Blastic Plasmocytoid Dendritic Cell Neoplasm (BPDCN): Clinical Features and Histopathology with a Therapeutic Overview.

Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCNs) are a rare, highly aggressive hematological malignant neoplasm that primarily involve the skin, bone marrow, lymph nodes and even extra-nodal sites. The rarity and relative poor description of cases in the literature make it necessary to review and further studies that deeply investigate this entity not only in a histopathological but also molecular field. In August-September 2023, we searched MEDLINE, PubMed and Scopus for randomized controlled trials (RCTs), narrative and systematic reviews, meta-analyses, observational studies (either longitudinal or retrospective), and case series published in English in the last 25 years using the keywords BPDCN, PDCs, Blastic NK-cell lymphoma, agranular CD4+ NK leukemia/lymphoma, agranular CD4+ CD56+ hematodermic neoplasm/tumor. Despite the progress made in recent years in the diagnosis and biological understanding of the disease, until 2018 there was no clear consensus regarding its treatment and the main therapeutic schemes used were based on chemotherapy regimens already used in the treatment of lymphomas, acute lymphoblastic leukemia (ALL) and/or acute myeloid leukemia (AML). In this narrative review, we address the definition and epidemiological features of BPDCN, provide the different theories on the etiopathogenesis with particular attention to the presumed cell of origin, discuss the main clinical manifestations that provide a sign of its presence, summarize the main histopathological and immunophenotypic characteristics with special attention to the most important markers, and finally, we provide some of the most effective information on the therapeutic treatment modalities of BPDCN.

Endocrine Mucin-Producing Sweat Gland Carcinoma: Case Presentation with a Comprehensive Review of the Literature.

(1) Background: Endocrine Mucin-Producing Sweat Gland Carcinoma (EMPSGC) is a rare, low-grade, neuroendocrine-differentiated, cutaneous adnexal tumor, officially recognized by the World Health Organization (WHO) Skin Tumors Classification in 2018 as a separate entity and homologue of endocrine ductal carcinoma in situ (eDCIS)/solid papillary carcinoma of the breast. Although it is more frequent in the female sex, between 60 and 70 years old, in the peri-orbital region, EMPSGC has also been described in the male sex, in subjects under 60 and over 80, and in extra-eyelid localizations (cheek, temple, scalp), but also in extra-facial localizations (chest and scrotum). (2) Methods: We present the clinical case of a 71-year-old woman with an undated lesion of the scalp, which presented as a nodule, skin-colored, and 2.5 cm in maximum diameter. We also conduct a comprehensive literature review from 1997 to the end of 2022, consulting PubMed, Scopus, Web of Science (WoS), and Google Scholar using the following keywords: "Endocrine mucin-producing sweat gland carcinoma" and/or "EMPSGC" and/or "skin" and "cutaneous neoplasms". In addition, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 253 patients were recorded; 146 were females (57.7%) and 107 were males (42.2%). The vast majority of the lesions were in the eyelids (peri-ocular region), and only a minority of cases involved the cheeks, supra-auricular, retro-auricular, and occipital region, with very rare cases in the scalp, to which the present is also added. (4) Conclusions: The morphological and immunophenotypical features are essential both for the correct diagnosis and to be able to classify this lesion among the corresponding eDCIS/solid papillary carcinoma of the breast, with neuroendocrine differentiation. Recent papers have attempted to shed light on the molecular features of EMPSGC, and much remains to be conducted in the attempt to subtype the molecular profiles of these entities. Future studies with large case series, and especially with molecular biology techniques, will be needed to further add information about EMPSGC and its relationship in the PCMC spectrum.

The Tumor Microenvironment in Classic Hodgkin's Lymphoma in Responder and No-Responder Patients to First Line ABVD Therapy.

Although classical Hodgkin lymphoma (CHL) is typically curable, 15-25% of individuals eventually experience a relapse and pass away from their disease. In CHL, the cellular microenvironment is constituted by few percent of H/RS (Hodgkin/Reed-Sternberg) tumor cells surrounded from a heterogeneous infiltration of inflammatory cells. The interplay of H/RS cells with other immune cells in the microenvironment may provide novel strategies for targeted immunotherapies. In this paper we analyzed the microenvironment content in CHL patients with responsive disease (RESP) and patients with relapsed/refractory disease to treatment (REL). Our results indicate the increase of CD68+ and CD163+ macrophages, the increase of PDL-1+ cells and of CD34+ microvessels in REL patients respective to RESP patients. In contrast we also found the decrease of CD3+ and of CD8+ lymphocytes in REL patients respective to RESP patients. Finally, in REL patients our results show the positive correlation between CD68+ macrophages and PDL-1+ cells as well as a negative correlation between CD163+ and CD3+.

Molecular Features and Diagnostic Challenges in Alpha/Beta T-Cell Large Granular Lymphocyte Leukemia.

Large granular lymphocyte leukemia is a rare chronic lymphoproliferative disease of cytotoxic lymphocytes. The diagnosis, according to the WHO, is based on a persistent (>6 months) increase in the number of LGL cells in the peripheral blood without an identifiable cause. A further distinction is made between T-LGL and NK-LGL leukemia. The molecular sign of LGL leukemia is the mutation of STAT3 and other genes associated with the JAK/STAT pathway. The most common clinical features are neutropenia, anemia, and thrombocytopenia, and it is often associated with various autoimmune conditions. It usually has an indolent course. Due to the rarity of the disease, no specific treatment has yet been identified. Immunosuppressive therapy is used and may allow for disease control and long-term survival, but not eradication of the leukemic clone. Here, we discuss the clinical presentation, diagnostic challenges, pathophysiology, and different treatment options available for alpha/beta T-LGL leukemia, which is the most common disease (85%), in order to better understand and manage this often misunderstood disease.

Diffuse Large B Cell Lymphoma Arising in Patients with Preexisting Hodgkin Lymphoma.

The metachronic onset of diffuse large B-cell lymphoma (DLBCL) after classic Hodgkin lymphoma (cHL) is a rare event affecting patients' outcomes. However, although several studies have investigated the prognostic role of this event, little is known about a hypothetical common origin of the two different neoplastic cells. AIMS: To investigate a possible relationship between DLBCL and cHL, in this retrospective study of 269 patients with newly diagnosed cHL treated at Bari University Hospital (Italy) between 2007 and 2020, we analyzed data from 4 patients (3 male and 1 female) with cHL who subsequently developed DLBCL. METHODS: Gene expression profile analysis, assessed by NanoString Lymphoma Subtype Assay, was performed to identify the cell of origin in the DLBCL cases, in addition to Hans's algorithm. RESULTS: Using Hans's algorithm, all DLBCL cases showed a germinal center-B-Cell subtype. The gene expression profile evaluated by the NanoString Lymphoma Subtype Assay revealed two cases of the GCB molecular subtype, while the others were unclassified. After first-line chemotherapy, 1 patient achieved complete remission, 3 were non-responders (2 died of lymphoma within 6 months, whereas the other achieved complete remission after autologous and allogeneic stem cell transplantation and is still alive). CONCLUSIONS: The origin of the second neoplastic cell in patients with DLBCL with a previous history of cHL remains controversial, although the different immunophenotypic characteristics suggest that it may mainly arise de novo in a subject with a possible individual predisposition to develop lymphoid neoplasms.

Indolent Lymphoproliferative T-Cell Disorders Associated With Gastrointestional Disease: Diagnostic Challenges and Outcomes.

Lymphoproliferative diseases arise when the physiological mechanisms that control the proliferation of T and B lymphocytes are disrupted, resulting in an uncontrolled and autonomous increase in immune cells leading to lymphocytosis and lymphadenopathy, and often to the involvement of extranodal sites. The differential diagnosis of malignant T cell tumors involves other neoplasms and non-clonal T cell proliferations. Immunological markers are essential, as a first step, to distinguish between T-cell and non-T-cell disorders. It must be established based on the configuration of the genes of the TCR chain to rule out that the picture is not reactive to other underlying diseases. This clinical review and accompanying case reports highlight the diagnostic challenges associated with indolent lymphoproliferative T-cell disorders, which in many cases may represent the clinical manifestation of a single disease. Particularly we focus on gastrointestinal manifestations that could be expression either of lymphoproliferative disorder either of autoimmune disease either of both. The correct interpretation of the different clinical situations can help in the diagnostic and therapeutic process.

Balloon Cell Melanoma: Presentation of Four Cases with a Comprehensive Review of the Literature.

BACKGROUND: balloon cell melanoma represents less than 1% of all histological forms of malignant melanoma and represents a diagnostic challenge for the dermatopathologist. METHODS: in this paper we present our cases of BCM found in our daily practice from 1 January 2008 to 31 December 2021, and we conduct a review of the literature relating to this entity in the period from the first description, 1970, to early 2022. RESULTS: four cases of melanoma balloon cell have been extrapolated from our electronic database, while in the review of the literature we have identified 115 cases of patients with primary and/or metastatic BCM. CONCLUSIONS: we believe that future studies with numerous case series are essential not only to increase the knowledge of the pathophysiology of this neoplasm but also to correctly evaluate the response of BCM patients to new oncological therapies.

The Effect of the Tumor Microenvironment on Lymphoid Neoplasms Derived from B Cells.

Lymphomas are characteristic tumors surrounded by an inflammatory microenvironment. The cells of the microenvironment are essential for the growth and survival of neoplastic cells and are recruited through the effect of cytokines/chemokines. Lymphomas include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state. In this review article, we analyze the literature data concerning the involvement of the tumor microenvironment (TME) in the progression of lymphomas and the recent advances in the analysis of microenvironment components in the most common forms: some mature B cell lymphoma neoplasms and classic Hodgkin lymphomas. The complex crosstalk between the TME and tumor cells led to the discovery of many mechanisms usable as molecular-targeted therapy through the control of diverse elements of the TME, varying from inhibitors of angiogenic cytokines and their receptors to the regulation of cells' activities and the novel immune checkpoint inhibitors.

Alteration of the translational readthrough isoform AQP4ex induces redistribution and downregulation of AQP4 in human glioblastoma.

Glioblastoma multiforme (GBM) is characterized by a remarkable cellular and molecular heterogeneity that make the behavior of this tumor highly variable and resistant to therapy. In addition, the most serious clinical complication of GBM and other brain tumors is the development of vasogenic edema which dramatically increase the intracranial pressure. In the present study we evaluate the expression, supramolecular organization and spatial distribution of AQP4 and AQP4ex, the new readthrough isoform of AQP4, in relationship with the degree of vasogenic brain edema and tumor progression. To this purpose, tissue samples from regions of tumor core, peritumoral and non-infiltrated tissues of each GBM patient (n = 31) were analyzed. Immunofluorescence experiments revealed that the expression of AQP4ex was almost absent in tumoral regions while the canonical AQP4 isoforms appear mostly delocalized. In peritumoral tissues, AQP4 expression was found altered in those perivascular astrocyte processes where AQP4ex appeared reduced and partially delocalized. Protein expression levels measured by immunoblot showed that global AQP4 was reduced mainly in the tumor core. Notably, the relative amount of AQP4ex was more severely reduced starting from the peritumoral region. BN-PAGE experiments showed that the supramolecular organization of AQP4 is only partially affected in GBM. Edema assessment by magnetic resonance imaging revealed that the level of AQP4ex downregulation correlated with edema severity. Finally, the degree of BBB alteration, measured with sodium fluorescein content in GBM biopsies, correlated with the edema index and AQP4ex downregulation. Altogether these data suggest that the AQP4ex isoform is critical in the triggering event of progressive downregulation and mislocalization of AQP4 in GBM, which may affect the integrity of the BBB and contributes to accumulation of edema in the peritumoral tissue. Thus, AQP4ex could be considered as a potential early biomarker of GBM progression.

GLUT1, GLUT3 Expression and 18FDG-PET/CT in Human Malignant Melanoma: What Relationship Exists? New Insights and Perspectives.

BACKGROUND: Malignant melanoma is the most aggressive of skin cancers and the 19th most common cancer worldwide, with an estimated age-standardized incidence rate of 2.8-3.1 per 100,000; although there have been clear advances in therapeutic treatment, the prognosis of MM patients with Breslow thickness greater than 1 mm is still quite poor today. The study of how melanoma cells manage to survive and proliferate by consuming glucose has been partially addressed in the literature, but some rather interesting results are starting to be present. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a search of PubMed and Web of Sciences (WoS) databases was performed until 27 September 2021 using the terms: glucose transporter 1 and 3 and GLUT1/3 in combination with each of the following: melanoma, neoplasm and immunohistochemistry. RESULTS: In total, 46 records were initially identified in the literature search, of which six were duplicates. After screening for eligibility and inclusion criteria, 16 publications were ultimately included. CONCLUSIONS: the results discussed regarding the role and expression of GLUT are still far from definitive, but further steps toward understanding and stopping this mechanism have, at least in part, been taken. New studies and new discoveries should lead to further clarification of some aspects since the various mechanisms of glucose uptake by neoplastic cells are not limited to the transporters of the GLUT family alone.

Unexpected endometrial malacoplakia related to abortion and placental rests retention: a case report.

BACKGROUND: Malacoplakia is a rare chronic inflammatory disease. The name derives from the Greek "µαλακός" meaning "soft" and "πλάξ" meaning "plaque", describing its usual macroscopic presentation as a friable yellow soft plaque. It was first described by von Hansemann in 1901 and by Michaelis and Gutmann in 1902. The urinary system is the most commonly involved site. Female genital tract involvement is extremely rare. Treatment is prevalently based on antibiotics with surgical intervention sometimes necessary. Prognosis is usually good, but relapse may frequently occur. CASE PRESENTATION: This report illustrates the first case of endometrial malacoplakia in a 40 years-old patient who received endometrial curettage due to the retention of placental rests following an abortion. After conspicuous vaginal sero-hematic secretions, the patient received a further curettage. The histological examination did not show any retention of chorionic rests, but an endometrial and myometrial infiltration of histiocytes with large granular cytoplasm within a chronic inflammatory background. Immunoreactivity for CK-pool was negative, while CD68 immunostaining was strongly positive. CONCLUSIONS: Malacoplakia of endometrium is an extremely rare condition, with few cases reported in the whole international literature. In this paper, we present the first case associated to an abortion followed by endometrial curettage procedures. This rare disease should always be attentively examined, considering, among differential diagnoses, uterine neoplasms or physiological conditions such as cumulus of foamy macrophages in the endometrium.