Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of ...hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. Methods: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. Results: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity.
Mastocytosis represents a heterogeneous group of neoplastic mast cell disorders. The basic classification into a skin-limited disease and a systemic form with multi-organ involvement remains valid. ...Systemic mastocytosis is a disease often hard to diagnose, characterized by different symptoms originating from either the release of mast cell mediators or organ damage due to mast cell infiltration. Gastrointestinal symptoms represent one of the major causes of morbidity, being present in 60–80% of patients. A high index of suspicion by clinicians and pathologists is required to reach the diagnosis. Gastrointestinal mastocytosis can be a challenging diagnosis, as symptoms simulate other more common gastrointestinal diseases. The endoscopic appearance is generally unremarkable or nonspecific and gastrointestinal mast cell infiltration can be focal and subtle, requiring an adequate sampling with multiple biopsies by the endoscopists. Special stains, such as CD117, tryptase, and CD25, should be performed in order not to miss the gastrointestinal mast cell infiltrate. A proper patient’s workup requires a multidisciplinary approach including gastroenterologists, endoscopists, hematologists, oncologists, and pathologists. The aim of this review is to analyze the clinicopathological features of gastrointestinal involvement in systemic mastocytosis, focusing on the relevance of a multidisciplinary approach.
Aims
Mantle cell lymphoma (MCL) is characterized by distinctive histological and molecular features. Aberrant expression of BCL6 and CD10 has been reported occasionally, but the biological features ...of such cases are largely unknown. This study aimed to define the epidemiological, histological and cytogenetic characteristics of BCL6 and CD10‐positive MCLs, also investigating possible biological features.
Methods and results
A total of 165 cases of cyclin D1 and t(11;14)(q13;q34)‐positive MCLs were studied for CD10 and BCL6 immunohistochemical expression, which was documented in 26 of 165 (15.8%) cases (BCL6 17 of 165; CD10 11 of 165; BCL6 and CD10 co‐expression two of 165). CD10‐positivity was significantly more frequent in females (63.3%; P < 0.01). Either expression correlated significantly with higher mean proliferation index and higher prevalence of MUM1 positivity (P < 0.05). Fluorescence in‐situ hybridization (FISH) for BCL6 (3q27) gene derangements was performed on the BCL6‐ and CD10‐positive cases and 98 matched controls: amplifications were documented more frequently in BCL6‐positive than ‐negative cases (50.0% versus 19.4% of cases) (P < 0.05). The mutational status of the variable immunoglobulin heavy chain genes (IGVH) was investigated by Sanger sequencing: five of the six successfully tested cases (83.3%) showed no somatic hypermutations.
Conclusions
Aberrant CD10 and BCL6 expression defines a subset of MCLs with higher mean Ki‐67 index and higher prevalence of MUM1 expression. BCL6 protein positivity correlates with cytogenetic aberrations involving the BCL6 gene. Although examined successfully in few cases, the high prevalence of unmutated IGVH genes also points at a pregerminal cell origin for these phenotypically aberrant cases.
Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the ...biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an
in situ
aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management.
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•Colchicine can be mistaken for saffron leading to fatal intoxication.•Reconstruction of the mechanism of death is essential in forensic pathology.•The male victim died of acute ...cardiovascular collapse due to fluid losses.•Multi organ failure, immunosuppression and infection led the female victim to death.•Integrating circumstantial, autopsy, histology and toxicology is recommended.
Although fatal colchicine intoxications are rare and mostly related to suicidal intake or accidental overdose, other hypotheses should be considered when dealing with colchicine poisoning. We present a case of double, acute, and subacute, fatal colchicine intoxication in a married couple. The 70-year-old male victim suddenly died after vomiting and diarrhea. The next day his wife showed aggravating gastrointestinal symptoms and was hospitalized with a diagnosis of septic shock. A complete postmortem examination on the man was performed, together with histopathological analysis. Toxicological examination performed through liquid chromatography coupled to mass spectrometry revealed a colchicine blood peripheral concentration of 33 ng/mL. A few days after hospitalization, the woman showed a colchicine plasma concentration of 32 ng/mL. Despite veno-venous hemofiltration, she ultimately died of septic shock and multi-organ failure.
Death scene investigation revealed that, a few days before the death of the male victim, the couple had collected wild saffron and had eaten a presumed saffron risotto.
The integrated analysis of circumstantial, clinical, postmortem and toxicological data allowed to establish that the couple had died of a fatal accidental intoxication due to the ingestion of natural colchicine, mistaken for saffron. The death of the male was deemed caused by acute cardiovascular collapse induced by acute intoxication, while the female had suffered a subacute poisoning by antimitotic agent, resulting in immunosuppression and systemic infection. Toxicological analyses, promptly performed on the man for forensic purposes, directed the investigations and suggested the clinical diagnosis on the woman.
About 30% of patients with diffuse large B-cell lymphoma (DLBCL) relapse or exhibit refractory disease (r/r DLBCL) after first-line immunochemotherapy. Bone marrow (BM) involvement confers a dismal ...prognosis at diagnosis, likely due to the interaction between neoplastic cells and a complex tumor microenvironment (TME). Therefore, we developed a 3D
in-vitro
model from human decellularized femoral bone fragments aiming to study the role of mesenchymal stromal cells (MSC) and the extracellular matrix (ECM) in the adaptation, growth, and drug resistance of DLBCL lymphoma cells. The 3D spatial configuration of the model was studied by histological analysis and confocal and multiphoton microscopy which allowed the 3D digital reproduction of the structure. We proved that MSC adapt and expand in the 3D scaffold generating niches in which also other cell types may grow. DLBCL cell lines adhered and grew in the 3D scaffold, both in the presence and absence of MSC, suggesting an active ECM–lymphocyte interaction. We found that the germinal center B-cell (GCB)-derived OCI-LY18 cells were more resistant to doxorubicin-induced apoptosis when growing in the decellularized 3D bone scaffold compared to 2D cultures (49.9% +/- 7.7% Annexin V
+
cells in 2D condition compared to 30.7% + 9.2% Annexin V
+
3D adherent cells in the ECM model), thus suggesting a protective role of ECM. The coexistence of MSC in the 3D scaffold did not significantly affect doxorubicin-induced apoptosis of adherent OCI-LY18 cells (27.6% +/- 7.3% Annexin V
+
3D adherent cells in the ECM/MSC model after doxorubicin treatment). On the contrary, ECM did not protect the activated B-cell (ABC)-derived NU-DUL-1 lymphoma cell line from doxorubicin-induced apoptosis but protection was observed when MSC were growing in the bone scaffold (40.6% +/- 5.7%
vs
. 62.1% +/- 5.3% Annexin V
+
3D adherent cells
vs
. 2D condition). These data suggest that the interaction of lymphoma cells with the microenvironment may differ according to the DLBCL subtype and that 2D systems may fail to uncover this behavior. The 3D model we proposed may be improved with other cell types or translated to the study of other pathologies with the final goal to provide a tool for patient-specific treatment development.
Progression in Ph-chromosome-negative myeloproliferative neoplasms (MPN) develops with variable incidence and time sequence in essential thrombocythemia, polycythemia vera, and primary myelofibrosis. ...These diseases show different clinic-pathologic features and outcomes despite sharing deregulated JAK/STAT signaling due to mutations in either the Janus kinase 2 or myeloproliferative leukemia or CALReticulin genes, which are the primary drivers of the diseases, as well as defined diagnostic criteria and biomarkers in most cases. Progression is defined by the development or worsening of marrow fibrosis or the progressive increase in the marrow blast percentage. Progression is often related to additional genetic aberrations, although some can already be detected during the chronic phase. Detailed scoring systems for clinical usage that are mostly applied in patients with primary myelofibrosis have been defined, and the most recent ones include cytogenetic and molecular parameters with prognostic significance. Additional different clinic-pathologic changes have been reported that may occur during the course of the disease and that are, at present, classified as WHO-defined types of progression, although they likely represent such an event. The present review is meant to provide an updated overview on progression in Ph-chromosome-negative MPN, with a major focus on the pathologic side.
The disease course of chronic lymphocytic leukemia (CLL) is frequently characterized by the occurrence of various complications, such as second primary cancer, which can impact patients' prognoses. ...While therapies for CLL have evolved tremendously in the past decades, overlooking the possibility of rare neoplasms that arise along with CLL may hinder the benefit that these therapies grant to patients. Moreover, the ability of newer therapies to alter the landscape of these complications is still largely unknown. Primary myelofibrosis (PMF) is not commonly associated with CLL, with only a few cases reported in the literature, with little information regarding the clinico-biological features and the optimal management for these associated conditions. Here, we report two unusual cases of PMF that occurred a few months after the start of therapy for CLL with targeted agents (ibrutinib and venetoclax). Both cases represented a diagnostic and therapeutic challenge, underscoring the need for clinicians to remain vigilant about the possible co-occurrence of these two hematological malignancies, especially in the era of targeted therapy for CLL.
Granulomatosis with polyangiitis (GPA) is characterised by granulomatous inflammation and small-to-medium vessel necrotising vasculitis, mainly affecting respiratory tract and kidneys. Renal ...involvement presenting as tumour-like lesions poses diagnostic and treatment challenges.
Following the observation of a GPA patient presenting with multiple renal tumour-like lesions, we conducted a systematic literature review on MEDLINE/PubMed, EMBASE, and Cochrane databases. Data gathered from the literature were analysed to summarise the diagnostic approach, management, and outcome of renal GPA-related tumour-like lesions.
a 49-year-old female presented with persistent constitutional symptoms and multiple bilateral renal lesions. Renal biopsy showed chronic interstitial inflammation with necrotising granulomas. Laboratory tests disclosed positive anti-proteinase 3 (PR3) anti-neutrophil cytoplasmic antibody (ANCA) leading to a final diagnosis of GPA. She was effectively treated with high-dose glucocorticoids and rituximab. Literature search yielded 41 articles, concerning 42 GPA patients with renal masses, presenting bilaterally in 23.8% of the cases. Positive PR3-ANCA was observed in 86.5% of the cases. Half of 42 patients showed kidney abnormalities. Treatment with glucocorticoids (83.3%) and immunosuppressive agents (80.9%) resulted in an overall good remission rate and favourable prognosis.
GPA should be considered in the differential diagnoses of kidney tumour-like lesions. The diagnosis is challenging, and histological examination greatly contributes to the diagnostic work-up.
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