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The mechanism(s) of immune checkpoint inhibitor (ICI)-induced myasthenia gravis (MG), an immune-related adverse event (irAE) that is fatal and limits subsequent ICI use, remain unexplored. Here, through comparative genomic analysis, we identified a pathogenic p.S467C germline variant inSLC22A5in a thymoma case with ICI-induced MG, which was found to be associated with fatty acid oxidation through its regulation on L-carnitine levels. Remarkably, ICI rechallenge with L-carnitine pretreatment led to durable response without MG-related symptoms. Thus, we provide the first clinical evidence of genetic test-directed irAE management, which integrates individualized ICI treatment into the evolving paradigm of cancer management.

Neuronal intranuclear inclusion disease (NIID) is a rare, progressive neurodegenerative disorder. This study aimed to investigate clinical, imaging, genetic, and dermatopathological characteristics of a family with adult-onset NIID. The proband was a 62-year-old woman with 3 brothers and 2 sisters. Of these, 4 had symptoms of paroxysmal visual field defect, extrapyramidal symptoms, dysautonomia, emotional changes, and cognitive dysfunction. Genetic examination revealed no abnormality related to cerebrovascular diseases. More than 200 CGG repeats of FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS) whereas repeats of the proband were found 29 times, which excluded FXTAS. Quantitative reverse transcription polymerase chain reaction (PCR) and GC-rich-PCR identified an expanded GGC repeat (with ∼100 repeats) in the 5' region of NOTCH2NLC in the patient and her 2 younger brothers. Pathological examination found eosinophilic intranuclear inclusions inside adipocytes, fibrocytes, and sweat gland cells. Immunohistochemistry and immunofluorescence staining revealed positive staining for ubiquitin and p62. The detailed pathological and genetic features of this NIID family provide a valuable contribution to the existing knowledge base of this rare disorder.

A 34-year-old Chinese woman found a lump in her left leg for more than 3 weeks without any discomfort. Grossly, the tumor was relatively well delineated with focal infiltration. Histopathologic evaluation showed a compact fascicular spindle cell proliferation with variable myxoid and collagenous stroma and scattered inflammatory infiltrate. Immunohistochemically, the tumor cells showed positive expression of ALKD5F3 and SMA and negative expression of CD34, desmin, and cytokeretin. Fluorescence in situ hybridization analysis of the ALK locus showed break-apart signals in 20% of tumor cells, and DNA sequencing discovered a novel CLIP2-ALK fusion gene. The lesion was diagnosed as an inflammatory myofibroblastic tumor (IMT). To the best of our knowledge, this is the first case with CLIP2-ALK gene fusion in the somatic soft tissue IMTs.

BACKGROUND Multifocal Papillary thyroid carcinoma (PTC) is a very common condition. In certain cases, it is possible to find tens to hundreds of foci with a diffuse intrathyroidal spread in the whole thyroid with no stromal fibrosis. Herein, PTC with such features was nominated as diffuse disseminate variant (DDV) PTC. The aim of the present study was to investigate the histopathological characteristics, molecular features, and biological behavior of DDV and compare the characteristics of DDV to diffuse sclerosing variant (DSV) PTC. MATERIALS AND METHODS Thirty-four DDV and 23 DSV cases were identified from consecutive surgical specimens diagnosed with PTC between 2014 and 2019. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of DDV and DSV. RESULTS DDV was commonly diagnosed in young patients and exhibited high rates of LNM (100 %), ETE (61.8 %), and LVI (44.1 %); however, they did not differ from DSV (P > 0.05). Male patients were more frequently diagnosed with DDV than with DSV (P

Recently, a novel group of spindle cell tumors defined by S100 and CD34 co-expression harboring recurrent fusions involving RET, RAF1, BRAF, and NTRK1/2 gene has been identified. Morphologically, they are characterized by monomorphic neoplasm cells, "patternless" growth pattern, stromal, and perivascular hyalinization, lacked necrosis. We reported a 52-year-old Chinese female patient with a S100 and CD34 co-expression sarcoma presenting in the right proximal forearm. The forearm mass initially emerged 19 months ago when it was misdiagnosed as a solitary fibrous tumor and was surgically removed without further treatment. Microscopically, the primary and the recurred tumors share the same features, resembling the morphology of the recently characterized group. Nevertheless, some distinct features, such as predominantly epithelioid tumor cells and focally staghorn vessels, were also present in our case. Genomic profiling with clinical next-generation sequencing was performed and revealed CDC42SE2-BRAF gene fusion, MET amplification, and CDKN2A/B deletion. Both FISH and nested RT-PCR were performed to confirm the gene fusion. The patient was treated with crizotinib for two cycles but showed no obvious benefit. The presented case adds to the spectrum of the novel, characterized solid tumors, and provides suggestions for emerging therapeutic strategies for precision medicine involving targeted kinase inhibitors.

AimCD30+ diffuse large B-cell lymphoma (DLBCL) has emerged as a new immunophenotypic variant of de novo DLBCLs. However, the prevalence of CD30 positivity is variable according to different studies, and the prognostic significance of CD30 is also controversial. This study aimed to investigate the positive expression rate and prognostic impact of CD30 in de novo DLBCLs and try to find the correlated influences.MethodsA total of 241 patients with de novo DLBCL in east China from 2008 to 2015 were included to investigate the prevalence, clinicopathological features and outcomes of CD30+ de novo DLBCLs. Immunohistochemical evaluation for CD10, CD30, BCL2, BCL6, MUM1/IRF4, MYC and Ki67, and fluorescence in situ hybridisation for MYC and BCL2 gene alterations were performed.ResultsUsing a >0% threshold, CD30 expression was detected in approximately 10% patient with de novo DLBCL. These predominately presented with centroblastic or anaplastic morphological patterns, less frequently showing immunoblastic morphology or ‘starry sky’ pattern, mutually exclusive with MYC gene rearrangement, and negatively associated with BCL2 protein expression. CD30 expression was associated with a favourable prognosis of patients’ outcomes. However, the multivariate analysis revealed that it was not an independent prognostic factor in de novo DLBCLs. The impact of CD30 might be influenced by the international prognostic index and the expression of MYC and BCL2 proteins.ConclusionCD30+ DLBCL may be a subset of de novo DLBCLs with characteristic clinicopathological features, but the prognostic role of CD30 is limited.

Angiomyolipoma is the most common member of perivascular epithelioid cell tumors that characteristically express myogenic and melanocytic markers. E-cadherin is a calcium-dependent cell-cell adhesion molecule that is repressed in epithelial to mesenchymal transition occurring in carcinomas. E-cadherin has not, thus far, been systematically studied in angiomyolipoma. We analyzed a series of 42 angiomyolipomas with E-cadherin and discussed its clinicopathologic significance. Forty-two cases of angiomyolipomas (35 renal, 5 hepatic, and 2 retroperitoneal) were examined histologically. E-cadherin was investigated immunohistochemically and compared with other significant markers found in angiomyolipoma in all cases. The percentages of tumors staining positively were E-cadherin (98%), smooth muscle actin (98%), actin (93%), HMB-45 (93%), Melan-A (90%), S-100 (38%), and CD117 (60%). The intensity of E-cadherin staining was moderate to strong in 30 cases (71%). E-cadherin stained both the cytoplasm and cell membrane of tumor cells, but membrane staining was stronger in the epithelioid tumor cells than in the spindle-shaped tumor cells. E-cadherin may serve as an additional diagnostic marker for angiomyolipoma. Angiomyolipoma should be included in the differential diagnosis of E-cadherin-positive tumors. Stronger membrane immunoreactivity for E-cadherin in epithelioid tumor cells is possibly related to constitution of their epithelioid architecture, but the pathogenetic significance of E-cadherin in angiomyolipoma remains to be further studied.

Genetic alterations on 8p22 have been implicated in multiple cancers, including lung cancer. In this region, genetic variants of the class A scavenger receptor (SR-A) gene have been associated with prostate cancer risk and have been highlighted as a potential susceptibility gene of cancer.To determine whether common polymorphisms in the SR-A gene are associated with human lung cancer risk and to clarify the role of SR-A in lung carcinogenesis.The relationship of three potentially functional polymorphisms (T-365C, T+25C, and Ala275Pro) in the SR-A gene with lung cancer risk was evaluated in 1287 lung cancer case subjects and 1261 control subjects from the Chinese population. At the same time, SR-A null mice were used to investigate its role in lung cancer development.The T+25C polymorphism was independently associated with lung cancer risk and significantly correlated with decreased expression of SR-A. The decreased SR-A expression was also found in tumor tissues as compared with normal tissues. Depletion of SR-A boosted the growth and angiogenesis of implanted Lewis lung carcinoma in mice. The cancer-suppressing capability of SR-A was attributable to its expression in bone marrow-derived cells as evidenced by bone marrow transplantation. Further analysis revealed augmented expression of proangiogenic factors including matrix metalloproteinase-9 (MMP9) in SR-A-deficient mice, indicative of a more procarcinogenic microenvironment. Last, zoledronate, an MMP9 inhibitor, abrogated acceleration of tumor growth conferred by SR-A loss-of-function.Evidence from the population study and mouse model strongly indicates that SR-A may function as a tumor modulator to inhibit lung cancer growth through affecting the tumor microenvironment.

To study the clinicopathologic features, diagnosis and differential diagnosis of succinate dehydrogenase (SDH) deficient gastrointestinal stromal tumors (GISTs) as a unique tumor subtype.SDHB and SDHA immunohistochemistry was performed in 120 gastric GISTs, in addition to CD117, DOG-1, CD34, smooth muscle actin (SMA), desmin, S-100 protein, cytokeratin (CK) and Ki-67. Subset of the cases was further evaluated for the presence of mutations in CKIT exons 9, 11, 13 and 17 mutations and platelet derived growth factor receptor alpha(PDGFRA) exons 12 and 18.Eight of 120 (6.6%) GIST cases were found SDH-deficient including 3 male and 5 female patients (median age of 36.2 years; ranging 16 to 65 years of age). The tumors involved antrum (6 cases), lesser curvature (1 case) and fundus (1 case). Macroscopically, the dominant tumor masses varied from 3 to 10 cm in diameter with a multinodular or plexiform pattern involving the gastric wall. Microscopically,tumor cells had predominantly epithelioid morphology, with occasional mixed spindle cell nodules. Lymphovascular invasion was identified in 5 cases. Immunohistochemistry for SDHB was negative in all 8 cases, and SDHA was negative in 5 cases. All 8 SDHB negative cases also expressed CD117, DOG-1 and CD34, but were negative for SMA, desmin, S-100 and CK. All 8 cases were found to have wild-type CKIT and PDGFRA genes. Available clinical follow-up were obtained in 7 cases, ranging from 2 to 60 months (median follow-up 23.3 months), and all patient were alive. Three cases were found to have liver metastases at their first diagnosis, and one developed omental and mesenteric metastases in 17 months.SDH-deficient GIST is a distinct subtype of GIST, with a predilection to occur in young and female patients. Characteristic pathological findings include multinodular gastric wall involvement, epithelioid cell morphology, frequently lymphovascular invasion with occasional lymph node and liver metastases, but an overall indolent clinical behavior. Immunohistochemistry for SDHB is required for the diagnosis.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined as patients older than 50 years alone. However, recent studies showed young patients with sound immune status could also be affected. In this study, we investigated the clinical features and outcomes of patients with EBV positive DLBCL in the different age groups using different EBER cut-off values. The prevalence of EBV positive DLBCL was 14.0% (35/250) and 10.4% (26/250) for EBER cut-off of 20% and 50%, respectively. With both EBER cut-off values, patients with EBV DLBCL shared many unfavorable prognostic characteristics, regardless of age. EBV positive patients, both in the elderly and young groups, showed significantly worse overall survival and progression-free survival than negative cases. Moreover, no significant differences of outcomes were identified between different age groups with EBV positive DLBCL. In conclusion, EBV positive DLBCL patients, regardless of age, shared similar poor prognostic features and showed worse outcome than negative cases. We suggest that the age criterion of EBV positive DLBCL of the elderly and possibly the name itself, be modified in future.

To study the clinicopathologic characteristics and diagnostic criteria of interdigitating dendritic cell sarcoma/tumor (IDCS/T).The clinical features, histologic findings and results of immunohistochemical study in six cases of IDCS/T were analyzed, with review of literature.The age of patients ranged from 20 to 68 years. The sites of involvement included lymph node, tonsil and soft tissue. Histologically, the tumor cells were arranged in sheets, fascicles or whorls and intimately admixed with abundant lymphocytes and plasma cells. They were oval to spindly in shape and contained pale eosinophilic cytoplasm, oval nuclei and distinct nucleoli.Immunohistochemical study showed that the tumor cells were positive for S-100 protein and CD68.IDCS/T is a rare malignant tumor with poor prognosis. It carries distinctive histologic pattern and immunophenotype. The entity needs to be distinguished from follicular dendritic cell sarcoma/tumor, anaplastic large cell lymphoma and other spindle cell sarcomas in occurring soft tissue.

Primitive myxoid mesenchymal tumor of infancy is a recently recognized soft tissue tumor with only a few cases reported. Here, we reported another two cases of the lesion, a 5-month-old boy presenting with a soft tissue mass in the neck region that recurred 2 months later and a 3-day-old girl with a congenital superficial dorsal lumbar mass that extended to the spinal canal 1 month later. They shared similar histological patterns, such as unusual diffuse myxoid background, delicate vascular network, small cystic spaces, low to moderate cellularity, and primitive mesenchymal tumor cells. Immunohistochemically, the tumor cells showed positive for vimentin, CD99, CD117 and nestin, negative for myoid, lipoblastic, histiocytic, and neural markers. In conclusion, primitive myxoid mesenchymal tumor of infancy is a distinctive entity with its own clinical pathological features. Expression of CD99, CD117 and nestin may be consistent with the primitive nature of the tumor and may serve as ancillary markers for differential diagnosis from the other infantile tumors.