Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas.

Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.

Nasal Fibrolipomatous Hamartoma, an Idiosyncratic Connective Tissue Malformation in an Infant.

We describe a congenital mass in the nasopharynx of an infant presenting with dyspnea and feeding difficulties. Magnetic resonance imaging demonstrated 2 separate polypoid nasal cavity masses that were endoscopically resected. Histologically, both lesions were composed of mature adipose tissue with broad fibrous bands and several foci of brown fat. PLAG-1 and HMGA-2 were negative by immunostains. The best diagnosis was a fibrolipomatous hamartoma.

The clinical spectrum of fetal Niemann-Pick type C.

Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.

Leiomyosarcoma of the parapharyngeal space: a very rare entity.

Leiomyosarcoma of the head and neck is very rare, as only about 100 cases have been reported; of these, only 3 cases have been previously reported in the parapharyngeal space. We report the fourth such case, and we review the features of this entity. The patient was an 84-year-old woman who presented to the emergency department for treatment of an 18-month history of right-sided headache, a 6-month history of right-sided hearing loss and nasal obstruction, and a 2-month history of dysphagia. Physical examination revealed a bulge in the right side of the soft palate and the right lateral nasopharyngeal wall and complete obstruction of the right eustachian tube. Indirect laryngoscopy detected a bulge in the right lateral hypopharyngeal wall. Otoscopy revealed otitis media with effusion in the right ear. Imaging demonstrated a space-occupying lesion in the right parapharyngeal space that extended from the base of the skull to the level of the hypopharynx. Biopsy and histology identified the mass as a leiomyosarcoma. Metastasis to the brain was discovered shortly thereafter, and the patient died 10 months later. The unusual presentation of head and neck leiomyosarcoma requires a high index of suspicion and appropriate diagnostic imaging. Surgical excision is the recommended treatment when feasible; chemoradiotherapy does not appear to affect disease progression.

Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2.

We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.

Chorioangioma and its severe infantile sequelae: case report.

OBJECTIVE: This case report describes a rare clinical presentation of chorioangioma diagnosed prenatally because of raised-maternal serum (MS) alpha-fetoprotein. METHODS: A thirty-year-old woman gravida 2, para 1 was referred to the ultrasound unit at 18 weeks of gestation because of abnormal MS triple-test results. This included AFP level of 14.9 MoM; hCG of 3.42 MoM and uE3 of 1.01 MoM. A detailed anomaly scan revealed a singleton fetus with no sonographically detectable malformations and normal amniotic fluid. The placenta was posterior. A well-circumscribed, rounded, predominantly hypoechoic lesion near the chorionic surface measuring 5 x 5 cm and protruding into the amniotic cavity was detected. Color Doppler sonogram showed no blood flow within the mass, but clear fetal waveforms in its periphery were demonstrated, and the diagnosis of chorioangioma was made. The pregnancy was followed uneventfully until 35 weeks of gestation when polyhydramnios and severe fetal cardiomegaly developed. Labor was therefore induced. RESULTS: A euploid female, who had multiple diffuse cutaneous and liver angiomatosis was born. She died at the age of one month because of cardiac failure and infection. CONCLUSIONS: The present case alerts to the interrelationship between placental and fetal angiomas. This may lead to severe infantile sequelae because of similar lesions.