Successful treatment of metastatic pancreatoblastoma in an adult with autologous hematopoietic cell transplant.

BACKGROUND: Pancreatoblastoma is a rare pediatric malignant neoplasm characterized by its histological resemblance to fetal pancreatic tissue and poor clinical outcomes. Preoperative diagnosis of the neoplasm is difficult due to its rarity, variable clinical presentation, and its lack of distinct laboratory markers. Current mainstay of treatment is surgical resection of the tumor, although a standard of care has not yet been established. METHODS: Data were collected on one patient admitted to the University of Virginia Hospital System. Radiology, hematopoietic cell transplant, and biopsy data were collected according to the best clinical practice. RESULTS: Herein, we describe the case of an adult patient with pancreatoblastoma treated with high-dose chemotherapy and autologous peripheral blood hematopoietic cell transplantation. To the authors' knowledge, this is the first documented successful treatment of pancreatoblastoma using autologous hematopoietic cell transplantation in the United States, and the first successful treatment in an adult patient worldwide. CONCLUSIONS: While it is difficult to draw conclusions based on a single case, we would like to highlight the success of this treatment modality in the management of our patient with a 51-month remission and open further discussion into exploring the use of autologous hematopoietic cell transplantation for pancreatoblastoma. Our patient is currently living 57 months after diagnosis despite the average survival rate being less than 18 months.

Expression of the Immune Checkpoints LAG-3 and PD-L1 in High-grade Serous Ovarian Carcinoma: Relationship to Tumor-associated Lymphocytes and Germline BRCA Status.

Ovarian high-grade serous carcinomas (HGSC) have shown lackluster responses to immunotherapies targeting the PD-1/PD-L1 axis, perhaps due to the coexistence of other mechanisms of immune evasion in this tumor type. Lymphocyte activation gene-3 (LAG-3) is another inhibitory immune checkpoint often expressed on tumor-associated lymphocytes which is targeted by drugs currently in clinical trials. Forty-eight HGSC with known germline BRCA mutation status were immunohistochemically stained for LAG-3, CD8, and FOXP3. Positive tumor-associated lymphocytes were enumerated and averaged over 10 high-power fields (HPF). PD-L1 immunostaining was also preformed and expression was evaluated on tumor cells and using the combined positive score (CPS). The average number of LAG-3-positve tumor-associated lymphocytes was 6/HPF (range: 0-25.6). Cytotoxic (CD8) T cells averaged 30/HPF (range: 0-168.9), and regulatory (FOXP3) cells averaged 6.6/HPF (range: 0-76.3). Tumoral PD-L1 expression of ≥1% was observed in 27% (13/48) of cases, with only 8% (4/48) showing >5% staining; 81% (39/48) cases had a CPS ≥1. LAG-3-positive lymphocytes and PD-L1 expression were positively correlated, even after controlling for the overall level of CD8 and FOX3P lymphocyte infiltration. Germline BRCA status was not significantly associated with LAG-3, CD8, FOXP3, or PD-L1 expression. These findings indicate that immunotherapies targeting LAG-3 may benefit some ovarian HGSC patients, particularly when used in conjunction with anti-PD-1/PD-L1 approaches. The typically limited expression of LAG-3 and PD-L1 suggests that immunotherapeutic response may be muted in most HGSC even with a combination approach.

Emerging biomarkers in ovarian granulosa cell tumors.

OBJECTIVE: Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches. METHODS: Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence. RESULTS: 59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation. CONCLUSIONS: Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

Hit and Run: Bilateral Massive Intraocular Lymphomatous Infiltration after CAR-T Therapy.

PURPOSE: We report a case of bilateral intraocular infiltration of DLBCL after CAR-T therapy. METHODS: Retrospective case report. RESULTS: A 62-year-old Caucasian male with medical history of high-grade DLBCL presented with papillitis and vitritis upon completion of CAR-T therapy. Thorough infectious and diagnostic work-ups were performed. Diagnostic vitreous tap revealed intraocular lymphoma. The patient received external beam radiotherapy to both orbits with dramatic improvement in disc edema and vitritis. However, subsequent MRI showed development of intracranial metastatic disease, and the patient died within the same month. CONCLUSION: Atypical intraocular metastasis of DLBCL may occur following CAR-T therapy and may indicate secondary changes in immunosurveillance within immune-privileged sites such as the eye.

Increased IgG4+ plasma cells are common in excised lymph nodes from children and adolescents without IgG4-related disease.

Lymphadenopathy is a common finding in patients with IgG4-related disease (IgG4-RD) and often associated with increased IgG4+ plasma cells in this setting. The histologic features of so-called IgG4-related lymphadenopathy (IgG4-LAD) have seldom been investigated in children and adolescents, and step-wise progression to extranodal IgG4-RD has not been described. This study was performed to further evaluate the frequency, pathologic features, and clinical significance of IgG4-LAD-like histologic changes in the pediatric setting. We analyzed 37 benign lymph nodes collected semi-consecutively from children aged 0-18 years at our institution for both absolute and relative IgG4+ plasma cell abundance and recurrent histomorphologic patterns associated with IgG4-LAD. The combination of IgG4+/IgG+ plasma cell ratio >40% and IgG4+ plasma cell count ≥50 were considered as IgG4-LAD-like per expert consensus guidelines. Seven cases (19%) met both diagnostic criteria. The dominant histomorphologic patterns were follicular hyperplasia (n = 6), interfollicular expansion (n = 3), and progressive transformation of germinal centers (n = 3). Extranodal manifestations of IgG4-RD were not identified in this cohort (38 months average follow-up). Instead, clinical and laboratory findings indicated that lymph node enlargement in most patients could likely be attributed to alternative processes including antecedent dentistry, concurrent infection, and incipient Crohn's disease. Our findings suggest that the histologic features of IgG4-LAD are likely much more common in children and adolescents than previously recognized, often existing in complex with common reactive lymphadenopathies. The diagnostic value of routine immunohistochemical assessment for IgG4+ plasma cells in benign lymph nodes from pediatric patients without established extranodal IgG4-RD and/or other supportive clinical and laboratory data is therefore uncertain.

Minimal Change Disease Secondary to Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplant for Myelodysplastic Syndrome.

Chronic graft-versus-host disease (cGVHD) is a leading cause of non-relapse mortality in allogeneic hematopoietic cell transplant (HCT) recipients. While the current standard of care is proactive in detecting cGVHD in the lungs, liver, and skin, cGVHD involving kidneys is an underrecognized and likely underdiagnosed cause of post-HCT renal dysfunction. Nephrotic syndrome (NS) is a very rare complication of HCT that is postulated to be a glomerular manifestation of cGVHD. Herein, we report 2 cases of post-HCT minimal change disease likely secondary to cGVHD. In both cases, the onset of NS coincided with tapering of calcineurin inhibitors, and 1 patient had previously been diagnosed with cGVHD of the lungs. One patient was treated with corticosteroids alone and the other with a corticosteroids and tacrolimus. Complete, sustained remission was achieved in both cases. Our cases illustrate the implications of the association between cGVHD and post-HCT NS for patient care, including the importance of obtaining a renal biopsy to establish an accurate histopathological diagnosis and guide-appropriate treatment.

The cytologic and immunohistochemical findings of pancreatic mixed acinar-endocrine carcinoma.

BACKGROUND: The classification of epithelioid pancreatic neoplasms based on fine-needle aspiration (FNA) is important for proper management, as distinction of pancreatic neuroendocrine neoplasms from other similar appearing lesions can result in significantly different treatment. Mixed acinar-endocrine carcinomas (MAEC) are genetically related to acinar carcinomas and are treated as such. We reviewed cases of MAEC to better characterize their cytologic and immunohistochemical features. METHODS: Eight FNAs of MAECs were identified and reviewed. A chart review for each case was conducted. RESULTS: All patients were male, 42-68 years of age, and presented with either Stage 3 or 4 disease. Smear backgrounds of all cases showed naked nuclei without significant necrosis. The smears were cellular with cells arranged in either three-dimensional (3D) clusters with intervening capillaries or singly dispersed. Acinar formation was a prominent feature. Cells were round to oval with small to moderate amounts of delicate cytoplasm. The nuclei were round to oval with mild to moderate anisonucleosis with granular chromatin and small nucleoli. Apoptotic bodies and mitoses were noted in most cases, with Ki67 indices of 10%-48%. All tumors, by definition, demonstrated expression of trypsin and synaptophysin with variable chromogranin expression (50%). CONCLUSION: The cytology of acinar cell carcinoma shares features with aspirates of other nonductal adenocarcinoma neoplasms of the pancreas. A clue to the diagnosis is that tumors show high Ki67 indices and a diagnosis of MAEC should be excluded anytime a diagnosis of Grade 2 or 3 well-differentiated neuroendocrine tumor or high-grade neuroendocrine carcinoma is in the differential.

Myeloid Cell Infiltration Correlates With Prognosis in Cholangiocarcinoma and Varies Based on Tumor Location.

Cholangiocarcinoma (CC) is an uncommon malignancy with increasing incidence and dismal prognosis. We conducted a comprehensive analysis of the CC tumor immune microenvironment (TIME) based on tumor location to identify therapeutic targets. We hypothesized that the TIME of CC would vary by primary tumor location and that high tumor infiltration by CD8+ T cells and low infiltration by M2 macrophages would be associated with improved survival. A retrospective analysis was conducted of 99 CC tumor samples surgically resected between 2000 and 2014. Tissue microarrays were constructed from each tumor and stained by immunohistochemistry for 24 markers of immune cells, immune activation or inhibition, programmed cell death-ligand 1, and mesothelin. Most tumors were amply infiltrated with by CD4+, CD8+, and FoxP3+ T cells, as well as by myeloid cells. Mesothelin expression ≥1+ by immunohistochemistry was found in 68% of tumors. We identified higher densities of M1 macrophages in primary distal extrahepatic CC, as well as metastatic lesions. Mesothelin expression was also significantly higher in distal extrahepatic CC. There was no association with survival of infiltration by CD4+, CD8+, or FoxP3+ T cells, mesothelin expression, or programmed cell death-ligand 1 percentage expression, however, high CD14+ myeloid cells and high CD163+ M2 macrophages were associated with worse survival. In conclusion, the CC TIME is a heterogenous milieu highly infiltrated by innate and adaptive immune cells, which differs based on primary tumor location and between primary tumors and metastatic lesions. The correlation of intratumoral M2 macrophages and myeloid cells with a worse prognosis may suggest promising immunotherapeutic targets in CC.