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.

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.

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.

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.