Myelodysplastic Neoplasms (MDS): The Current and Future Treatment Landscape.

Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality.

Ductal Adenocarcinoma of the Prostate with Novel Genetic Alterations Characterized by Next-Generation Sequencing.

Ductal adenocarcinoma of the prostate (DAP) is an uncommon variant of prostate cancer associated with aggressive disease and poor outcome. It presents most frequently as a mixed tumor combined with acinar adenocarcinoma. Although the histopathological features of DAP are well known, its genomic characteristics are still evolving, prompting the suggestion that all DAP would benefit from molecular analysis with the purpose of improving tumor recognition, genetic classification, and, ultimately, personalized therapy. Herein, we report a case of DAP with novel genetic alterations (BCOR P1153S, ERG M219I, KDR A750E, POLE S1896P, and RAD21 T461del).

Androgen receptor amplification in mesonephric remnants.

Mesonephric remnants (MRs) are embryonic vestiges most commonly found in female pathology specimens from the lateral wall of the cervix. The highly regulated genetic programme of mesonephric duct development has been well characterised in animals based on traditional surgical castration and knockout mouse experiments. However, the process is incompletely understood in humans. MRs are believed to give rise to mesonephric neoplasms, which are rare tumours with uncertain pathophysiology. There is a dearth of molecular studies on mesonephric neoplasms in part due to their rarity. Here, we report the results of next-generation sequencing of MR, which identified amplification of the androgen receptor gene for the first time to the best of our knowledge and discuss the potential implications in the context of the literature.

KRAS G12D mutation in Brunner gland adenoma.

Brunner gland lesions (BGLs) encompass benign proliferations of the homonymous glands and have been designated as hyperplasia, adenoma (BGA), hamartoma or nodule. In general terms, lesions larger than 0.5 cm are considered true neoplasia with unknown malignant potential and unclear pathogenesis. Genetic alterations have seldom been reported in BGL, and include SMAD4/DPC4 and LRIG1, but not KRAS (Kirsten rat sarcoma viral oncogene homologue) to the best of our knowledge.We present the case of a man in his 60s, evaluated for iron deficiency anaemia harbouring a 1.5 cm BGA found by duodenoscopy. Immunohistochemistry failed to reveal microsatellite instability, and next-generation sequencing revealed a KRAS G12D point mutation.

Rosai-Dorfman Disease of the Rectum: Newly Identified Genetic Point Mutations and Robotic Resection.

Rosai-Dorfman disease (RDD) is a rare disease characterized by histiocytic proliferation which typically presents as massive, painless, cervical lymphadenopathy in children or young adults. GI involvement is exceedingly rare with only 20 documented cases to date. Of those 20 cases, only 3 cases have involved the rectum. Here, we present 2 cases of rectal RDD with attention paid to the diagnostic and technical challenges presented by this disease. When presenting as a perirectal mass, RDD can be mistaken for other lesions to include malignancy, leading to surgical removal. We present a video of a robotic low-anterior resection with intracorporeal anastomosis in order to remove a pelvic mass involving the rectum, initially considered to be a stromal tumor. In addition, we describe a copy number variation in AKT and 3 point mutations detected by next generation sequencing, which had not been previously reported in association with this disease.

The prevalence and clinical significance of HER2 expression in prostate adenocarcinoma.

AIMS: Abnormalities in HER2 are well-established oncogenic drivers and are approved therapeutic targets in various malignancies. Prior studies evaluating HER2 expression in prostate cancer (PCa) have yielded variable results. Most of these studies used immunohistochemistry scoring systems based on breast cancer data. The goal of this study was to determine the prevalence and clinical significance of HER2 expression using a scoring system that better reflects the HER2 staining pattern observed in PCa. METHODS: We randomly selected similar numbers of localized low risk (AJCC stage I), locally advanced (AJCC stages II & III), and metastatic (AJCC stage IV) PCa patients treated at the DC VA Medical Center between 2000 and 2022. Among them, we included patients who had sufficient PCa tissue samples and clinical information required for this analysis. Two experienced pathologists independently scored HER2 expression (Ventana Pathway anti-HER2) according to a modified gastric cancer HER2 scoring system. RESULTS: Out of the 231 patients included, 85 % self-identified as Black. 58.9 % of patients expressed HER2 (1+: 35.5 %; 2+: 18.2 %; 3+: 5.2 %). Validity of the results was confirmed using the HercepTest antibody. Higher HER2 expression was associated with a higher Gleason Score/Grade Group and advanced disease. CONCLUSIONS: Our findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in future PCa trials.

Neurothekeoma With PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M Genetic Alterations.

ABSTRACT: Neurothekeoma, a lesion of possible fibrohistiocytic origin, is a rare, benign, superficial soft tissue tumor, histologically subclassified in 3 types: myxoid, cellular, or mixed. It clinically presents as a solitary, pink to brown nodule, ranging from 0.3 to 2.0 cm. Four point mutations (PI3K w552*, ALK P1469S, SMO G461S, and ERBB3 L77M) were identified by next-generation sequencing of a neurothekeoma presenting in the left inner thigh of a 53-year-old man. We highlight novel genetic alterations (SMO G461S and ERBB3 L77M) and previously known mutations (PI3KCA w552* and ALK P1469S) that play a role in other pathogenic pathways, but to the best of our knowledge, these have not yet been reported in neurothekeoma.

Concurrent Waldenstrom's Macroglobulinemia and Myelodysplastic Syndrome with a Sequent t(10;13)(p13;q22) Translocation.

Myelodysplastic syndromes (MDS) and Waldenstrom's macroglobulinemia (WM) are rarely synchronous. Ineffective myelopoiesis/hematopoiesis with clonal unilineage or multilineage dysplasia and cytopenias characterize MDS. Despite a myeloid origin, MDS can sometimes lead to decreased production, abnormal apoptosis or dysmaturation of B cells, and the development of lymphoma. WM includes bone marrow involvement by lymphoplasmacytic lymphoma (LPL) secreting monoclonal immunoglobulin M (IgM) with somatic mutation (L265P) of myeloid differentiation primary response 88 gene (MYD88) in 80-90%, or various mutations of C-terminal domain of the C-X-C chemokine receptor type 4 (CXCR4) gene in 20-40% of cases. A unique, progressive case of concurrent MDS and WM with several somatic mutations (some unreported before) and a novel balanced reciprocal translocation between chromosomes 10 and 13 is presented below.

Refractory Splenic Marginal Zone Lymphoma Responsive to Combination Venetoclax and Bortezomib (Velcade) (V2) Therapy.

Standard treatment regimens for the management of patients with refractory splenic marginal zone lymphoma (SMZL) are currently unavailable. Here, we report a case of SMZL, which, after failing multiple therapeutics, demonstrated an impressive clinical response to combined Venetoclax and Velcade (V2), a treatment combination currently being investigated in the setting of refractory multiple myeloma. We also report a unique histopathology and mutational profile that may have important implications for the characterization and prognosis of SMZL.

Hepatoid prostatic carcinoma with adrenal metastasis and novel genetic alterations.

Hepatoid carcinoma (HC) encompasses epithelial extrahepatic tumors exhibiting features of hepatocellular carcinoma (HCC) both by morphology and immunohistochemistry. Distinguishing metastatic HCC from HC may be challenging, particularly when limited material, such as a cytologic specimen, is available. HC from prostatic origin is unusual and has only rarely been characterized by cytology. Herein we present an 86-year-old male with history of castration-resistant prostate cancer developing a left adrenal gland nodule. Fine needle aspiration revealed a poorly differentiated malignant neoplasm diagnosed as metastatic hepatoid prostatic adenocarcinoma based on immunohistochemistry (positive for HepPar1, AFP, NKX3.1, PSMA, and Racemase; and negative for CK7, CK20, cytokeratin 34betaE12, p63, and Arg-1). Because prostatic carcinoma with hepatoid features is rare, and the patient had failed standard therapy, next generation sequencing was performed in an attempt to identify druggable molecular targets. Well-known prostate carcinoma-related alterations were found in three genes (CDK12, AR, and SPOP). In addition, three variants of uncertain significance (DDR2 R128C, SRC P428L, and HNRNPU K574Sfs*32) were identified, which to the best of our knowledge have not been previously reported. Our results support the power of an immunohistochemistry panel including Arg-1 and HepPar1 when HC is suspected, and highlight the value of cytology for comprehensive diagnostic evaluation.

Concurrent B Cell Acute Lymphoblastic Lymphoma/Leukemia and Monoclonal B Cell Lymphocytosis: A Case Report with Extensive Molecular Analysis.

Although acute lymphoblastic leukemia (ALL) and monoclonal B cell lymphocytosis (MBL) are common neoplasia, a simultaneous presentation is very unusual. Here, we present two different B cell clones, MBL and B-ALL, cocirculating in a 78-year-old African American male. Detailed molecular characterization revealed an unusual MPL (T487I) point mutation and unmutated VH4-39. After nonstandard chemotherapy, the patient remains in morphologic remission. These findings may stimulate further research to clarify the pathogenesis of hematologic neoplasms.

Noncoding-RNA-Based Therapeutics with an Emphasis on Prostatic Carcinoma-Progress and Challenges.

Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as "the dark matter of the nucleus", and unraveling their role in physiologic and pathologic processes will provide vast opportunities for basic and translational research with the potential for significant therapeutic progress. Consequently, strong efforts are underway to exploit the therapeutic utility of ncRNA, some of which have been approved by the US Food and Drug Administration and the European Medicines Agency. The use of ncRNA therapeutics (or "vaccines" if defined as anti-disease agents) may result in improved curative strategies when used alone or in combination with existing treatments. This review will focus on the role of ncRNA therapeutics in prostatic carcinoma while exploring basic biological aspects of these molecules that represent about 97% of the transcriptome in humans.

A Review on Splenic Diffuse Red Pulp Small B-Cell Lymphoma.

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is a rare disease, representing <1% of all non-Hodgkin lymphomas (NHL). The most common clinical manifestations include splenomegaly, lymphocytosis, and hemocytopenia. A diagnosis of SDRPL can be challenging, as it shares multiple clinical and laboratory features with splenic marginal zone lymphoma (SMZL), hairy cell leukemia (HCL), and HCL variant (HCL-v). Obtaining splenic tissue remains the gold standard for diagnosis. In the cases where splenic tissue is not available, diagnosis can be established by a review of peripheral blood and bone marrow studies. SDRPL is characterized by a diffuse involvement of the splenic red pulp by monomorphous small-to-medium sized mature B lymphocytes effacing the white pulp. The characteristic immunophenotype is positive for CD20, DBA.44 (20 to 90%), and IgG, and typically negative for CD5, CD10, CD23, cyclin D1, CD43, annexin A1, CD11c, CD25, CD123, and CD138. The Ki-67 proliferative index is characteristically low. Cyclin D3 is expressed in the majority of SDRPL in contrast with other types of small B-cell lymphomas, thus facilitating the recognition of this disease. There is no standard treatment regimen for SDRPL. Initial treatment options include splenectomy, rituximab monotherapy, or a combination of both. Chemoimmunotherapy should be considered in patients with advanced disease at baseline or progression.

How to Diagnose and Treat CD5-Positive Lymphomas Involving the Spleen.

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5-10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen.

Low-Grade Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma.

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm.

Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2 + myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.