Therapy-related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype.

Therapy-related myeloid neoplasms (t-MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t-MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t-MN at three institutions and compared the mutational profile and survival data between t-MNs with NK and t-MNs with abnormal karyotype (AK). A total of 204 patients with t-MN were identified including 158 with AK and 46 with NK. NK t-MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t-MNs as compared to NK cases (p = 0.0094). In our study, NK t-MNs showed a significantly better OS, a higher prevalence of MN-associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t-MNs merits a separate classification.

Adult-onset multifocal kaposiform hemangioendothelioma in the bone marrow, lung, liver, and brain: a case report.

Kaposiform hemangioendothelioma (KHE), a rare form of vascular neoplasm, is typically seen in children. In this paper, we report a unique case of KHE replacing bone marrow tissue mimicking myeloproliferative neoplasm with additional involvement in the lung, liver, and brain in a 60-year-old Caucasian woman. The patient was initially seen in the hematology department for the chief complaint of epigastric pain and anemia. Abdominal magnetic resonance imaging (MRI) revealed mild splenomegaly with iron deposition secondary to extramedullary hematopoiesis. Additional workup was inconclusive. Subsequent bone marrow and lung biopsies eventually revealed bone marrow with extensive grade 3 fibrosis and multiple foci of low-grade vasoformative neoplasm in the lung suggestive of KHE. Although rare, KHE can present as an aggressive disease with indolent behavior in adults and can be distinguished from other vascular malignancies based on histopathology and imaging findings.

Diagnostic Capability of Next-Generation Sequencing Fusion Analysis in Identifying a Rare CASE of TRAF1-ALK-Associated Anaplastic Large Cell Lymphoma.

Background: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a rare T-cell neoplasm, accounting for approximately 3% of adult non-Hodgkin lymphomas. Although NPM1 is the most common fusion partner with ALK, many others have been described, necessitating break-apart FISH studies for confirmation of the diagnosis. TNF receptor-associated factor 1 (TRAF1) is a rare ALK partner that is thought to confer a worse prognosis in patients. We describe the utility of next-generation sequencing (NGS) RNA analysis in detection of this uncommon ALK partner. Case Description: A 42-year-old male with cervical lymphadenopathy presented for excisional biopsy. Following a tissue diagnosis of ALCL, ALK+, RNA from the biopsy was extracted from Formalin-fixed paraffin-embedded (FFPE) tissue and prepared for Anchored Multiplex PCR using the Archer® FusionPlex® v2 assay, which employs unidirectional gene-specific primers using NGS to detect novel or unknown gene partners. Results: Histologic evaluation of the excised lymph node showed atypical cells, including "horseshoe/kidney"-shaped nuclei. Neoplastic cells were immunoreactive against CD30, ALK (diffuse, cytoplasmic), CD2, CD4, granzyme B, and TIA-1. A diagnosis of ALCL, ALK+ was made. The pattern of ALK immunostaining suggested a non-NPM1-associated ALK translocation pattern, prompting further investigation. NGS fusion analysis showed a translocation involving exon 7 of TRAF1 and exon 20 of ALK. Conclusion: ALK positivity suggests an overall favorable prognosis of ALCL as compared to ALK-negative cases. However, in the rare published cases of TRAF1-ALK, an aggressive clinical course has been observed, which may reflect the aggressive propensity of this particular fusion, as these cases appear to be refractory to standard chemotherapy and also to the first generation ALK inhibitors. This study highlights the advantage of using NGS in RNA-based fusion assays to detect rare translocations, which can be of some clinical importance in detecting rare but aggressive fusion partners of ALK. As these technologies become more available, there is potential to identify such changes and effectively stratify the prognosis of ALCL patients.

Primary epithelioid sarcoma of the kidney and adrenal gland: report of 2 cases with immunohistochemical and molecular cytogenetic studies.

Epithelioid sarcoma (ES) is a malignant mesenchymal neoplasm with some morphologic or immunophenotypic evidence of epithelial differentiation. The "classic" subtype occurs in younger patients, often in distal extremities as compared with the "proximal" type. Tumors of the proximal type primarily arising in solid organs are rare with only few case reports in the literature. We report 2 cases of primary ES in the kidney of a 27-year-old woman and the adrenal gland of a 73-year-old man. Clinical examination and imaging, including computed tomography and positron-emission tomography, did not reveal tumor elsewhere in both cases. Histologic features were those of ES, proximal type with epithelioid/rhabdoid phenotype. Immunohistochemical study in both cases showed strong, diffuse expression of epithelial markers, CD34, and CD31. Nuclear expression of SMARCB1 protein was lost, but fluorescence in situ hybridization analysis was negative for SMARCB1 deletion. We believe that these are the first reports of primary kidney and adrenal gland ES.

Melanotic PEComa of the Sinonasal Mucosa With NONO-TFE3 Fusion: An Elusive Mimic of Sinonasal Melanoma.

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal tumors with features of both smooth muscle and melanocytic differentiation, with or without true melanin pigment. The highly variable morphology of PEComas results in a broad differential diagnosis that is also dependent on anatomic site. A subset demonstrates rearrangements involving the TFE3 (Xp11) locus, which can be used in diagnostically difficult cases. Here we describe a case of a melanotic PEComa with NONO-TFE3 fusion occurring in the sinonasal mucosa, as demonstrated by both next-generation sequencing and molecular cytogenetic studies. This case is the first of its kind in the literature and only the second documented PEComa harboring a NONO-TFE3 rearrangement. In light of unequivocal molecular ancillary studies, this case illustrates that PEComa must enter the differential for pigmented lesions of the sinonasal mucosa, where malignant melanoma would be much more likely to occur.

Burkitt leukemia limited to the bone marrow has a better prognosis than Burkitt lymphoma with bone marrow involvement in adults.

Burkitt lymphoma patients with bulky disease often have bone marrow involvement. However, leukemic presentation of Burkitt lymphoma in the absence of a mass (pure Burkitt leukemia; PBL) is uncommon. Both PBL and Burkitt lymphoma/leukemia, presenting with a tumor mass and marrow involvement (BLL), are considered stage IV disease, which is associated with a poor prognosis. However, there is limited information on the prognosis in adults with PBL because they have typically been included in cohorts of patients with BLL. This study identified 23 patients, which included 10 PBL and 13 BLL cases. Complex karyotypes (100%) were seen in all BLL cases compared to the PBL group (40%; p = 0.061). Patients with PBL had a significantly better 5-year overall survival of 87.5% vs only 24.3% in the BLL group (p = 0.005). The 5-year overall survival of patients with PBL treated with intensive chemotherapy is superior to those with BLL who are similarly treated.

Cytopathologic diagnosis of Kaposi sarcoma in unusual clinical settings.

INTRODUCTION: Kaposi sarcoma (KS) is a rare disease that presents as 1 of 4 distinct clinicopathologic subtypes; however, it may present in populations outside those normally encountered. In such cases, it will be important to consider KS in the differential diagnosis, as it may mimic other neoplastic and non-neoplastic entities. MATERIALS AND METHODS: We describe 2 cases of KS, 1 in a patient not clinically fitting any of the 4 subtypes and the other in a patient with atypical presentation in human immunodeficiency virus (HIV)-associated disease. The first is an 81-year-old African American (AA) woman with a history of KS of the leg, who presented with groin lymphadenopathy and the second is a 42-year-old AA man with a known history of HIV infection, no skin lesions, and new axillary lymphadenopathy. RESULTS: Fine-needle aspiration of the groin and axillary lymph node, respectively, showed atypical spindle cells in a lymphoplasmacytic background. The spindle cells were positive for human herpesvirus-8 on the cell block and subsequent lymph node excision. In patients with HIV infection, in addition to reactive and lymphoproliferative processes, KS should be considered. In the former case, the demographic of an elderly AA woman without immunosuppression would not cause concern for systemic KS, but for a metastatic tumor or lymphoma. CONCLUSIONS: Cytology is a helpful tool in narrowing the differential diagnosis for spindle cell lesions. With a diagnosis of KS, clinicians would be able to query the clinical history for a possible etiology, such as HIV, and exclude the possibility of metastatic disease.