Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n = 76). In contrast, <5% of classic Hodgkin lymphoma cases (n = 70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.

Mesothelioma in situ of the peritoneum: report of three cases and review of the literature.

AIM: Diagnosis of mesothelioma in situ (MIS) is historically controversial and, until recently, specific features defining the entity have not been well characterized. Most reported cases of MIS occurred in the pleura; peritoneal MIS is very rare. This study investigates the morphologic features and results of ancillary testing in peritoneal MIS. METHODS: We present three patients with peritoneal MIS, as defined by a single layer of mesothelial cells with loss of nuclear BRCA-1-associated protein-1 (BAP1) immunostaining and without evidence of invasive tumour by microscopic evaluation, imaging, or direct examination of the peritoneum. Histology and immunostains were reviewed by three expert thoracic pathologists with multidisciplinary input. Next-generation sequencing (NGS) was performed in all three cases. A literature review was conducted to characterize this rare precursor lesion. RESULTS: BAP1 was lost in all three lesions, while methylthioadenosine phosphorylase (MTAP) was retained in two (not performed in the third). NGS revealed BAP1 pathogenic alterations in all three cases as well as mutations of SMO, ERCC3, TET2, and U2AF1. Progression to invasive mesothelioma occurred in one patient at 13 months postdiagnosis (case 1). One patient was diagnosed at age 24 and was later found to harbour a BAP1 germline mutation (case 3). CONCLUSION: This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS.

Primary Cutaneous B-Cell Lymphoma Complicated by Clonal T-Cell Populations: A Diagnostic Dilemma.

ABSTRACT: Cutaneous lymphomas, both B-cell and T-cell, are not uncommonly seen in the skin, but those lymphomas exhibiting clonality for both B-cell and T-cell populations are scarce. Characterization of dual receptor rearrangement as primary composite lymphoma versus primary lymphoma with reactionary response is complex and often a challenge that goes unrecognized. In this study, we report a unique case of T-cell gene rearrangement positivity complicating the diagnosis of primary cutaneous low-grade B-cell lymphoma along with a review of reported cases containing dual receptor rearrangement to identify trends among final diagnostic decisions. As one might guess, for cutaneous lymphomas presenting with clonality for both T-cell and B-cell receptors, diagnosis can be difficult and confusing because the differential is broad. The literature suggests the majority of these cases may be cutaneous composite lymphomas. However, immunohistochemical, clinical, and histomorphologic features must all be assessed for an accurate diagnosis, which is critical for proper prognosis and therapy.

Cytomorphologic and molecular characterization of spindle cell carcinoid tumors of the lung.

BACKGROUND: Spindle cell carcinoid tumor (SCCT) is a rare variant of lung carcinoid tumor consisting predominantly or exclusively of spindle cells. To the authors' knowledge, this is the first study to date investigating the molecular characteristics of SCCTs. METHODS: Eighty-five carcinoid tumors initially diagnosed by fine-needle aspiration over a period of 10 years were reviewed. The final diagnostic classification was based on resection specimens. Six SCCTs were identified and characterized based on cytomorphology, and immunohistochemical and molecular features. RESULTS: Most patients with SCCT were Caucasian (100.0%), women (83.3%), asymptomatic (66.7%), and nonsmokers (83.3%). The median age at diagnosis was 78.0 years (range, 58.2-80.3 years). A higher proportion of patients who had SCCT were diagnosed with distant metastasis. The smears were cellular and demonstrated clean backgrounds without necrosis or mitotic activity. SCCTs comprised of bipolar-to-elongated cells with finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and minimal atypia or pleomorphism. The tumor cells sometimes appeared boomerang-shaped and might mimic granulomas or blood vessels. SCCTs showed strong expression for pan-cytokeratin, synaptophysin, chromogranin, and CD56, with weak TTF-1 and a very low Ki-67 proliferation index. All SCCTs had low tumor mutational burden and were microsatellite-stable. One case showed multiple whole-gene losses in chromosome 11, whereas another harbored duplication in ARID1A. Two cases demonstrated gains in chromosomes 17, one of which also showed gains in chromosome 18. None had a single nucleotide mutation. CONCLUSIONS: SCCT is a rare subset of lung carcinoid tumors. These tumors harbor unique cytologic, prognostic, and molecular features that may have significant diagnostic and clinical implications.

Lung adenocarcinomas with isolated TP53 mutation: A comprehensive clinical, cytopathologic and molecular characterization.

BACKGROUND: TP53 mutation is present in about 50.8% of lung adenocarcinomas, frequently in combination with other genetic alterations. However, a rare subset harbors the TP53 mutation alone. METHODS: Next-generation sequencing was performed in 844 lung adenocarcinomas diagnosed by fine needle aspiration. Fourteen cases (1.7%) showed isolated TP53 alteration and were subjected to a comprehensive analysis. RESULTS: The average age at diagnosis was 65.7 years (range 48-79); 9 males and 5 females. All were smokers with an average pack-year of 40.7 (range 10-70). Ten had metastases, mostly in the brain (n = 4) and pleura (n = 4). After a follow-up period of up to 102 months, 9 died, 3 were alive free of disease, 1 was alive with disease, and 1 was lost to follow-up. The median survival was 12.2 months. Most tumors exhibited poor differentiation, composed of solid sheets with moderate to severe atypia, increased mitotic activity, and necrotic background. Half were positive for TTF-1 and showed p53 overexpression. PD-L1 was positive in 5 cases. Most alterations were missense mutations in exons 5-8, and this mutation type was associated with p53 overexpression. Tumors with combined missense mutation and truncated protein had higher PD-L1 expression along with a trend towards an increase in tumor mutational burden (TMB). CEBPA deletion of undetermined significance was the most common copy number alteration. CONCLUSION: Isolated TP53 mutation was seen in association with smoking, high-grade cytomorphologic features, adverse prognosis, and recurrent CEBPA deletions. These tumors tend to have strong PD-L1 expression and high TMB, suggesting potential benefit from immune checkpoint inhibitors. Hence, the recognition of this molecular group has prognostic and therapeutic implications.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Utility of non-contrast head computed tomography in poisoned patients.

OBJECTIVE: To investigate the utility of non-contrast head computed tomography (CT) in poisoned patients. METHODS: A retrospective cohort study of patients referred to a toxicology unit between August 2010 and December 2017. Our database yielded patients who underwent head CT at presentation to the ED. Pre-specified information was compiled from the medical records. RESULTS: There were 6261 presentations of which 1142 underwent head CT (17%). Median age was 41 years, and 437 (38%) were female. There were 492 (43%) recreational ingestions and 466 (41%) deliberate self-poisonings. The commonest agents were sedatives 376 (33%) and opioids 282 (24%); 334 (29%) cases were intubated. Signs of head injury were found in 153 cases (13%) and focal neurological signs in 68 (6%). No acute pathology was reported in 884 head CTs (77%), chronic changes in 193 (17%) and incidental findings in 26 (2%). Acute pathology was found in 39 (4%) patients: 15 with hypoxic-ischaemic injury, three infarctions, nine with intra-cranial haemorrhage, 11 facial bone fractures and one retro-bulbar haematoma. No patient required an immediate surgical intervention, and only one patient had a change to clinical treatment. Acute head CT pathology was associated with at least one of the following clinical features: need for intubation, signs of head injury, seizure, headache, and unexpected neurological signs. CONCLUSION: Non-contrast head CT is a low-yield investigation in patients presenting with poisoning. Consideration should be given as to whether the clinical presentation is consistent with the expected toxidrome and whether the patient would benefit from head CT.