Pleomorphic Features Research Articles

Primary leptomeningeal melanocytic neoplasms: A clinicopathologic, immunohistochemical, and molecular study of 12 cases

This study investigated the clinicopathological, immunohistochemical, and molecular features of primary leptomeningeal melanocytic neoplasms (LMNs). Twelve LMN cases were retrospectively reviewed. We performed Fluorescence in-situ hybridization (including a 4-probe FISH assay with CDKN2A and MYC assay) and Next-Generation sequencing analyses on available cases. Histologically, 2 tumours were classified as melanocytomas (MC), 2 as intermediate-grade melanocytomas (IMC), and 8 as leptomeningeal melanomas (LMM). Two rare cases of LMM were associated with large plaque-like blue nevus. One MC case was associated with Ota. Ten cases (83.3%) showed melanocytic cells with benign features diffusely proliferating within the meninges. The Ki-67 in three categories differed (MC 0–1%, IMC 0–3%, LMM 3–10%). 57.1% of LMM cases (4/7) were positive for FISH. Nine of 10 tumours harboured activating hotspot mutations in GNAQ, GNA11, or PLCB4. Additional mutations of EIF1AX, SF3B1, or BAP1 were found in 40%, 30%, and 10% of tumours, respectively. During the follow-up (median = 43 months), 5 LMM patients experienced recurrence and/or metastasis, 3 of them died of the disease and the other 2 are alive with the tumour. Our study is by far the first cohort of LMN cases tested by FISH. In addition to morphological indicators including necrosis and mitotic figures, using a combination of Ki-67 and FISH helps to differentiate between IMC and LMM, especially in LMM cases with less pleomorphic features. SF3B1 mutation is first described in 2 cases of plaque-type blue nevus associated with LMM. Patients with SF3B1 mutation might be related to poor prognosis in LMN.

RET Fusion Testing in Patients With NSCLC: The RETING Study

IntroductionRET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. MethodsThis situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. ResultsThe most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). ConclusionsIn-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.

Surgical Management and Outcomes of Patients with Multifocal Hepatoblastoma

ObjectiveTo compare the outcomes of patients with multifocal hepatoblastoma (HB) treated at our institution with either orthotopic liver transplant (OLTx) or hepatic resection to determine outcomes and risk factors for recurrence. BackgroundMultifocality in HB has been shown to be a significant prognostic factor for recurrence and worse outcome. The surgical management of this type of disease is complex and primarily involves OLTx to avoid leaving behind microscopic foci of disease in the remnant liver. MethodsWe performed a retrospective chart review on all patients <18 years of age with multifocal HB treated at our institution between 2000 and 2021. Patient demographics, operative procedure, post-operative course, pathological data, laboratory values, short- and long-term outcomes were analyzed. ResultsA total of 41 patients were identified as having complete radiologic and pathologic inclusion criteria. Twenty-three (56.1%) underwent OLTx and 18 (43.9%) underwent partial hepatectomy. Median length of follow-up across all patients was 3.1 years (IQR 1.1–6.6 years). Cohorts were similar in rates of PRETEXT designation status identified on standardized imaging re-review (p = .22). Three-year overall survival (OS) estimate was 76.8% (95% CI: 60.0%–87.3%). There was no difference in rates of recurrence or overall survival in patients who underwent either resection or OLTx (p = .54 and p = .92 respectively). Older patients (>72 months), patients with a positive porta hepatis margin, and patients with associated tumor thrombus experienced worse recurrence rates and survival. Histopathology demonstrating pleomorphic features independently associated with worse rates of recurrence. ConclusionsThrough proper patient selection, multifocal HB was adequately treated with either partial hepatectomy or OLTx with comparable outcome results. HB with pleomorphic features, increased patient age at diagnosis, involved porta hepatis margin on pathology, and the presence of associated tumor thrombus may be associated with worse outcomes regardless of the local control surgery offered. Level of EvidenceIII.

Reliability of assessing morphologic features with prognostic significance in cytology specimens of epithelioid diffuse pleural mesothelioma and implications for cytopathology reporting.

The World Health Organization incorporates morphologic features with prognostic significance in the 2021 classification of epithelioid diffuse pleural mesothelioma (E-DPM). Although cytology specimens are often the first and occasionally the only specimen available for patients with DPM, these features have not yet been investigated in cytology. Nuclear atypia, pleomorphic features, necrosis, and architectural patterns were retrospectively assessed in 35 paired cytology and concurrent/consecutive surgical pathology specimens of E-DPM. Agreement between pairs was determined via unweighted κ scores. Discordant cases were re-reviewed to determine the reasons for disagreement. Interpretation of nuclear atypia in cytology was concordant with histology in all cases (κ=1.000; p<.001). The presence of pleomorphic features and necrosis was concordant in 97.1% (κ=0.842; p<.001) and 85.7% (κ=0.481; p=.001) of paired cases, respectively. Assessment of architectural patterns in cytology showed only slight agreement with histology (κ=0.127; p=.037). In cytology cases (n=23) with cell block material available, assessment of nuclear atypia and the presence of pleomorphic features showed perfect agreement (κ=1.000; p<.001, each), the presence of necrosis showed moderate agreement (κ=0.465; p=.008), and assessment of architectural patterns showed slight agreement (κ=0.162; p=.15) in paired specimens. Most disagreements were due to sampling differences between cytology and histology specimens. Although complete nuclear grading of E-DPM is not possible given the unreliability of mitotic counts in cytology, assessment of nuclear atypia in cytology specimens is shown to be reliable. Identification of pleomorphic features and necrosis is also reliable despite occasional sampling issues. Assessment of architectural patterns is more limited in cytology.

Solitary extramedullary plasmacytoma of the gingiva—A case report with literature review

Abstract Extramedullary solitary plasmacytoma (EMP) is a plasma cell neoplasm involving the soft tissues without the involvement of the bone marrow. In this case report, we present an isolated soft tissue growth on the lingual gingiva of the left mandibular canine-premolar region diagnosed as EMP based on clinical, histological, and laboratory results. Orthopantomogram and occlusal radiographs showed no osteolytic lesions. Hematoxylin and Eosin staining showed sheets of inflammatory cells, predominantly atypical plasma cells with varying degrees of differentiation showing features of pleomorphism, and multinucleated giant cells with intervening collagen fibers. Positive immunoreactivity for CD56, CD138, and kappa light chain restriction were observed. Serum protein electrophoresis demonstrated an increase in IgA levels and immunofixation electrophoresis confirmed the presence of the M band in the IgG and kappa lanes, indicating monoclonal gammopathies. Based on the above findings, the case was diagnosed as EMP; the consultant pathologist, however, recommended excluding multiple myeloma.

Bone and soft tissue tumors: clinicoradiologic-pathologicmolecular-genetic correlation of novel fusion spindled, targetable-ovoid, giant-cell-rich, and round cell sarcomas.

New entities in the classification of bone and soft tissue tumors have been identified by use of advanced molecular-genetic techniques,including next-generation sequencing. Clinicoradiologic and pathologic correlation supports diagnostic classification. Tumors from four morphologically grouped areas are selected to enhance diagnosis and awareness among the multidisciplinary team. These include select round cell tumors, spindle cell tumors, targetable tyrosine kinase/RAS::MAPK pathway-ovoid (epithelioid to spindled)tumors, and giant-cell-rich tumors of bone and soft tissue. Round cell tumors of bone and soft tissue include prototypical Ewing sarcoma, newer sarcomas with BCOR genetic alteration and CIC-rearranged, as well as updates onFUS/EWSR1::NFATc2, an EWSR1 non-ETS tumor that is solid with additional amplified hybridization signal pattern of EWSR1.This FUS/EWSR1::NFATc2 fusion hasnow been observed in seemingly benign to low-grade intraosseous vascular-rich and simple (unicameral) bone cyst tumors. Select spindle cell tumors of bone and soft tissue include rhabdomyosarcoma with FUS/EWSR1::TFCP2, an intraosseous high-grade spindle cell tumor without matrix. Targetable tyrosine-kinase or RAS::MAPK pathway-tumors of bone and soft tissue include NTRK, ALK, BRAF, RAF1, RET, FGFR1, ABL1, EGFR, PDGFB,and MET with variable ovoid myopericytic to spindled pleomorphic features and reproducible clinicopathologic and radiologic clues to their diagnosis. Giant-cell-rich tumors of bone, joint, and soft tissue are now respectivelycharacterized by H3F3A mutation, CSF1 rearrangement (targetable), and HMGA2::NCOR2 fusion. This article is an update for radiologists, oncologists, surgeons, and pathologists to recognize these novel ovoid, spindled, giant-cell-rich, and round cell tumors, for optimal diagnostic classification and multidisciplinary team patient care.

Spectacular and Prompt Response to Extracorporeal Photopheresis for Refractory Cutaneous Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report

Chronic graft-versus-host disease (cGVHD) is a serious complication after allogenic hematopoietic stem cell transplantation (allo-HSCT), negatively affecting the morbidity and mortality of recipients. Skin involvement is the most common cGVHD manifestation with a wide range of pleomorphic features, from scleroderma to ulcerations and microangiopathic changes. Despite the access to many immunosuppressive drugs, therapy for cGVHD is challenging. Systemic steroids are recommended as the first-line treatment; but, in steroid-resistant patients, extracorporeal photopheresis (ECP) remains one of the subsequent therapeutic options. Here, we present a case report of a 31-year patient suffering from advanced steroid-refractory skin and oral mucosa cGVHD who was spectacularly treated with ECP. It was the first time we observed such "overnight" resolution of the graft-versus-host disease syndrome. The present report proves the important role of ECP in the treatment of steroid-resistant cGVHD, especially when other immunosuppressive therapies have failed.

99. Histopathologic Correlation Somatic Variants in Non Small Cell Lung Cancer with High Tumor Mutation Burden

<h3>Introduction</h3> High tumor mutation burden (TMB), having at least 10 mutations/megabase (mut/Mb), is reported to be as high as 42% of non small cell lung adenocarcinoma (LADC). Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC) and is often associated with a poor prognosis. <h3>Methods</h3> We performed next-generation sequencing (NGS) with and explored histologic and molecular features in 33 consecutive TMB High LADC utilizing the Ion Oncomine Comprehensive Panel Plus (OCAPlus). <h3>Results</h3> LADC with high tumor mutation burdens (TMBs) were more likely to display necrosis, as well as papillary and aggressive micropapillary features. Interestingly, RBM10 truncations were enriched in aggressive TMB LACD, seen in 2/2 cases of pleomorphic carcinoma and 4/7 cases with papillary or micropapillary features. BRAF class 2 mutations (non V600E) were also more likely to be seen in these aggressive tumors, identified in 5/33 cases of TMB high LADC, while no class 1 BRAF V600E mutations were observed. <h3>Conclusions</h3> A subset of high TMB LADC is especially aggressive, with histology including necrosis, micropapillary, and pleomorphic features. A subset of these tumors, with an especially poor overall survival rate contain either class 2 BRAF variants or truncated RBM10 mutations in 7/10 cases identified with these aggressive histologic features.

Significance Of Tumor Giant Cells In Oral Squamous Cell Carcinoma: A Case Report

Background : Oral squamous cell carcinoma (OSCC) is the most common cancer of the oral cavity. OSCC presents with some typical histopathological characteristics like dysplastic epithelial cells with variable degrees of squamous differentiation. These histopathological features make it relatively easy to diagnose conventional squamous cell carcinoma. However, some cases show certain unique features that help in determining the prognosis of the disease. These features include epithelial-mesenchymal interaction, stromal hyalinization, clear cell change, stromal desmoplasia, perineural invasion, vascular invasion, tissue eosinophilia, giant cells and tertiary lymphoid follicle formation. The presence of giant cells in OSCC can be the result of foreign body reaction to keratin or due to formation of malignant tumor giant cells in poorly differentiated carcinomas. The giant cells showing pleomorphic features can be helpful in predicting the prognosis of the disease.

Abstract P1-02-08: Comparison of clinical features and outcomes for pleomorphic invasive lobular carcinoma vs. non-pleomorphic invasive lobular carcinoma

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common invasive breast cancer histology. Within ILC histology, there are multiple subtypes. The most common subtype is “classic” characterized by small single files of cells invading the stroma. Another subtype of clinical interest is “pleomorphic” which is characterized by larger cells with varied nuclear appearance. Rare and not well understood, pleomorphic ILC is traditionally viewed as an aggressive form of ILC. Studies have shown a relatively consistent association between pleomorphic ILC and certain high risk features such as advanced stage, HER2 positivity, and lymph node involvement. Survival outcome data comparing pleomorphic ILC to non-pleomorphic ILC has yielded varied results. Methods: A retrospective study of a large institutional database was conducted to characterize patients with ILC treated from 2004-2017. Patient and disease characteristics were recorded, including disease staging, biomarker profile, specific ILC histology, treatment details, and recurrence events. Findings were analyzed and overall survival (OS) and recurrence free survival (RFS) were compared between pleomorphic and non-pleomorphic ILC cohorts. Propensity score matching was also completed to account for confounding variables. Results: A total of 691 patients who had surgery were studied (mean age 61.6 ± 11.6 years old, 86.9% Caucasian, 98.3% with endocrine therapy), including 100 (14.4%) with pleomorphic ILC and 591 (85.5%) with non-pleomorphic ILC. Compared to non-pleomorphic ILC, pleomorphic ILC was less likely to be estrogen receptor (ER) positive (94% vs. 98%, p=0.004), more likely to be HER2 positive (12% vs. 7%, p=0.07), more likely to be grade 3 (33% vs. 2%, p&amp;lt;0.001), less likely to be diagnosed at a lower T stage (Stage I 38% vs. 58%, Stages II-III 61% vs. 41%, p&amp;lt;0.001), and less likely to be diagnosed with axillary lymph node involvement (node positivity 48.5% vs. 66%, p&amp;lt;0.001). Mastectomy rates were 65% in pleomorphic ILC and 52% in non-pleomorphic ILC (p=0.022). Patients with pleomorphic ILC were more likely to receive chemotherapy (66% vs. 36%, p&amp;lt;0.001). Pleomorphic ILC patients were also more likely to receive HER2-directed therapy (12% vs. 5.8%, p=0.02). Median follow-up was 6 years. There was no significant difference in OS and RFS between cohorts before matching for age, BMI, stage, surgery type, and chemotherapy. Although not statistically significant, pleomorphic ILC appears to have better RFS and OS between propensity score matched 91 pairs (10-year RFS: 79% vs. 71.5%, p=0.27 and 10-year OS: 86% vs. 76%, p=0.13). Exploratory analysis also suggests that multifocal pleomorphic ILC is associated with worse RFS and OS compared to unifocal pleomorphic ILC. Conclusions: Pleomorphic ILC was found to have more advanced disease at presentation in the breast but not in lymph nodes. At our institution, it was treated with more chemotherapy compared to non-pleomorphic ILC, likely related to higher grade, lower ER-positivity, and higher HER2-positivity. After propensity score matching, pleomorphic ILC appears to have better RFS and OS compared to non-pleomorphic ILC. This was particularly noticeable three years after surgery and may reflect more aggressive management. These data reveal some unexpected trends that challenge the notion of pleomorphic ILC having worse outcomes compared with non-pleomorphic ILC. This highlights the need for additional studies to better understand multiple aspects of ILC and its subtypes. Citation Format: Matthew D. Wright, Marcus S. Dempster, Ayat ElSherif, Daniela Cocco, Stephanie A. Valente, Hong Li, Megan L. Kruse. Comparison of clinical features and outcomes for pleomorphic invasive lobular carcinoma vs. non-pleomorphic invasive lobular carcinoma [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-08.

Inducing substances for chondrogenic differentiation of dental pulp stem cells in the conditioned medium of a novel chordoma cell line.

We successfully established a chordoma cell line, designated TSK-CHO1, derived from the clival chordoma. Currently, there is only one skull base chordoma cell line, UM-chor1, freely available to researchers. The established TSK-CHO1 cells were neoplastic, exhibited pleomorphic features, and secreted brachyury, as revealed by immunocytochemical staining or ELISA of conditioned medium (CM). Cells also secreted SOX9, which enhanced brachyury production. The CM of TSK-CHO1 cells promoted the production of hyaluronic acid and type II collagen during differentiation of human dental pulp stem cells (DPSCs) into fibrocartilage cells. Culture of DPSC pellets in a growth medium supplemented with 10% CM of TSK-CHO1 cells for 2weeks resulted in the induction of fibrocartilage tissue under normoxic conditions. Brachyury produced by TSK-CHO1 cells promoted the production of collagen type II, peculiar to cartilage, in a dose-dependent manner. The newly established skull base chordoma cell line, TSK-CHO1, is expected to be used for elucidating the pathogenesis of skull base chordoma and for investigating the mechanism underlying the production of fibrocartilage.

FDG avid cerebellar atypical meningioma masquerading as solitary brain metastases in a recently diagnosed breast malignancy: a toss between MR and CT

BackgroundSUV Max is a glycolytic index obtained from PET imaging, relates to tumour cell proliferation. FDG uptake (i.e. SUV max) is found to be high in aggressive tumours and is used to identify malignant from benign pathologies. Meningiomas are intracranial tumours which display varying grades of FDG avidity based on its biological aggressiveness. Benign grade I meningiomas are FDG non-avid, while the rest of the typical and atypical meningiomas show varying degrees of FDG avidity. Uptake of FDG can be high in certain infectious and inflammatory brain etiologies and pose a diagnostic challenge in differentiating benign brain lesions from neoplasms. MRI is the preferred modality for accurately identifying meningiomas, providing superior contrast differentiation and its ability to differentiate extra-axial from intra-axial brain lesions. CT is said to be superior in specific types of meningioma where there is calcification and adjacent changes in calvarium. Although typical meningiomas have characteristic MRI features, care must be taken to avoid misleading diagnosis between brain tumours and atypical meningiomas.Case presentationWe are presenting a recently diagnosed case of invasive breast carcinoma (Ca) referred for staging by PET/MR imaging. Based on atypical DWI and ADC map findings, MRI falsely reported an atypical meningioma as a brain metastasis. Abnormal intense FDG uptake was noted in a well-defined homogeneously enhancing mass lesion in posterior fossa in left paramedian aspect and broad base to left transverse sinus protruding into left cerebellar hemisphere. Atypical meningioma Grade III, i.e. papillary meningioma was later histologically proven.ConclusionsWe wish to highlight the inconsistency of DWI and ADC map MR findings in papillary meningioma masquerading as solitary brain metastases in a Ca breast patient on 18F FDG PET/MR imaging. From an imaging standpoint, it is important to recognize the variable and pleomorphic features exhibited by meningiomas in MR based on atypical location, histological subtypes, and biologic behaviours. Further FDG PET was incremental in displaying a high SUV max indicating biologic aggressiveness of lesion and correlating with the CT diagnosis of papillary meningioma.

Morphologic subtypes of lobular carcinoma in situ diagnosed on core needle biopsy: clinicopathologic features and findings at follow-up excision.

Lobular carcinoma in situ (LCIS) is currently classified as classic (CLCIS), florid (FLCIS), and pleomorphic (PLCIS). Given the rarity of FLCIS and PLCIS, information on their clinico-pathologic features and biologic potential remains limited. We evaluated the upgrade rates at excision of FLCIS and PLCIS diagnosed on inhouse core needle biopsy (CNB) and their clinical presentation and follow-up. Over a period of 11 and a half years, there were a total of 36 inhouse CNBs with pure PLCIS (n = 8), FLCIS (n = 24), or LCIS with pleomorphic features (LCIS-PF) (n = 4). The upgrade rates to invasive carcinoma or ductal carcinoma in situ (DCIS) were 25% for PLCIS (2/8), 17% for FLCIS (4/24), and 0% for LCIS-PF (0/4). The overall upgrade rate of PLCIS and FLCIS combined was 19% (6/32). All but one case (not upgraded at excision) were radiologic-pathologic concordant. Apocrine features, previously reported only in PLCIS, were also noted in FLCIS. HER2 overexpression was seen in 13% of cases. This study highlights the more aggressive biologic features of PLCIS and FLCIS compared to CLCIS and supports surgical management for these lesions.

ES17.04 Updates in Mesothelioma

The histologic subtype of malignant mesothelioma of the pleura has an impact on prognosis and treatment decisions and therefore has to be documented in diagnostic pathology reports. Epithelioid morphology is associated with a better prognosis when compared to sarcomatoid and biphasic subtypes. Surgical treatment may also have a prognostic impact in epithelioid subtype, while the same benefit is not seen in biphasic and sarcomatoid mesotheliomas. The 2020/21 WHO classification divides mesothelial proliferations into benign and preinvasive (adenomatoid tumor, well-differentiated papillary mesothelial tumor, mesothelioma in situ) and mesothelioma (localized pleural mesothelioma, diffuse pleural mesothelioma). The main change is the introduction of mesothelioma in situ (MIS) in the classification. Until recently the consensus was that MIS cannot be separated from reactive surface mesothelial proliferations on morphology alone. However, the concept of MIS was recently reintroduced for surface, usually flat or simple papillary, mesothelial proliferations with loss of BAP1 nuclear staining by immunohistochemistry or CDKN2A homozygous deletion, in the absence of radiologic or clinical gross evidence of the disease.1-3 Clinically, MIS is suspected in patients with unexplained recurrent effusions in the setting of heavy asbestos exposure, after irradiation and in patients with familial predisposition. The diagnosis requires sufficient tissue usually large biopsy samples. Small biopsy and cytology samples are not appropriate. Patients with MIS have a high incidence of eventual development of invasive mesothelioma. The updated classification of epithelioid mesotheliomas includes architectural patterns (tubular, papillary, tubulopapillary, trabecular, solid, adenomatoid and microcystic), stromal (myxoid) and cytologic (pleomorphic ,rhabdoid, deciduoid, small cell, clear cell, signet ring) features. Their identification is important for correct diagnosis, and some have prognostic values. Two cytologic features, transitional and pleomorphic, were previously classified as epithelioid patterns. They have shown a similar survival to biphasic and sarcomatoid mesothelioma and should be reclassified.5-8 Transitional features have appearance between epithelioid and sarcomatoid morphology, and have genomic characteristics similar to sarcomatoid subtype, and therefore were reclassified as cytologic feature of sarcomatoid mesothelioma. 6. Epithelioid mesotheliomas with transitional features should be reclassified as biphasic mesothelioma. Transitional features within biphasic mesothelioma carry negative prognostic significance, with a median survival of 6 months for cases with transitional features compared to 12 months for those without transitional features .6 Pleomorphic features, as described in epithelioid mesothelioma, can also be seen in sarcomatoid mesotheliomas. In contrast to transitional features, emerging genomic data suggest that a mesothelioma with pleomorphic features genomically can cluster with either sarcomatoid or epithelioid subtypes. Therefore, mesotheliomas with pleomorphic features should be classified based on the most predominant morphology as either sarcomatoid or epithelioid. A two-tier grading system for epithelioid mesothelioma allows the identification of more aggressive mesotheliomas and can be applied to biopsy and resection specimens 9, 10 It is primarily based on the combination of nuclear features, mitotic rate and the presence or absence of necrosis (Figure 1). Molecular testing in mesothelioma compared to other cancers is very limited. Recently, there have been several sequencing efforts to provide insights into the genomic characteristics and improved prognostic classification of mesothelioma. 10

Outcomes of Acalabrutinib Failures in Relapsed Mantle Cell Lymphoma

Outcomes of Acalabrutinib Failures in Relapsed Mantle Cell Lymphoma

Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade.

Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E-MPM and (ii) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. 614 consecutive cases of E-MPM from our institution over a period of 15years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2months) followed by solid (10.5months), microcystic (15.3months), discohesive (16.1months), trabecular (17.6months) and tubulo-papillary (18.6months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

BackgroundMET amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in MET amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or MET amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup.MethodsA total of 373 unselected patients with NSCLC were consecutively tested for MET gene copy number (GCN) by FISH. Mean GCN, MET/CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data.ResultsBased on the variability of obtained data a top-level category of MET amplification was newly defined (>90th percentile of average GCN; ≥10 MET gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected (KRAS mutation or MET exon 14 skipping mutation). In this top-level group, there were no EGFR mutations or ALK or ROS1 alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 vs. 23.6 months). Worse prognosis did not depend on initial stage or treatment.ConclusionsThe newly defined top-level category of MET amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of MET gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.

Abstract P5-07-04: Patient-administered breast cancer risk assessment: BIRADS and pathology outcomes

Abstract Materials and Methods: A total of 32,024 women were offered the CRA survey at the time of their screening mammograms between January 2017 and June 2018. 8,438 women who declined the CRA and 7 symptomatic women were excluded. Of the remaining 23,579 women, 16,548 had one screening, and 7,031 had two screenings in this time period, leading to 30,610 total screening mammograms in women who filled out the CRA. Lifetime risk of breast cancer was assessed using the BRCAPRO, and Tyrer-Cuzick v7 (TC7) models, while the risk of BRCA mutation was estimated using the BRCAMUTATION model. Patients were identified as HR if either their BRCAPRO or TC7 lifetime risk was greater than 20%, or if their BRCAMUTATION risk was higher than 5%. Otherwise, patients were identified as LR. Pathologies were broken down into four groups: “Invasive Cancer”, “In Situ Cancer” (excluding lobular carcinoma in situ without pleomorphic features), “Benign Excision” (which often are surgically excised, including atypia and complex sclerosing lesion), and “Benign”. The Call Back Rate (percent of BIRADS 0 per screening mammogram, CBR), Cancer Detection Rate (number of “Invasive” plus “In Situ” cancers per 1,000 screening mammograms, CDR), and percent (as a fraction of screening mammograms) of each of the four pathology groups were calculated for HR and LR patients. Results: 13.6% (4,150) of screens were HR, and 86.4% (26,460) were LR. CBR was 11.1% (460) and 8.1% (2,133) for HR and LR, respectively (p&amp;lt;0.0001). On subsequent diagnostic imaging, 2.4% (101) and 1.7% (442) received a BIRADS 4 or 5 (HR &amp; LR respectively, p&amp;lt;0.05). Of these, only 4 HR and 18 LR did not undergo biopsy, in part due to comorbidities. The CDR was 7.7 and 4.6 (HR &amp; LR respectively, p&amp;lt;0.05). The number of “Invasive Cancer”, “In Situ Cancer”, “Benign Excision”, and “Benign” pathologies were 26 (0.63%), 6 (0.14%), 9 (0.22%), and 56 (1.35%) for HR and 91 (0.34%), 32 (0.12%), 70 (0.26%) and 231 (0.87%) for LR with p-values of p&amp;lt;0.05, p=0.73, p=0.63, and p&amp;lt;0.05, respectively. Conclusion: The cancer detection rate was greater in high risk vs. low risk patients (7.7 vs. 4.6, HR vs. LR, p&amp;lt;0.05). High risk patients had a higher percent of “Invasive Cancer” compared to low risk patients (0.63 vs. 0.34, HR vs. LR, p&amp;lt;0.05). These results indicate that this self-administered breast cancer risk stratification is clinically relevant.

Pathology and genetics of anaplastic large cell lymphoma.

Anaplastic large cell lymphomas are a rare subtype of peripheral/mature T-cell lymphomas which are clinically, pathologically and genetically heterogeneous. Both ALK-positive (ALK+) and ALK-negative (ALK-) ALCL are composed of large lymphoid cells with abundant cytoplasm and pleomorphic features with horseshoe-shaped and reniform nuclei. ALK+ ALCL were considered as a definite entity in the 2008 World Health Organization classification of hematopoietic and lymphoid tissues. ALK-ALCL was included as a provisional entity in the WHO 2008 edition and in the most recent 2017 edition, it is now considered a distinct entity that includes cytogenetic subsets that appear to have prognostic implications (e.g. 6p25 rearrangements at IRF4/DUSP22 locus). ALK+ ALCLs are distinct in epidemiology and pathogenetic origin and should be distinguished from ALK-ALCL, cutaneous ALCL and breast implant associated ALCL which have distinct clinical course and pathogenetic features. Breast implant-associated ALCL is now recognized as a new provisional entity distinct from other ALK-ALCL; notably that it is a noninvasive disease associated with excellent outcome. In this article, we will provide an overview of the salient themes relevant to the pathology and genetic mechanisms in ALCL.

High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features.

Background: Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished. Methods: To investigate the molecular alterations of invasive lobular carcinoma with pleomorphic features, a total of 39 tumour samples (in situ and invasive lesions and lymph node metastases) from 27 patients with nuclear grade 3 invasive lobular carcinomas were subjected to morphological, immunohistochemical and massive parallel sequencing analyses. Results: Our observations indicated that invasive lobular carcinomas with pleomorphic features were morphologically and molecularly heterogeneous. All cases showed absence or aberrant expression of E-cadherin and abnormal expression of β-catenin and p120. CDH1 (89%), PIK3CA (33%) and ERRB2 (26%) were the most common mutated genes. ERBB2 mutations preferentially affected the tyrosine-kinase activity domain, being the most frequent the targetable mutation p.L755S (57%). We also observed higher frequency of mutations in ARID1B, KMT2C, MAP3K1, TP53 and ARID1A in PLC than previously reported in classic ILC. Alterations related to progression from in situ to invasive carcinoma and/or to lymph node metastases included TP53 mutation, amplification of PIK3CA and CCND1 and loss of ARID1A expression. Conclusions: The high frequency of ERBB2 mutations observed suggests that ERBB2 mutation testing should be considered in all invasive lobular carcinomas with nuclear grade 3.