET. The fibrotic progression of both PV and ET was associated with a significant reduction in GATA1, particularly affecting the GATA1 full length isoform. The fibrotic progression of pre-PMF to PMF was associated with a significant reduction of the overall GATA1 protein and a trend in reduction of GATA1s. Our findings support a role of GATA1 in the pathogenesis of BCR-ABL1 negative MPN, particularly in their fibrotic progression and suggest that the immunohistochemical evaluation of GATA1 may be of use in the differential diagnosis of these neoplasms.

Vascular neoplasms and non-neoplastic vascular lesions of the spleen.

Vascular neoplasms are among the most common conditions affecting the spleen. The majority of these are idiopathic, benign in nature and asymptomatic and therefore treated with a conservative management. Only rare cases cause splenomegaly and/or chronic consumption coagulopathies, thus requiring splenectomy. Among these, the most common is splenic hemangioma, followed by littoral cell angioma and lymphangioma. Peliosis is a peculiar tumor-like non-neoplastic vascular lesion that diffusely affects the spleen and frequently presents with concomitant hepatic involvement. As a distinctive feature, peliosis can occur as a secondary manifestation of infections, malignancies and in individuals using certain drugs. On the opposite spectrum of clinical behavior lies splenic angiosarcoma, a vascular endothelial malignancy with aggressive presentation and poor prognosis. In some cases the endothelial nature of this neoplasm may not be evident on routine histologic examination and immunohistochemistry is used to disclose such phenotype. The term hemangioendothelioma is rarely used to describe borderline vascular neoplasms which appear more aggressive than conventional hemangiomas, but that do not entirely fulfill the diagnostic criteria for angiosarcoma. Some of these neoplasms coexpress endothelial and histiocytic markers and therefore have been proposed as the borderline counterpart of littoral cell angioma. The existence of hemangioendothelioma as a diagnostic entity per se is debated and this diagnosis should be rendered with caution. The current review aims at highlighting the main histologic features of vascular neoplasms and non-neoplastic vascular lesions of the spleen.

Non-hematopoietic neoplastic and pseudoneoplastic lesions of the spleen.

The spleen can be affected by several different non-hematopoietic neoplasms as well as pseudoneoplastic lesions. Generally such conditions affect asymptomatic adults and are detected only as incidental findings; in a minority of the cases vague, unspecific symptoms including abdominal discomfort can occur. Most of these conditions present as a "solitary splenic mass" and have been traditionally diagnosed on partial or total splenectomy, which also represents the most common therapeutic strategy; however, the increasing use of splenic needle biopsies for such lesions creates new diagnostic challenges for pathologists. Splenic cysts (including true cysts, pseudocysts and parasitic cysts) and hamartomas are common benign proliferations which generally pose little problems in their identification. More challenging is the diagnostic workup of "spindle cell and inflammatory rich" lesions of the spleen, whose correct identification is crucial. Indeed, some of these are considered reactive (such as sclerosing angiomatoid nodular transformation of the spleen), whilst others are clonal in nature, the main example being represented by the so called "inflammatory pseudotumour- like follicular/fibroblastic dendritic cell sarcoma". A further degree of complexity is represented by the detection of the Epstein-Barr virus (EBV), which is invariably present in inflammatory pseudotumour- like follicular/fibroblastic dendritic cell sarcoma, but also in other proliferations including the rare "EBV- related smooth muscle tumor of the spleen". Finally, the spleen can host rare dendritic/reticulum cell sarcomas and metastases from extrasplenic malignancies. The current review aims at highlighting the main histologic features of non-hematopoietic and non-vascular neoplasms as well as pseudoneoplastic lesions of the spleen.

Adult primary cervical rhabdomyosarcomas: A Multicentric cross-national case series.

OBJECTIVES: Adult primary cervical rhabdomyosarcoma is a very rare disease and data regarding treatment are sparce. The goal of this study was to report on our experience with the management of this rare entity, along with an evaluation of the literature. METHODS: We conducted a review of the medical records at four centers from January 1990 to December 2017. We reviewed clinical characteristics including age at diagnosis, BMI, medical history and tumor stage, as well as treatment in the primary and recurrent settings and follow-up data. We reclassified tumors according to the Intergroup Rhabdomyosarcoma Study (IRS) clinical group. RESULTS: A total of 15 patients were included in the analysis. Median age at diagnosis was 35 years (range 17-55). Median tumor size at presentation was 5 cm (range 3-10). Eleven patients had the embryonal variant, including five showing the botryoid subtype. Four patients had a pleomorphic rhabdomyosarcoma. Eleven patients had disease classified as IRS Clinical Group I, while the remaining four fell into groups II or III. Fertility-sparing treatment was offered to five patients. Primary treatment types were: surgery alone in eight patients, surgery followed by adjuvant chemotherapy in six patients, and neoadjuvant chemotherapy in two patients. The main risk factors for relapse were: IRS clinical group greater than I, tumor size greater than 5 cm, lymph nodal involvement, and non-embryonal histology. At a median follow-up of 35 months (range 3-282), we observed a 5-year overall survival rate of 78.2% and a progression-free survival of 58.2%. No patient in the IRS I group died of the disease. Three out of four patients in the IRS II-III group died of the disease (survival range 5-16 months following treatment). CONCLUSION: Our data show that cervical rhabdomyosarcomas account for at least two prognostic groups, demonstrating the existence of low-risk and high-risk patterns. The best predictor of prognosis appearsd to be the IRS clinical group classification system. IRS Group I tumors had an overall good prognosis and rarely recurred; when they did recur they were mainly local, following conservative treatment.

How I investigate chronic myelomonocytic leukemia.

The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 109 /L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of "overlapping" myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing "dysplastic" features and others a predominant "proliferative" phenotype. Accounting for this diversity, two variants of CMML are recognized: "dysplastic" CMML defined by WBC < 13 × 109 /L and "proliferative" CMML with WBC ≥ 13 × 109 /L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the "oligomonocytic" variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5-0.9 × 109 /L. It can be considered a "pre-phase," as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new "CMML-0" category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.

Ultrasound-guided fine needle aspiration cytology in the diagnosis of hepatic and pancreatic perivascular epithelioid cell tumors: A case series.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors that can affect any part of the body. They can be sporadic or arise in the setting of tuberous sclerosis (TSC). In this article, we report a series of three hepatic and two pancreatic PEComas diagnosed preoperatively with ultrasound-guided fine needle aspiration (FNA). All patients were female (age range 28-70), had no personal history of TSC and presented with a single, localized painless mass. Rapid on-site evaluation (ROSE) of cytologic samples was performed for all cases to evaluate for cellular content and adequacy of specimens. Direct smears and cell block preparations revealed a proliferation of medium to large polygonal epithelioid cells, with abundant eosinophilic and vacuolated cytoplasm, arranged in sheets and nests. On immunohistochemistry (IHC), neoplastic cells showed co-expression of melanocytic and smooth muscle markers and a diagnosis of PEComa was rendered. PEComas of the pancreas and liver are rare neoplasms, but should always be considered when examining "clear cell" neoplasms, especially in young female patients. If good quality cytologic samples are obtained by FNA, a correct diagnosis can be achieved with the help of IHC. This is of particular importance in order to plan adequate surgical strategy and to avoid overtreatment.

Tissue-based multigene expression tests for pretreatment prostate cancer risk assessment: current status and future perspectives.

Prostate cancer is a highly prevalent disease with ample spectrum of aggressiveness and treatment options. Low-risk disease can be safely managed by nonintervention strategies, such as active surveillance; however, accurate risk assessment is warranted. Molecular tests have been developed and validated to complement standard clinicopathological parameters and help to improve risk stratification in prostate cancer. Herein, we review selected tissue-based assays, including genomic prostate score, cell cycle progression score and genomic classifier, with particular emphasis on their role in patient risk assessment in a pretreatment setting, in view of their current or potential utilization in active surveillance.

Fibroblastic Malignant Peripheral Nerve Sheath Tumour of the Uterine Cervix: Report of a Case and Literature Review With Emphasis on Possible Differential Diagnosis.

Cervical sarcomas are rare neoplasms, accounting for <1% of all cervical malignancies and characterized by an aggressive course despite radical excision. We report the clinical and microscopic features of a spindle cell sarcoma arising as a polypoid endocervical mass in a 45-yr-old woman. The neoplasm was characterized by a monotonous, mildly atypical proliferation of spindle cells, displaying a fibrosarcoma-like parallel pattern of highly dense fascicles, growing under the cervical epithelium. Mitotic activity was conspicuous, with up to 40 mitoses per 10 HPF. On immunohistochemistry, tumor cells were patchy S-100 protein positive. Additional immunohistochemical markers performed to rule out smooth muscle, melanocytic, epithelial, and sarcomatous differentiation were negative. A possible monophasic synovial sarcoma was also excluded by negative fluorescence in situ hybridization t(X;18) analysis. Interestingly, the neoplasm showed a focal CD34 positivity, as reported in normal fibrocytic cells of the endocervical stroma. Giving the morphologic and immunohistochemical features, the neoplasm was eventually defined as malignant peripheral nerve sheath tumor. Histologic examination following radical surgery revealed the neoplasm was confined to the uterine cervix (FIGO stage IB1) and at 12 mo of follow-up, the patient is still free of disease. Malignant peripheral nerve sheath tumors are highly aggressive sarcomas that can rarely involve the uterine cervix. They have to be differentiated from melanoma, leiomyosarcoma, endometrial stromal sarcoma, synovial sarcoma, and other spindle cell neoplasms.