Molecular Profiling of a Hepatocellular Neoplasm Not Otherwise Specified (HCN-NOS) Demonstrates Distinct Molecular Features in Hepatoblastoma and HCC-Like Components.

Hepatoblastomas (HB) are embryonal tumors with quiet genomes diagnosed mostly in children under 3 years of age and often cured by surgical resection and chemotherapy. However, a subset of HBs behave aggressively, displaying characteristic histologic features and higher genomic instability. Hepatocellular neoplasm-not otherwise specified (HCN-NOS) is a provisional diagnostic category for tumors exhibiting either intermediate or a combination of both HB and hepatocellular carcinoma (HCC) histological features. In this study, we characterized an HCN-NOS diagnosed in a 3-year-old patient presenting with a liver mass, in which both HB and HCC histological components were amendable to macro-dissection and molecular profiling. The spectrum of mutations, copy number changes, mRNA, and protein expression profiles within these 2 histologically distinct tumor areas demonstrate molecular heterogeneity and suggest intratumoral clonal evolution of this hepatocellular CTNNB1-mutant lesion.

Metastatic prostate adenocarcinoma and high-grade appendiceal mucinous neoplasm mimicking acute appendicitis in a post-radiation therapy patient.

Prostate cancer is the most common visceral malignancy diagnosed in males. Surveillance for post-treatment neoplasms is very crucial. Here we report the first case of recurrent metastatic prostate cancer presenting as acute appendicitis in a background of a high-grade appendiceal mucinous neoplasm. In addition, this case also includes an unusually early presentation of a secondary primary malignancy after radiation therapy. A 70-year-old male with a history of prostate adenocarcinoma status post-proton radiation therapy presented with recurrent poorly differentiated prostate adenocarcinoma with disease progression and extra-prostatic extension. He underwent salvage proton therapy and testosterone replacement therapy. Two years later, the patient presented with right lower quadrant pain. A computed tomography scan showed perforated acute appendicitis with intra-abdominal abscess, which was treated with interval appendectomy. Upon histologic analysis, metastatic prostatic adenocarcinoma was noted in the appendiceal wall and mesoappendix. In addition, an incidental background of high-grade appendiceal mucinous neoplasm was found. Four months later, he presented with persistent abdominal pain, rapid weight loss, fatigue, and fever for 3 months. An abdominal CT scan revealed a 6.1 cm rectal mass. Pathologic analysis diagnosed an aggressive post-radiation spindle cell sarcoma, intermediate to high grade. The patient opted for palliative care. This case shows that a clinical presentation of acute appendicitis in an older patient may sometimes portend a neoplastic rather than infectious etiology. Clinical history and patient epidemiology should always be considered when evaluating an older patient with clinical signs and symptoms of acute appendicitis.

Severe chronic bowel obstruction associated with brown bowel syndrome.

A 61-year-old alcoholic male with history of cholecystectomy presented with a 20-year history of recurrent bowel obstruction and a 30 lb weight loss. After numerous attempts at conservative management, exploratory laparotomy was performed, which showed no mechanical cause. Despite no clear etiology, the obstruction persisted and intensified. A follow-up computed tomography scan revealed a small bowel obstruction with concurrent megacolon. A total abdominal colectomy was performed, with ileostomy. Grossly, there was intestinal dilation up to 15 cm with prominent brown discoloration of bowel wall. No strictures or other fixed obstruction were identified. Microscopic examination revealed prominent lipofuscin-like pigment deposition, involving the muscularis propria, muscularis mucosae, and vascular smooth muscle. Histochemical staining was positive for periodic acid-Schiff and negative for iron and calcium, consistent with lipofuscin. The gross and histologic findings fit with brown bowel syndrome. Brown bowel syndrome is a very rare condition characterized by lipofuscin deposits predominantly within the smooth muscle of the muscularis mucosae and/or muscularis propria that imparts a brown color to the bowel. It is generally thought to be a smooth muscle mitochondrial myopathy due to chronic vitamin E deficiency secondary to fat malabsorption syndromes, resulting in free radicals causing peroxidation of unsaturated membrane lipids with accumulation of lipofuscin. Brown bowel syndrome may be seen in patients with alcohol abuse, maldigestion, chronic bowel inflammation, and intestinal lymphangiectasia. Our patient's severe chronic intestinal pseudo-obstruction, low levels of certain fat-soluble vitamins (A, D, and E), significant weight loss and history of cholecystectomy with alcohol abuse correlates with brown bowel syndrome clinically.

Differential MicroRNA-Signatures in Thyroid Cancer Subtypes.

Thyroid cancer is one of the most common endocrine cancers, with an increasing trend in the last few decades. Although papillary thyroid cancer is the most frequent subtype compared with follicular or anaplastic thyroid cancer, it can dedifferentiate to a more aggressive phenotype, and the recurrence rate is high. The cells of follicular adenomas and follicular carcinomas appear identical in cytology, making the preoperative diagnosis difficult. On the other hand, anaplastic thyroid cancer poses a significant clinical challenge due to its aggressive nature with no effective therapeutic options. In the past several years, the roles of genetic alterations of thyroid tumors have been documented, with a remarkable correlation between genotype and phenotype, indicating that distinct molecular changes are associated with a multistep tumorigenic process. Besides mRNA expression profiles, small noncoding microRNA (miRNA) expression also showed critical functions for cell differentiation, proliferation, angiogenesis, and resistance to apoptosis and finally activating invasion and metastasis in cancer. Several high-throughput sequencing studies demonstrate that miRNA expression signatures contribute clinically relevant information including types of thyroid cancer, tumor grade, and prognosis. This review summarizes recent findings on miRNA signatures in thyroid cancer subtypes.

Regional Lymph Node Enlargement in Clinically Severe Cherubism.

Cherubism is a rare benign autosomal dominant disorder characterized by progressive, painless, bilateral enlargement of the mandible and/or maxilla because of bone replacement by fibrotic stromal cells and osteoclast-like cells forming multilocular cysts. The lesions typically stabilize and regress after puberty. We present a 14-year-old male with severe familial cherubism. Bilateral mandibular enlargement began around age 4 and progressed until puberty, affecting his speech and mastication without subsequent involution. Composite mandibulectomy and mandible reconstruction with fibula free flap technique improved functionality and cosmesis. Histology was consistent with the diagnosis of cherubism, showing large areas of bland spindle-cell fibrous tissue and moderately abundant collagen and multiple nodules of giant cell-rich tissue resembling central giant cell granuloma. Regional lymph nodes were sampled due to enlargement, demonstrating hemosiderin-laden macrophages and basophilic laminated concretions localized to the cortical interfollicular space and along the peripheral follicular marginal zone, findings which have not been previously reported.

Chronic oxidative stress increases the integration frequency of foreign DNA and human papillomavirus 16 in human keratinocytes.

Cervical cancer is the second most common cancer, and the fourth most common cause of cancer death in women worldwide. Nearly all of these cases are caused by high-risk HPVs (HR HPVs), of which HPV16 is the most prevalent type. In most cervical cancer specimens, HR HPVs are found integrated into the human genome, indicating that integration is a key event in cervical tumor development. An understanding of the mechanisms that promote integration may therefore represent a unique opportunity to intercept carcinogenesis. To begin identifying these mechanisms, we tested the hypothesis that chronic oxidative stress (OS) induced by virus- and environmentallymediated factors can induce DNA damage, and thereby increase the frequency with which HPV integrates into the host genome. We found that virus-mediated factors are likely involved, as expression of E6*, a splice isoform of HPV16 E6, increased the levels of reactive oxygen species (ROS), caused oxidative DNA damage, and increased the frequency of plasmid DNA integration as assessed by colony formation assays. To assess the influence of environmentally induced chronic OS, we used L-Buthionine-sulfoximine (BSO) to lower the level of the intracellular antioxidant glutathione. Similar to our observations with E6*, glutathione depletion by BSO also increased ROS levels, caused oxidative DNA damage and increased the integration frequency of plasmid DNA. Finally, under conditions of chronic OS, we were able to induce and characterize a few independent events in which episomal HPV16 integrated into the host genome of cervical keratinocytes. Our results support a chain of events leading from induction of oxidative stress, to DNA damage, to viral integration, and ultimately to carcinogenesis.