Glutamine Synthetase Immunoreactivity in Peritumoral Hyperplasia in Liver: Case Report of a Metastatic Paraganglioma With Focal Nodular Hyperplasia-Like Changes and Review of an Additional 54 Liver Masses.

OBJECTIVES: Focal nodular hyperplasia (FNH) and peritumoral hyperplasia in the liver exhibit increased immunoreactivity for glutamine synthetase (GS). We observed FNH-like changes with map-like GS staining surrounding a metastatic paraganglioma and sought to determine how often such changes occur around primary and metastatic liver lesions. METHODS: We performed GS immunohistochemistry in liver cases of 20 metastatic neuroendocrine carcinomas (NECs), 21 metastatic colon carcinomas (CCs), seven hepatocellular carcinomas (HCCs), and six FNHs and assessed lesions for size, degree of fibrosis (scored 1-3), and peritumoral hyperplasia. RESULTS: Most NEC or CC cases had few peritumoral hyperplastic features. Three NECs, two CCs, and one HCC (13%) had patchy GS staining at the periphery of the lesions. One CC case had both histologic and immunohistochemical peritumoral hyperplasia. CONCLUSIONS: Peritumoral hyperplasia or FNH-like changes are uncommon findings around primary or metastatic lesions in the liver. GS immunohistochemistry assists in distinguishing true peritumoral hyperplasia from mass effect.

An update on clinicopathological, immunohistochemical, and molecular profiles of colloid carcinoma of the lung.

Colloid carcinoma is a rare subtype of lung adenocarcinoma characterized by abundant pools of extracellular mucin and scant malignant epithelium. Because of the rarity of these tumors, many of the reported clinicopathological and immunohistochemical characteristics are contradictory. Moreover, the molecular alterations that underlie these tumors are unknown. We present the clinicopathological, immunohistochemical, and molecular features of 13 cases of colloid carcinoma of the lung. The patients were 9 women and 4 men between the ages of 48 and 86 years. Surgical resection and staging were performed in all patients. Seven patients were in stage T1N0M0, 3 in T2N0M0, 2 in T2N1M0, and 1 in T2N0M1. The tumor was 100% mucinous in 9 patients, whereas in 4 cases, the lesions consisted of 50% to 90% mucin pools with the remainder being a noncolloid adenocarcinoma component ranging in morphology from bronchioalveolar to acinar, papillary, solid, or mixed patterns. Follow-up ranged from 35 to 128 months. Three patients died, 1 of disease and 2 of unrelated causes. The remaining 10 patients are alive at the time of reporting, 3 with recurrent disease. Immunohistochemical studies showed CK7, CK20, and CDX2 expression in all tumors, whereas TTF-1, surfactant A, and napsin A were not present or were only focally positive in most cases. Analysis showed KRAS mutations in 2 cases. All tumors were negative for ALK gene rearrangement and EGFR mutation. Our study highlights the clinicopathological, immunohistochemical, and molecular features of lung colloid adenocarcinoma and attempts to clarify some misconceptions regarding this rare tumor.

Stemness characteristics of fibrolamellar hepatocellular carcinoma: immunohistochemical analysis with comparisons to conventional hepatocellular carcinoma.

The involvement of cancer stem cells (CSC) in tumorigenesis has been studied in several malignancies, but their presence in fibrolamellar hepatocellular carcinoma (FLHCC) has not previously been evaluated. General characteristics of "stemness" include the expression of putative stem cell antigens, reduced cell cycle progression, and limited functional differentiation or dedifferentiation under the influence of the microenvironment. Immunohistochemical probes applied to 8 archival cases of FLHCC vis-à-vis contiguous non-neoplastic parenchyma, which was present in 5 cases, revealed such stemness characteristics by showing: (a) stem cell antigens, with moderate to intense expression of CD133 in the cytoplasm (6 of 8 FLHCC cases and comprising >40% of the tumoral areas) and of CD44 on the plasmalemmal aspect (7 of 8 FLHCC cases and comprising 50 to 95% of the tumor cells), vs foci of such overexpressions in only 1 of 5 of the contiguous liver parenchyma (p = 0.053 and p = 0.015, respectively); (b) limited G1 to S phase progression ( <1 % of tumor cells with nuclear S phase kinase-associated protein [Skp]2 expression); and (c) dedifferentiation or reduced functional differentiation in the form of minimal to absent expression of a differentiation-associated marker, peroxisomal proliferator-activator receptor (PPAR)-gamma in tumoral nuclei and loss of plasmalemmal expression of beta-catenin in 6 of 8 FLHCC cases vs expression of these proteins in the non-neoplastic, differentiated hepatocytes in 5 of 5 and 4 of 5 cases, respectively, in contiguous liver parenchyma (p <0.01 and p = 0.053, respectively). In contrast, only 1 of 11 cases of well-differentiated, conventional hepatocellular carcinoma (HCC) showed mild to moderate expression of CD133 in the cytoplasm, but with the majority (8 of 11) showing occasional nuclear expression. Similarly, only 3 of 11 cases of conventional HCC expressed plasmalemmal CD44. Notably, 11 of 11 cases of conventional HCC expressed beta-catenin on the plasmalemmal aspect of the tumor cells, and 3 of 11 showed nuclear translocation. These findings in conventional HCC were significantly different from those in FLHCC (p = 0.003, 0.009, and 0.0005, respectively). This study provides evidence of stemness in FLHCC and discusses the implications of stemness in the histogenesis of FLHCC vs conventional, well-differentiated HCC.

Morphoproteomic confirmation of constitutively activated mTOR, ERK, and NF-kappaB pathways in Ewing family of tumors.

In 3 patients with the Ewing family of tumors (EFT), morphoproteomic analyses of the tumors revealed constitutive activation of the mTOR, ERK, and NF-kappaB pathways, as evidenced by: (a) expression of phosphorylated (p)-mTOR, p-p70S6K, p-ERK 1/2, and p-NF-kappaB proteins using phosphospecific immunohistochemical probes directed against the activation sites; (b) nuclear translocation of p-p70S6K, p-ERK 1/2, and p-NF-kappaB p65; and (c) correlative expression of Ki-67 and Skp2 proteins consistent with cell cycling consequent to signal transduction by these pathways of convergence. This study examines the cytogenetic and molecular correlates and provides insight into therapeutic strategies relevant to this morphoproteomic profile. Based on a literature review, these observations appear to be the first morphoproteomic study of such pathways of convergence in tumors from EFT patients.

Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) is an aggressive neoplasm due to high frequency of recurrence after surgical resection and resistance to chemotherapy and radiation therapy. Activation of transcription factor NF-kB signaling pathway has been recognized for involvement in progression of various malignant neoplasms. The role of NF-kB pathway in FLHCC has not been studied to date. Formalin-fixed, paraffin-embedded tissue sections of 8 FLHCC, 10 normal liver tissues (NLT) were evaluated immunohistochemically for the expression of p-NF-kBp65 using phosphospecific antibody directed against phosphorylated (p)-NF-kBp65 (Ser 536). The level of p-NF-kBp65 (Ser 536) expression was categorized into four grades: 0 (background), 1+ (weak), 2+ (moderate), or 3+ (strong) based on intensity of intranuclear staining, and was further assessed using two scales: high expression (2+ or 3+) and low expression (0 or 1+). Only high expression of p-NF-kBp65 (Ser 536) in cells with nuclear translocation was considered as constitutive NF-kB activation. High expression of p-NF-kBp65 (Ser 536) was found in 88 % (7/8) of FLHCC tissue. In contrast, only 10 % (1/10) of NLT showed high expression for p-NF-kBp65 (Ser 536). The differences in p-NF-kBp65 nuclear expression between FLHCC tissue and NLT were significant (P < 0.001). There was no significant correlation between the expression of intranuclear p-NF-kBp65 and the stage of FLHCC. Constitutive NF-kB activation was observed in FLHCC. The findings suggest that NF-kB activation is involved in the tumorigenesis of FLHCC and may represent novel targets for therapeutic intervention to FLHCC.