Ahmed Alomari

Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment

This case report documents pseudoprogression in brain metastases treated with antibodies to PD-1. Use of immune checkpoint inhibitors in melanoma and other malignancies is increasing, making it important to recognize and treat effects unique to brain metastases. The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential. Cancer Immunol Res; 4(3); 179–82. ©2015 AACR.

Aldosterone stimulates fibronectin synthesis in renal fibroblasts through mineralocorticoid receptor-dependent and independent mechanisms

In addition to its role in regulation of salt transport in the kidney, the mineralocorticoid hormone aldosterone plays an independent role as a mediator of kidney injury and progression of chronic kidney disease. Studies in both animal models and patients have shown that aldosterone enhances the accumulation of extracellular matrix and progression of fibrosis in the kidney. However, the cellular mechanisms that lead to aldosterone-dependent fibrogenesis are poorly understood. In this study we find that aldosterone stimulates fibronectin synthesis through mineralocorticoid receptor (MCR) dependent activation of the c-Jun NH2-terminal protein kinase (JNK) and subsequent phosphorylation of the AP1 transcription factor c-jun, which forms a nuclear complex with the mineralocorticoid receptor in a kidney fibroblast cell line (NRK 49f). Furthermore, MCR-independent phosphorylation of Src family kinase induces IgF1 receptor phosphorylation, which leads to stimulation of the extracellular signal-regulated kinase (ERK1/2) to enhanced fibronectin synthesis. We further find that the IgF1-R-dependent signaling pathway activates fibronectin expression faster than the MCR-dependent pathway. We propose that the mechanisms described in this study are important to aldosterone-dependent progression of interstitial fibrosis in the kidney. Due to the duality of aldosterone-dependent activation of fibronectin synthesis in kidney fibroblasts, MCR-specific inhibitors may not entirely prevent the progression of fibrosis by aldosterone in the kidney.

Possible Interaction of Anti–PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases

Patients undergoing stereotactic radiosurgery for brain metastases may show unexpected effects in the lesions after treatment with antibodies to PD-1. Assessments of clinical and radiologic changes need accurate interpretation in this growing patient population. Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the brain. The interaction of these systemic therapies with other modalities of treatment for brain metastases, namely, SRS, has not been fully characterized. We report two patients with metastatic malignancies to the brain who received SRS followed by immunotherapy with monoclonal antibodies (mAb) to programmed death 1 (PD-1). Both patients appeared to have early clinical and radiologic progression of their treated lesions, which was highly suspicious for tumor progression. Both patients underwent surgical resection of their lesions and the material was submitted for histopathologic examination. Pathologic examination in both cases showed predominantly radiation-induced changes characterized by reactive astrocytosis and vascular wall infiltration by T lymphocytes. The accelerated response to SRS in these two patients was temporally related to the initiation of immunotherapy. We propose a possible biologic interaction between SRS and the PD-1 mAbs. Additionally, awareness of this potential occurrence is critical for accurate interpretation and proper management of clinical and radiologic findings in these patients. Cancer Immunol Res; 4(6); 481–7. ©2016 AACR.

Solitary and multiple tumors of follicular infundibulum: a review of 168 cases with emphasis on staining patterns and clinical variants

Tumor of the follicular infundibulum (TFI) is an uncommon benign adnexal tumor that usually presents as a solitary keratotic papule in the head and neck area. Infrequently, it may present as multiple lesions or in association with other conditions. Although it was initially described in 1961, the pathogenesis of this lesion is still controversial.

Performance of endoscopic ultrasound-guided fine needle aspiration in diagnosing pancreatic neuroendocrine tumors

Background: Pancreatic neuroendocrine tumors (PNETs) are rare tumors of the pancreas, which are increasingly diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In this retrospective study, we assessed the performance of EUS-FNA in diagnosing PNETs. Materials and Methods: We identified 48 cases of surgically resected PNETs in which pre-operative EUS-FNA was performed. The clinical features, cytological diagnoses, and surgical follow-up were retrospectively reviewed. The diagnostic performance of EUS-FNA was analyzed as compared to the diagnosis in the follow-up. The cases with discrepancies between cytological diagnosis and surgical follow-up were analyzed and diagnostic pitfalls in discrepant cases were discussed. Results: The patients were 20 male and 28 female with ages ranging from 15 years to 81 years (mean 57 years). The tumors were solid and cystic in 41 and 7 cases, respectively, with sizes ranging from 0.5 cm to 11 cm (mean 2.7 cm). Based on cytomorphologic features and adjunct immunocytochemistry results, when performed, 38 patients (79%) were diagnosed with PNET, while a diagnosis of suspicious for PNET or a diagnosis of neoplasm with differential diagnosis including PNET was rendered in the 3 patients (6%). One case was diagnosed as mucinous cystic neoplasm (2%). The remaining 6 patients (13%) had non-diagnostic, negative or atypical diagnosis. Conclusions: Our data demonstrated that EUS-FNA has a relatively high sensitivity for diagnosing PNETs. Lack of additional materials for immunocytochemical studies could lead to a less definite diagnosis. Non-diagnostic or false negative FNA diagnosis can be seen in a limited number of cases, especially in those small sized tumors.

p40 is a more specific marker than p63 for cutaneous poorly differentiated squamous cell carcinoma

Poorly differentiated squamous cell carcinoma (SCC) of the skin may pose a diagnostic challenge for pathologists. p40 is a recently introduced antibody that recognizes specific p63 protein isoforms and has shown superior results labeling non‐cutaneous SCC. We hypothesize that p40 may improve diagnostic accuracy of poorly differentiated SCC.

Composite Peripheral T-cell Lymphoma Not Otherwise Specified, and B-cell Small Lymphocytic Lymphoma Presenting With Hemophagocytic Lymphohistiocytosis:

We report a case of a 68-year-old female patient who developed hemophagocytic lymphohistiocytosis (HLH) secondary to peripheral T-cell lymphoma (PTCL) not otherwise specified (NOS) that developed in the setting of treatment-resistant B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL). The patient’s B-cell lymphoma had a good initial response to chemotherapy for 4 years, after which it became less responsive and was thought to have undergone transition to a higher-grade lymphoma. Different regimens of chemoradiotherapy were then tried with modest response until the patient presented 3 years later with signs and symptoms of HLH. The patient died 1 month later, and an autopsy was performed. Significant para-aortic lymphadenopathy and splenomegaly were found. Microscopic, immunohistochemical and molecular evaluations confirmed the presence of composite B-cell and T-cell lymphoma in the para-aortic enlarged lymph nodes. Bone marrow examination showed hemophagocytosis, and the liver demonstrated infiltration by activated macrophages with hepatocellular necrosis. This report highlights the importance of searching for a possible underlying T-cell lymphoma in light of HLH. Different theories have been proposed to explain the rare occurrence of concurrent B- and T-cell lymphomas, but the development of HLH in this patient highlights the importance of immune dysregulation as a proposed mechanism to explain some cases of composite lymphomas. A review of the literature and discussion of the relative merits of these hypotheses are presented in the context of this case.

Clinicopathological and immunohistochemical characteristics of papillary renal cell carcinoma with emphasis on subtyping.

Papillary renal cell carcinoma (PRCC), a morphologically and genetically distinct subtype of RCC, is morphologically separated into 2 subtypes for therapeutic and prognostic purposes. Type 2 tumors are generally believed to have a poorer prognosis than type 1 tumors. In spite of multiple studies, many clinicopathological issues about PRCC remain vague. We studied the clinicopathological features associated with type 1 versus type 2 PRCC, and we compared the immunohistochemical profiles in both subtypes of PRCC. We identified a total of 144 cases (74 type 1, 46 type 2, and 24 mixed), 29 female and 115 male. Mean age was 56 years for type 1 and 59 years for type 2. Mean tumor size was 3.6 cm for type 1 and 4.6 cm for type 2. Type 1 tumors were more likely to have nuclear grade 2 and less, whereas type 2 tumors were more likely to have nuclear grade 3 and above (P = .0001). There was no significant association between tumor type and renal sinus fat invasion, invasion of muscular branches of renal vein, perinephric fat invasion, microvascular angiolymphatic invasion, and main renal vein invasion. Type 2 tumors have higher nuclear grades than type 1 tumors. Based on long follow-up data, both subtypes appear to have excellent prognosis when diagnosed at early stage. The immunohistochemical profiles of both types 1 and 2 PRCC are essentially the same. The similar immunohistochemical profile suggests that PRCC is one entity with divergent histologic features.

Frequent KRAS mutation in complex mucinous epithelial lesions of the endometrium

KRAS mutation correlates with mucinous differentiation in various human cancers, and recently, was found in a high proportion of a small cohort of papillary mucinous lesions of the endometrium. In this study, a large number of endometrial mucinous lesions were analyzed for the presence of KRAS mutation along with clinical progression. A total of 45 endometrial biopsy/curettage cases were included in the study and classified into the following categories: simple mucinous change (5 cases), complex mucinous change (33 cases) and mucinous adenocarcinoma (7 cases). Follow-up hysterectomy specimens were available in 14 of 33 patients (42%) with complex mucinous lesions, of which 9 cases (64%) showed atypical complex hyperplasia with an average interval of 21 weeks. None of the 5 cases of simple mucinous change showed KRAS mutation. KRAS mutation was observed in 18 of 33 patients with complex mucinous lesions (55%) and in 6 of 7 cases of mucinous adenocarcinoma (86%). Overall, KRAS mutation has a positive predictive value (PPV) of 88% (7/8 cases) for complex atypical hyperplasia or adenocarcinoma in the follow-up hysterectomy. In conclusion, the current data further emphasizes the architectural complexity as an important prognostic indicator for patients with mucinous endometrial lesions. The presence of KRAS mutation in both mucinous adenocarcinoma and complex mucinous changes indicates that KRAS mutational activation is implicated in the pathogenesis of a significant subset of endometrial mucinous carcinoma. With a high PPV, KRAS mutation analysis may offer an additional discriminatory power to refine risk stratification algorithm for patients with endometrial mucinous lesions.

Endoscopic ultrasound-guided fine-needle aspiration diagnosis of secondary tumors involving the pancreas: An institution's experience

Background: Pancreatic masses may seldom represent a metastasis or secondary involvement by lymphoproliferative disorders. Recognition of this uncommon occurrence may help render an accurate diagnosis and avoid diagnostic pitfalls during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). In this study, we review our experience in diagnosing secondary tumors involving the pancreas. Materials and Methods: The electronic database of cytopathology archives was searched for cases of secondary tumors involving the pancreas at our institution and a total of 31 cases were identified. The corresponding clinical presentations, imaging study findings, cytological diagnoses, the results of ancillary studies, and surgical follow-up, if available, were reviewed. Results: Nineteen of the patients were male and 12 female, with a mean age of 66 years. Twenty-three patients (74%) had a prior history of malignancy, with the latency ranging from 6 months to 19 years. The secondary tumors involving the pancreas included metastatic carcinoma (24 cases), metastatic sarcoma (3 cases), diffuse large B-cell lymphoma (2 cases), and plasma cell neoplasm (2 cases). The most common metastatic tumors were renal cell carcinoma (8 cases) and lung carcinoma (7 cases). Correct diagnoses were rendered in 29 cases (94%). The remaining two cases were misclassified as primary pancreatic carcinoma. In both cases, the patients had no known history of malignancy, and no ancillary studies were performed. Conclusions: Secondary tumors involving the pancreas can be accurately diagnosed by EUS-FNA. Recognizing uncommon cytomorphologic features, knowing prior history of malignancy, and performing ancillary studies are the keys to improve diagnostic performance and avoid diagnostic pitfalls.