Venetoclax monotherapy as front-line therapy for blastic plasmacytoid dendritic cell neoplasm.

Venetoclax is an approved treatment for relapsed/refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). We report a unique case of venetoclax monotherapy used for front-line induction and as a bridge to allogeneic hematopoietic stem cell transplantation (HCT). Venetoclax therapy resulted in rapid complete resolution of skin lesions, however, treatment interruption due to neutropenia led to brisk cancer recurrence. Fortunately, the patient responded to re-challenge and was able to undergo HCT. Venetoclax is active in the first-line treatment setting for BPDCN, however its effect on blood counts and durability of response should be further studied.

The Morphologic Spectrum of Gastric Type 1 Enterochromaffin-Like Cell Neuroendocrine Tumors.

Although most well-differentiated gastric neuroendocrine tumors (gNETs) arise from enterochromaffin-like (ECL) cells in patients with autoimmune metaplastic atrophic gastritis (AMAG), the morphologic spectrum of these type 1 ECL-cell gNETs is not well defined. The extent of metaplastic progression in the background mucosa of AMAG patients with gNETs is likewise unclear. Here we report the histomorphology of 226 gNETs, including 214 type 1 gNETs (78 cases from 50 AMAG patients) pooled from a population with high AMAG prevalence. Most type 1 gNETs were ≤1.0 cm, of low grade, and multifocal, consistent with the results of previous reports. However, a high proportion (70/214, 33%) displayed unusual gNET morphologies not previously appreciated in AMAG patients. Unlike other type 1 gNETs with conventional neuroendocrine tumor morphologies, unconventional type 1 gNETs displayed cribriform networks of atrophic cells embedded within myxoid matrix (secretory-cribriform variant, 59%), sheets of deceptively bland discohesive cells resembling inflammatory infiltrates (lymphoplasmacytoid variant, 31%), or wreath-like arrangements of columnar cells wrapped around collagenous cores (pseudopapillary variant, 14%). Another unusual feature was that unconventional gNETs grew laterally within the mucosa (50/70, 71%) and were only rarely sampled from the submucosa (3/70, 4%). These features also differed from the conspicuous radial nodules (99/135, 73%) and frequent submucosal involvement (57/135, 42%) observed for conventional gNETs (P < .0001). Irrespective of morphology, type 1 gNETs were nearly always detected at first AMAG diagnosis (45/50, 90%) and tended to persist thereafter (34/43, 79%), despite similar clinical symptoms and laboratory values between AMAG patients with gNETs and those without. However, unlike AMAG patients without gNETs (n = 50), the background mucosa in patients with gNETs (n = 50) had already progressed to the morphologic equivalent of end-stage metaplasia (P < .0001). This included diffuse loss of parietal cells (92% vs 52%), complete intestinal metaplasia (82% vs 40%), and pancreatic metaplasia (56% vs 6%). Thus, type 1 ECL-cell gNETs are morphologically heterogeneous with a high prevalence of unconventional gNET morphologies. They tend to present silently at first AMAG diagnosis as multifocal lesions that persist within fields of mature metaplasia.

CDK1 bridges NF-κB and ß-catenin signaling in response to H. pylori infection in gastric tumorigenesis.

Infection with Helicobacter pylori (H. pylori) is the main risk factor for gastric cancer, a leading cause of cancer-related death worldwide. The oncogenic functions of cyclin-dependent kinase 1 (CDK1) are not fully understood in gastric tumorigenesis. Using public datasets, quantitative real-time PCR, western blot, and immunohistochemical (IHC) analyses, we detect high levels of CDK1 in human and mouse gastric tumors. H. pylori infection induces activation of nuclear factor κB (NF-κB) with a significant increase in CDK1 in in vitro and in vivo models (p < 0.01). We confirm active NF-κB binding sites on the CDK1 promoter sequence. CDK1 phosphorylates and inhibits GSK-3ß activity through direct binding with subsequent accumulation and activation of ß-catenin. CDK1 silencing or pharmacologic inhibition reverses these effects and impairs tumor organoids and spheroid formation. IHC analysis demonstrates a positive correlation between CDK1 and ß-catenin. The results demonstrate a mechanistic link between infection, inflammation, and gastric tumorigenesis where CDK1 plays a critical role.

Valproic Acid Induced Thrombocytopenia and Dysmegakaryopoiesis in a Pediatric Patient.

OBJECTIVE: Valproic acid (VPA) is an effective first-line anticonvulsant that is associated with several side effects including bone marrow suppression and subsequent cytopenia. However, VPA associated myelodysplasia is not a well described entity that can be seen in patients on VPA treatment. CASE REPORT: Herein, we describe a 9-year-old female patient with a past medical history of seizure disorder who presented with 3-week history of intermittent fevers, fatigue, weakness, and multiple unexplained bruises. Complete blood count (CBC) was remarkable for marked thrombocytopenia. Trephine biopsy showed a normocellular marrow with maturing trilineage hematopoiesis and scattered atypical megakaryocytes including numerous small hypolobated forms with frequent forms showing separated nuclei. Her CBC showed normalization 7 months after VPA was stopped. CONCLUSIONS: The presence of bone marrow suppression and myelodysplasia in patients on VPA treatment should be taken into consideration as it can cause a diagnostic pitfall especially in pediatric and elderly populations. A careful review of past medical history and medications can help make the correct diagnosis.

Describing IgA Myeloma: An Immunophenotypic and Molecular Approach.

Plasma cell myeloma (PCM) is defined as a clonal disease of terminally differentiated plasma cells that secrete immunoglobulin. The biologic underpinnings of IgA-type multiple myeloma's (IgAMM) aggressive nature, including its increased morbidity and mortality, have not been elucidated. We describe the clinical, phenotypic, and cytogenetic characteristics of IgA-MM. Flow-cytometry analysis was performed to phenotype clonal plasma cell populations, and interface with fluorescent in situ hybridization (iFISH) to exploit cytogenetics to determine risk stratification; 68.1% of cases were of intermediate or high risk. On flow cytometry, samples from our IgA-PCM cohort revealed less frequent CD56 expression when compared to samples with other PCM subtypes. Our study demonstrated lower frequency of CD56 expression (52.8%). We hypothesize that loss of CD56 may play a significant role in the aggressive behavior of IgA-PCM due to the loss of cell-to-cell adhesion resulting in a higher propensity for extramedullary presentation.

Easy-To-Perform Dual Immunohistochemistry Can Solve Problems in Hematopathology.

Immunohistochemical analysis has become an integral component in the diagnostic work up of hematopoietic neoplasms. It is not uncommon that visualization of single protein expression by immunohistochemistry among cells of interest may become a difficult task. Common scenarios of such include extensive colonization of germinal centers in the differential diagnosis of marginal zone lymphoma and follicular lymphoma, low-level bone marrow involvement by lymphoma and paucity of neoplastic lymphocytes in the setting of numerous background reactive lymphocytes, among others. For this reason, we have developed a variety of easy-to-employ dual-color dual-antibody immunohistochemical assays to aid in solving these diagnostic dilemmas. Herein, we share examples of our use of dual immunohistochemistry to illustrate its beneficial and practical objective.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Marginal zone lymphoma of the colon: case series from a single center and SEER data review.

Colon extranodal marginal zone lymphoma (EMZL) is poorly characterized in the literature. We performed a retrospective review of patients with colon EMZL at our institution and from the Surveillance Epidemiology and End Results (SEER) database. Eight patients were identified in our institution with majority (88%) presenting with stage-I disease. Initial management included active surveillance, polypectomy followed by surveillance, and surgical resection followed by chemotherapy. One patient with concurrent prostate carcinoma received radiation to the rectum. Initial therapy led to complete remission in five out of six treated patients with four of them maintaining remission at 88 months. SEER database identified 361 patients with stage-I colon EMZL. Overall survival for this cohort was 73.9% at 10 years with no significant difference in outcomes between treatment groups. Our single institution experience and the SEER data analysis emphasize indolent nature of colon EMZL and need for non-aggressive therapeutic approaches.

Nonlymphoid Hematopoietic Diseases Presenting in Bone, Soft Tissue, and Other Extranodal Sites.

CONTEXT.­: Although rare in everyday practice, the initial presentation of hematopoietic neoplasms other than lymphoma in the musculoskeletal system and other extranodal sites can generate challenging diagnostic problems for surgical pathologists. OBJECTIVE.­: To review the morphologic and immunophenotypic features of various nonlymphoid hematopoietic diseases presenting at extranodal sites, with emphasis on the inherent diagnostic pitfalls and differential diagnoses of these entities to aid surgical pathologists in their accurate recognition. DATA SOURCES.­: Cases reviewed herein represent both in-house and consult cases seen at our institution between 2010 and 2021. CONCLUSIONS.­: Entities that present in this way include myeloid neoplasms and histiocytic/dendritic cell neoplasms. These tumors commonly cause nonspecific symptoms, and their histologic appearance can overlap with a variety of benign neoplasms and reactive processes. This can lead to delay in diagnosis and intervention with potentially lifesaving therapy; thus, accurate and expedient recognition is of paramount importance.

Pitfalls in gastrointestinal tract haematopoietic lesions.

Specimens from the gastrointestinal (GI) tract are among the most commonly encountered in routine pathology practice worldwide. It is well known that the luminal GI tract is home to various areas rich in mucosa-associated lymphoid tissue (MALT), whether native or acquired. The latter may be particularly problematic due to its well-known predisposing factors such as Helicobacter pylori infection and autoimmune conditions. Nevertheless, native GI structures are often the subject of query, particularly in conditions that may mimic lymphoproliferative conditions, including infectious and inflammatory diseases. Herein, we describe and share common clinicopathological findings in our daily practice that are challenging to distinguish from subtle low-grade neoplastic lymphoproliferative disorders.

NF-kB-dependent activation of STAT3 by H. pylori is suppressed by TFF1.

BACKGROUND: H. pylori infection is the main risk factor for gastric cancer. In this study, we investigated H. pylori-mediated activation of STAT3 and NF-κB in gastric cancer, using in vitro and in vivo models. METHODS: To investigate the activation of NF-κB and STAT3 by H. pylori strains we used in vitro and in vivo mouse models, western blots, immunofluorescence, ChIP Assay, luciferase and quantitative real-time PCR assays. RESULTS: Following infection with H. pylori in vitro, we found an earlier phosphorylation of NF-kB-p65 (S536), followed by STAT3 (Y705). Immunofluorescence, using in vitro and in vivo models, demonstrated nuclear localization of NF-kB and STAT3, following H. pylori infection. NF-kB and STAT3 luciferase reporter assays confirmed earlier activation of NF-kB followed by STAT3. In vitro and in vivo models demonstrated induction of mRNA expression of IL-6 (p < 0.001), VEGF-α (p < 0.05), IL-17 (p < 0.001), and IL-23 (p < 0.001). Using ChIP, we confirmed co-binding of both NF-kB-p65 and STAT3 on the IL6 promoter. The reconstitution of Trefoil Factor 1 (TFF1) suppressed activation of NF-kB with reduction in IL6 levels and STAT3 activity, in response to H. pylori infection. Using pharmacologic (BAY11-7082) and genetic (IκB super repressor (IκBSR)) inhibitors of NF-kB-p65, we confirmed the requirement of NF-kB-p65 for activation of STAT3, as measured by phosphorylation, transcription activity, and nuclear localization of STAT3 in in vitro and in vivo models. CONCLUSION: Our findings suggest the presence of an early autocrine NF-kB-dependent activation of STAT3 in response to H. pylori infection. TFF1 acts as an anti-inflammatory guard against H. pylori-mediated activation of pro-inflammatory networks.

Unexpected Primary Extranodal Marginal Zone Lymphoma of Bone in Amputation and Arthroplasty Specimens.

OBJECTIVES: Amputation due to gangrene and arthroplasty for degenerative joint disease are common orthopedic procedures and are expected to increase as populations age. Histopathologic examination of these specimens can identify unsuspected diseases. METHODS: We reviewed gangrenous amputations and large joint arthroplasty specimens for diagnosis of unexpected lymphoma, January 2014 to January 2020. Pathology and medical records were reviewed to determine diagnosis, treatment, and outcome. RESULTS: Five cases (0.08%) of unexpected primary extranodal marginal zone lymphoma (MZL) centered in bone were identified in 1,624 amputations for gangrene and 4,163 arthroplasty specimens. The female-to-male distribution was 3:2. Median age was 71 years (range, 62-87). The 3 cases arising in the setting of gangrene involved the first toe phalanges and metatarsals, and the femoral head was involved in all cases of joint disease (2 cases). The bone showed variable (10%-80%) infiltration by dense populations of small lymphoid cells with MZL immunophenotype. One patient died from sepsis 18.5 months after diagnosis; all others are alive with a median follow-up of 27.45 months. CONCLUSIONS: Histopathologic examination of nonneoplastic orthopedic specimens identifies unexpected primary bone extranodal MZL in a small percentage of cases. This neoplasm may be the result of chronic antigenic stimulation in some circumstances.

Gastrointestinal Tract Lymphomas.

CONTEXT.­: The gastrointestinal (GI) tract is the most common site of extranodal non-Hodgkin lymphoma, accounting for 20% to 40% of all extranodal lymphomas. The majority of these are systemic processes secondarily involving the GI tract. Primary GI lymphomas are less common, accounting for approximately 10% to 15% of all non-Hodgkin lymphomas. Most non-Hodgkin lymphomas involving the GI tract are of B-cell lineage, of which diffuse large B-cell lymphoma is the most common subtype, irrespective of location. OBJECTIVE.­: To review the lymphoproliferative neoplasms of B-cell and T-cell lineage involving the luminal GI tract according to the most prevalent subtypes at each anatomic site. DATA SOURCE.­: Systematic search of the PubMed database for updated literature on GI lymphoma epidemiology, subtypes, clinical, endoscopic, and genetic findings. Histologic images are derived from our collection of clinical cases. CONCLUSIONS.­: The GI tract is the most common site of extranodal lymphoproliferative neoplasms. Recognition of the most frequently encountered GI lymphomas is imperative for patient management and treatment.

Expression of germinal center cell markers by extranodal marginal zone lymphomas of MALT type within colonized follicles, a diagnostic pitfall with follicular lymphoma.

We reviewed 341 consecutive cases of marginal zone lymphoma (MZL) (47) or follicular lymphoma (FL) (294) of which 7 were difficult to distinguish due to perceived coexpression of BCL6 and BCL2 by tumor cells in follicular foci. This stimulated us to develop dual BCL6/BCL2 immunohistochemistry, allowing us to assess coexpression among individual cells. Dual staining confirmed coexpression in 6 of 7 cases, all extranodal MZL (ENMZL) based on overall features and representing 13% of MZL in this series. These findings confirm that MZL cells have plasticity regarding protein expression within the germinal center (GC) microenvironment, an important diagnostic pitfall. Intriguingly, in all MZL expressing BCL6, non-neoplastic GC B cells within colonized follicles showed diminished or absent CD10 expression but preserved BCL6 and high ki67. This finding suggests plasticity of CD10 expression in non-neoplastic GC B cells in the context of colonization by MZL, possibly related to NF-kB dysregulation.

Silencing of miR490-3p by H. pylori activates DARPP-32 and induces resistance to gefitinib.

Infection with Helicobacter pylori (H. pylori) is the main risk factor for gastric carcinogenesis. In this study, we investigated the expression, molecular functions, and downstream effectors of miR490-3p in gastric cancer. We used in vitro and in vivo models to investigate the role of H. pylori in regulating miR490-3p, DARPP-32-dependent functions, and therapeutic resistance. Human and mouse neoplastic gastric lesions demonstrated a negative correlation between DARPP-32 and miR490-3p expression (R = -0.58, P < 0.01). This was also detected following infection with H. pylori (R = -0.66, P < 0.01). Molecular assays confirmed DARPP-32 as a direct target of miR490-3p. CHRM2, the host gene of miR490-3p, was hypermethylated and downregulated in neoplastic gastric tissues (P < 0.05). H. pylori induced methylation and downregulation of CHRM2 and miR490-3p. Functionally, the reconstitution of miR490-3p sensitized cancer cells to gefitinib by inactivating DRAPP-32-dependent AKT and STAT3 pathways. Patients with low miR490-3p or high DARPP-32 expression had decreased overall survival (P < 0.05). Hypermethylation-mediated silencing of CHRM2 and miR490-3p by H. pylori increased DARPP-32 expression. Downregulation of miR490-3p in gastric cancer plays a role in gefitinib response by inducing DARPP-32-mediated activation of PI3K/AKT, STAT3 signaling pathways.

Strongyloides Colitis as a Harmful Mimicker of Inflammatory Bowel Disease.

Autoinfection caused by Strongyloides stercoralis frequently becomes a life-long disease unless it is effectively treated. There is overlapping histomorphology between Strongyloides colitis and inflammatory bowel disease; a low index of suspicion can lead to misdiagnosis and fatal consequences. We present a case of Strongyloides colitis mimicking the clinical and pathologic features of inflammatory bowel disease. A 64-year-old female presented to the emergency department with a four-day history of abdominal pain, diarrhea, and hematochezia. Colonoscopy revealed diffuse inflammation suggestive of inflammatory bowel disease, which led to initiation of 5-aminosalicylic acid and intravenous methylprednisolone. Biopsies of the colon revealed increased lymphoplasmacytic infiltrate of the lamina propria with eosinophilic microabscesses and presence of larvae, consistent with Strongyloides stercoralis. Immunosuppressive medication was halted. The patient ultimately died a few days later. This case emphasizes the importance of identifying the overlapping clinical and pathologic features of Strongyloides colitis and inflammatory bowel disease. A high index of suspicion and recognition of particular histological findings, including eosinophilic microabscesses, aid in the correct diagnosis. Definitive diagnosis is crucial as each disease carries distinct therapeutic implications and outcome.

Pulmonary Empty Spaces: Silicone Embolism-A Decade of Increased Incidence and Its Histological Diagnosis.

Pulmonary embolism (PE) is a critical complication related to multiple disorders and different medical or cosmetic procedures. This case report presents two patients who were admitted for respiratory symptoms in the setting of previously receiving silicone injections for cosmetic purposes and were diagnosed with silicone pulmonary embolism. The relevance of including questions about all cosmetic procedures as a part of a medical history is highlighted, in particular about silicone injections. The diagnosis is confirmed by histological means. Additionally, our review showed the change of most common sites of silicone injections and a significant increase in cosmetic procedures causing silicone embolism during the past twelve years.

Irreversible Electroporation of Hepatic and Pancreatic Malignancies: Radiologic-Pathologic Correlation.

Irreversible electroporation (IRE) is a novel therapy that has shown to be a feasible and promising alternative to conventional ablative techniques when treating tumors near vital structures or blood vessels. The clinical efficacy of IRE has been evaluated using established imaging criteria. This study evaluates the histologic and imaging response of hepatic and pancreatic malignancies that were surgically resected after IRE. In total, 12 lesions ablated with IRE were included, including 3 pancreatic carcinomas, 5 primary tumors of the liver, and 4 metastatic tumors of the liver. The rate of complete response to IRE was 25% based on the histologic evaluation of the resected tumors. Although treatment-related vessel wall changes were noted in several cases in histologic findings, there was no evidence of vascular luminal narrowing or obliteration in any of the specimens. The imaging response to IRE before surgical resection usually resulted in underestimation of disease burden when compared with the histologic response seen on the resected specimens.

Numb chin syndrome secondary to leptomeningeal carcinomatosis from gastric adenocarcinoma.

Numb chin syndrome (NCS) can be a sign of malignancy. Its association with gastric adenocarcinoma is rare. We report a case of a 27-year-old Hispanic female that presented with complaint of left sided headache associated with numbness of the left side of chin and lower gingiva. Initial brain MRI, whole body gallium scan, high resolution CT of chest and elevated protein in the CSF were suggestive of sarcoidosis. She was treated with IV steroids with transient clinical improvement. Two weeks later, her symptoms worsened and further evaluation revealed the diagnosis of a poorly differentiated metastatic gastric adenocarcinoma with leptomeningeal involvement. This case report aims to emphasize the importance of identifying NCS as a possible indication of an underlying malignant condition. Reported cases of NCS associated with metastatic gastric adenocarcinoma are very rare.