Case Report: ASXL1, RUNX1, and IDH1 mutation in tyrosine kinase-independent resistant chronic myeloid leukemia progressing to chronic myelomonocytic leukemia-like accelerated phase.

Although the majority of patients with chronic myeloid leukemia (CML) enjoy an excellent prognosis tyrosine kinase inhibitor (TKI) therapy, resistance remains a significant clinical problem. Resistance can arise from mutations in the kinase domain of ABL preventing drug binding, or due to ill-defined kinase-independent mechanisms. In this case report, we describe the case of a 27-year-old woman with a long-standing history of chronic phase (CP) CML who developed kinase-independent resistance with mutations in ASXL1 and RUNX1. As a consequence of uncontrolled disease, she progressed to a chronic myelomonocytic leukemia-like (CMML) accelerated phase (AP) disease with the acquisition of a mutation in IDH1. This disease progression was associated with the development of an inflammatory serositis, a phenomenon that has been described in CMML but not in AP-CML. This case presents key features of kinase-independent resistance with insight into potential mechanisms, highlights management challenges, and describes a novel systemic inflammatory response that occurred in this patient upon disease progression.

SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression.

Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular and tumor biology of GBM. CRISPR/Cas9 mediated knockout (KO) of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2 and CD44. Loss of SLFN11 stimulated expression of NF-κB target genes, consistent with a negative regulatory role for SLFN11 on the NF-κB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-κB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.

Inflammatory leiomyosarcoma/rhabdomyoblastic tumor: A report of two cases with novel genetic findings.

Inflammatory leiomyosarcoma (ILMS) is a malignant neoplasm showing smooth muscle differentiation, a prominent inflammatory infiltrate, and near-haploidization. These tumors have significant pathologic and genetic overlap with the recently described "inflammatory rhabdomyoblastic tumor (IRT)," suggesting that ILMS and IRT may belong to one entity. Herein, we describe two cases of ILMS/IRT with attention to new cytogenetic and sequencing findings. The tumors were composed of sheets and fascicles of variably pleomorphic tumor cells showing spindled and epithelioid to rhabdoid morphology and a prominent histiocyte-rich inflammatory infiltrate typical of ILMS/IRT. In case 1, chromosomal microarray analysis showed a near-haploid pattern with loss of heterozygosity resulting from loss of one copy of all autosomes except for chromosomes 5, 20, 21, and 22. Case 2 showed areas with high-grade rhabdomyosarcomatous transformation. In this case, the low-grade tumor component revealed a hyper-diploid pattern with loss of heterozygosity for most of autosomes but with a normal diploid copy number state except for chromosomes 5, 20, and 22, which showed a relative gain. The high-grade tumor component showed a similar pattern of copy-neutral loss of heterozygosity with additional abnormalities, including mosaic segmental gains at 1p, 5p, 8q, 9p, 20q, and segmental loss at 8p. Next-generation sequencing identified sequence variants in NF1, TP53, SMARCA4, KRAS, and MSH6. MSH6 variant was confirmed as germline, consistent with the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in one of our study patients and suggestive that ILMS/IRT might be part of the HNPCC cancer spectrum.

Diagnosis of giant cell-rich bone tumors on core needle biopsy: A practical approach.

BACKGROUND: The differential diagnosis of giant cell-rich bone tumors comprises a broad spectrum of lesions with prominent reactive osteoclast-like and/or neoplastic giant cells, with substantial differences in biologic behavior and clinical management. Evaluation of giant cell-rich bone tumors on small biopsies can be challenging especially in specimens with limited representative material. An accurate diagnosis requires a high level of skill on the part of both radiologist and pathologist as correlation with clinical and radiologic characteristics is critical. The objective of the study was to assess the utility of touch preparations (TP), immunohistochemistry (IHC) for mutation-specific markers H3G34W and H3K36M, and fluorescence in situ hybridization (FISH) for USP6 rearrangements and MDM2 amplification in the diagnostic workup of core needle biopsy specimens. METHODS: A total of 27 core needle biopsies with TPs from patients with primary giant cell-rich bone tumors (16 giant cell tumors of bone (GCTBs) (including 3 with lung metastasis), 3 chondroblastomas (CBs), 4 primary aneurysmal bone cysts (ABCs), 2 non-ossifying fibromas (NOFs), 1 low grade osteosarcoma (OS), and 1 conventional OS with tumor giant cells were analyzed with IHC for H3G34W and H3K36M and in select cases FISH for USP6 rearrangements and MDM2 amplification. RESULTS: In all cases the core biopsies were sufficient for histologic examination and diagnostic workup. 16 of 16 GCTBs were positive for H3G34W and negative for H3K36M, and 3 of 3 CBs were positive for H3K36M and negative for H3G34W. All other cases were negative for H3G34W and H3K36M. 4 of 4 primary ABCs showed rearrangement of USP6 by FISH and the low grade OS showed amplification of MDM2 by FISH. CONCLUSIONS: On-site adequacy assessment of TPs proved to be an accurate, simple, and fast method for obtaining sufficient material for complete diagnostic workup. The application of IHC for H3G34W and H3K36M and FISH for detection of rearrangements of USP6 and amplification of MDM2 can improve the diagnostic accuracy in core needle biopsy specimens.

Solitary fibrous tumor of thoracic cavity, extra-thoracic sites and central nervous system: Clinicopathologic features and association with local recurrence and metastasis.

Published risk stratification models of solitary fibrous tumor (SFT) have been associated with distant metastases outside the central nervous system (CNS), but have not been studied for tumors occurring in the CNS. In a retrospective review, we identified 72 cases of solitary fibrous tumor or hemangiopericytoma (HPC) diagnosed between January 2011 and December 2020 at our institution. The tumors involved the central nervous system (N = 17), thoracic cavity (N = 28), and extrathoracic sites (N = 27). The risk of local recurrence, distant metastasis, or death at 5 years was 57% (95% CI 23%, 76%) in the CNS, 24% (95% CI 2%, 41%) in the thoracic cavity, and 13% (95% CI 0%, 25%) in extrathoracic sites. By contrast, the risk of distant metastasis or death at 5 years was 13% (95% CI 0%, 29%) in CNS primaries, 5% (95% CI 0%, 14%) in thoracic primaries, and 14% (95% CI 0%, 27%) in extrathoracic primaries. Using the published 3- and 4-variable risk stratification models by Demicco et al., we retrospectively assessed our cases for risk of local recurrence, distant metastasis, and death. For tumors outside the CNS, we show that three- and four-variable risk stratification models were associated with recurrence-free survival in addition to the previously known association with distant metastasis (all P < 0.05). In contrast, inside the CNS, we show that neither risk model is a significantly associated with clinical behavior, and that WHO grade is likely the best available prognostic tool, though none of the differences were significant. The lack of significant differences can be likely explained by the younger median age (47 years vs 61 years) and smaller median tumor size (3.5 cm vs 5.6 cm), downgrading the risk stratification scores in CNS compared to non-CNS primaries. In conclusion, existing risk stratification models of SFT are not associated with clinical behavior for tumors arising inside the CNS, but are associated with local recurrence in addition to distant metastasis outside the CNS.

Synovial sarcoma with overwhelming glandular (adenocarcinoma-like) component: A case report and review of the literature.

Synovial sarcoma is an uncommon tumor of soft tissue, characterized by a specific SS18-SSX1/2/4 fusion gene. It is generally a lesion composed of monomorphic spindle cells, and can sometimes show variable epithelial differentiation. Here, we present the case of a young woman with a synovial sarcoma of the abdominal wall that showed an overwhelming (>90 %) epithelial glandular component mimicking adenocarcinoma, and only rare spindled areas. The diagnosis was confirmed by detection of targeted fusion transcripts associated with synovial sarcoma. We review the literature pertaining to synovial sarcoma, and we show that this case is only the sixth molecularly proven epithelial predominant synovial sarcoma in the literature. This report emphasizes the importance of molecular approaches in modern soft tissue pathology. Recognition of synovial sarcoma with predominant glandular component is imperative in order to avoid misdiagnosis of the tumor as metastatic adenocarcinoma, another type of sarcoma with epithelial differentiation, or a carcinoma with a sarcomatous component (sarcomatoid carcinoma), all of which have markedly different clinical management.

Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, CDKN2A/B loss, and TP53 mutations: A multi-institutional study.

Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.