Combined hepatocellular-cholangiocarcinoma and its mimickers: Diagnostic pitfalls in surgical pathology.

BACKGROUND: The diagnosis of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) requires histomorphological detection of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). However, these primary liver cancers (PLCs) have a wide variety of microscopic appearances resulting in difficulties and uncertainties in cHCC-CCA's diagnosis. This study aims to perform a clinicopathologic analysis on the diagnosis of PLCs at a tertiary referral hospital in Thailand using traditional morphologic studies. METHODS: A 5-year retrospective analysis of pathologically diagnosed PLCs was conducted. Pathological features and clinical characteristics of cHCC-CCA and other PLCs with the histopathologic resemblance to cHCC-CCA were studied. The pathological diagnosis was rendered based on histomorphological context rather than immunoreactivity. A literature review containing diagnostic pitfalls of cHCC-CCA was carried out. RESULTS: PLCs from a total of 295 patients were retrieved, and cHCC-CCA accounted for 1.4% (n = 4) of the malignancies. Histomorphological evaluation is the most reliable diagnostic modality for cHCC-CCA. Extremely uncommon variants of iCCA (i.e., mucinous iCCA and adenosquamous iCCA) and iCCA arising with hepatocellular nodular lesions (i.e., iCCA with nodular regenerative hyperplasia (NRH), and iCCA in cirrhosis) could have a histomorphologic resemblance to that of cHCC-CCA. CONCLUSIONS: Although there has been an exceedingly high incidence of iCCA in Thailand, such a commonness is not valid for cHCC-CCA in our series. Rare forms of iCCA could have a morphologic resemblance to that of cHCC-CCA. Regardless of the differentiation and immunophenotype, iCCA without a distinct HCC component should never be diagnosed as cHCC-CCA.

PET/MRI and genetic intrapatient heterogeneity in head and neck cancers.

PURPOSE: The relation between functional imaging and intrapatient genetic heterogeneity remains poorly understood. The aim of our study was to investigate spatial sampling and functional imaging by FDG-PET/MRI to describe intrapatient tumour heterogeneity. METHODS: Six patients with oropharyngeal cancer were included in this pilot study. Two tumour samples per patient were taken and sequenced by next-generation sequencing covering 327 genes relevant in head and neck cancer. Corresponding regions were delineated on pretherapeutic FDG-PET/MRI images to extract apparent diffusion coefficients and standardized uptake values. RESULTS: Samples were collected within the primary tumour (n = 3), within the primary tumour and the involved lymph node (n = 2) as well as within two independent primary tumours (n = 1). Genetic heterogeneity of the primary tumours was limited and most driver gene mutations were found ubiquitously. Slightly increasing heterogeneity was found between primary tumours and lymph node metastases. One private predicted driver mutation within a primary tumour and one in a lymph node were found. However, the two independent primary tumours did not show any shared mutations in spite of a clinically suspected field cancerosis. No conclusive correlation between genetic heterogeneity and heterogeneity of PET/MRI-derived parameters was observed. CONCLUSION: Our limited data suggest that single sampling might be sufficient in some patients with oropharyngeal cancer. However, few driver mutations might be missed and, if feasible, spatial sampling should be considered. In two independent primary tumours, both lesions should be sequenced. Our data with a limited number of patients do not support the concept that multiparametric PET/MRI features are useful to guide biopsies for genetic tumour characterization.

Renal cell carcinoma metastatic to a pituitary FSH/LH adenoma: case report and review of the literature.

Abstract Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/α-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma.

[Mucocele of the appendix - a heterogenous surgical pathology]. / Die Mukozele der Appendix - eine inhomogene chirurgische Krankheitsentität.

BACKGROUND: Mucoceles of the appendix are rare. After appendectomy, mucoceles are detected with a frequency of 0.2 to 0.3 %. Both stenosing / obliterating processes and alterations of the epithelium (hyperplasia, mucinous cystadenoma, cystadenoma with uncertain malignant potential (UMP), mucinous cystadenocarcinoma lead to the occurrence of mucoceles. The perforation of a mucocele with possible spread of mucus and cells into the abdominal cavity constitutes a severe complication (pseudomyxoma peritonei). Surgical resection is the curative approach for mucoceles of the appendix. MATERIALS AND METHODS: Data of patients who were treated for an appendiceal mucocele between 1995 and 2009 were analysed retrospectively with regard to clinical presentation, diagnostic measures, surgical procedure and histopathological result. Follow-up was evaluated in telephone interviews. RESULTS: We extracted 5 cases from our database. Clinical symptoms varied greatly among the individual patients, ranging from peracute abdominal pain in the right lower quadrant to chronic obstipation. Results from abdominal ultrasound and / or abdominal CT scans contributed to the indication for surgical intervention in all cases. In 2 patients surgery was stated as urgent whereas in 3 the operation was scheduled electively. In one patient the diagnosis of an appendiceal mucocele was stated preoperatively and in another intraoperatively. In 3 patients only the histopathological result revealed the underlying mucocele. We performed 1 open and 1 laparoscopic appendectomy, 1 open appendectomy with a partial resection of the coecum and 2 laparoscopic ileocoecal resections. One of the patients had a pseudomyxoma peritonei. The histopathological diagnoses ranged from mere epithelial hyperplasia to an adenoma with uncertain malignant potential and a mucinous cystadenocarcinoma. One patient's long-term follow-up could not be evaluated. All other patients had neither recurrence nor any complications after discharge. CONCLUSIONS: Mucoceles of the appendix present with a wide spectrum of clinical symptoms and histopathological alterations. Only an accurate histological analysis reveals the underlying pathological lesion correctly. This study emphasises that a mucocele of the appendix constitutes an important differential diagnosis in patients presenting with pathologies in their right lower abdominal quadrant.

Chorangiocarcinoma: a case report and review of the literature.

Chorangiocarcinoma is the name designated to a chorangioma with trophoblastic proliferation manifesting increased proliferative activity. Only 3 such cases have been published so far. Other studies challenged this entity by demonstrating that proliferation of the trophoblast around chorangioma is a common phenomenon. We present a case of a unique vascular lesion in a term placenta with a malignant trophoblastic component. Microscopic examination of a well-demarcated placental mass revealed a chorangioma with multiple nodules composed of pleomorphic cells displaying focal multinucleation, large areas of necrosis, and high mitotic activity. Immunohistochemical stains of these cells were strongly positive for pancytokeratin and the beta subunit of human chorionic gonadotropin and focally positive for HSD3B1. There was no invasion of the basement membrane, and no free-floating tumor cells in the intervillous space. No evidence of metastasis was found on follow-up of the mother and newborn. It is concluded that the tumor presented herein, displaying a histologically unequivocal malignant trophoblastic component in a benign chorangioma, is a true chorangiocarcinoma, and should be included within the category of gestational neoplasia as a tumor closely related to choriocarcinoma.

Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study.

Subependymal giant-cell astrocytoma (SEGA) is a rare intra-ventricular low-grade tumor which frequently occurs as a manifestation of tuberous sclerosis complex. The histogenesis of SEGA is controversial and its astrocytic nature has been doubted. First studies suggested the astrocytic nature of SEGA while several recent reports demonstrate its glio-neuronal nature. In spite of this, in the recently revised WHO classification of the CNS tumors, SEGA has been still included in the group of astrocytomas. We studied nine tuberous sclerosis complex-associated SEGAs. Patients were 1-18 years old. Eight patients (89%) had a solitary lesion located in the lateral ventricle close to of the head of the caudate nucleus, the remaining patient (11%) had two tumors, one located close to the head of the left caudate nucleus and the other in the central part of the right lateral ventricle. Histologically, tumors were composed of three types of cells: spindle, gemistocytic and ganglion-like. Four tumors (44%) had a prominent vascularization and three (33%) showed an angiocentric pattern. Calcifications were observed in six cases (66%). By immunohistochemistry, the majority of the tumors were GFAP- (9; 100%), neurofilament- (8, 89%), neuron-specific enolase- (9, 100%), and synaptophysin- (8; 89%) positive. Ultrastructural studies were performed on four cases. In all four there were glial cell processes filled with intermediate filaments. In one case dense core putative neurosecretory granules were appreciable. Our results emphasize the glio-neuronal nature of SEGA. We suggest moving it into the group of mixed glio-neuronal tumors under the denomination of subependymal giant cell tumor.

Effect of primary site on prognosis in patients with cutaneous malignant melanoma. A study using a new model to analyse anatomical locations.

The prognostic impact of different anatomical sites in patients with cutaneous malignant melanoma (CMM) has been widely debated and requires further elucidation. Therefore, we developed EssDoll, a new computerized method to address the question of site in relation to prognosis. A population-based cohort of 1891 patients, diagnosed between 1976 and 1987 with invasive CMM without evidence of metastasis, was identified. The body surface was divided into 24 areas. Hazard ratios (HRs) for CMM death were calculated and areas were compared in both the whole model and in pairs. Cox's proportional hazard regression model was used and adjustments were made for established prognostic factors. Furthermore, the overall effect of site was calculated using the likelihood ratio test. Overall, the tumour site was of prognostic importance (P=0.0036). There was a significantly increased risk of CMM-specific death in patients with a primary tumour site in the middle and lower back (HR=1.8, P=0.04) and in the supramammary and mammary area (HR=1.8, P=0.05). When all areas were analysed in pairs, the dorsal shoulder, superior back and clavicular area also showed a worse prognosis. CMM diagnosed in other anatomical regions, including the calves, Achilles, upper arms, forehead, temples, cheeks and face, seemed to be related to a better prognosis. It can be concluded that the tumour site is of prognostic importance, and that the middle and lower back and supramammary and mammary areas are independent factors related to a poor prognosis.

Pulmonary metastatic leiomyosarcoma coexisting with pulmonary chondroma in Carney's triad.

The diagnosis of Carney's triad requires the coexistence of at least two of three rare disorders, including gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma. Seventeen cases have been reported so far, occurring predominantly in young female patients. We report herein the 18th case of this entity and the first case, to our knowledge, where pulmonary metastases from a gastric leiomyosarcoma coexisted in a patient with benign pulmonary chondromas.

Multiple trichoepitheliomas in an alpaca (Lama pacos).

A 13-yr-old male Alpaca (Lama pacos) presented with multiple ovoid, well-circumscribed, nonulcerated intradermal masses. Individual masses measured 1-4 cm in diameter, and the overlying skin was alopecic. Several of the masses were surgically removed and evaluated microscopically. Histopathologic evaluation demonstrated multiple dermal cysts lined by neoplastic follicular epithelium. The cysts were filled with multiple layers of lamellar keratin and lined by abortive inner and outer root sheaths exhibiting cellular atypia, supporting the diagnosis of trichoepitheliomas. No additional treatment was initiated, and the alpaca continues to do well.

Bronchioloalveolar cell adenomas.

In a series of 247 consecutive resections for lung carcinoma, 23 (9.3%) patients had a total of 41 incidentally found nodules measuring 1-7 mm in diameter. These lesions were characterized histologically by lepidic growth and variable cellular atypia; they were interpreted as bronchioloalveolar adenomas. Five additional patients had dozens of such nodules in addition to their dominant tumor. One of these patients had this process bilaterally. It appears that these adenomas are an early, premalignant phase of glandular neoplasia with a potential for evolution to carcinoma. This phenomenon may help explain the relatively high incidence of multicentric synchronous and metachronous lung cancer cited in the literature.

Small-cell undifferentiated carcinoma of the colon. A clinicopathological study of five cases and their association with colonic adenomas.

Colonic small-cell undifferentiated carcinoma (SCUC) is an extremely aggressive neoplasm. We describe five patients with colonic SCUC and review five additional, well-documented cases. The longest known duration of survival is 14 months and all patients with follow-up of this duration have died of disease. Regional lymph nodes are invariably involved at the time of diagnosis and when distant metastases were present, the liver was always affected. Four of our cases of SCUC arose in association with colonic adenomas and in two of these the SCUC component was confined to the superficial submucosa. Yet, both produced regional metastases and one had massive hepatic involvement. Ultrastructurally, colonic SCUC exhibits divergent, predominantly neuroendocrine differentiation. The ultrastructural features and association with colonic adenomas suggest an endodermal rather than neuroectodermal derivation.

Mixed acinar-endocrine carcinomas of the pancreas.

Acinar cell carcinoma is a rare pancreatic neoplasm that may contain scattered endocrine cells in as many as 40% of cases. In addition, unusual tumors exist in which the acinar and endocrine components each constitute a significant proportion (> 25%) of the neoplasm; we propose to designate them as "mixed acinar-endocrine carcinomas." In a study of five such cases, we found one case with segregated areas of acinar and endocrine cells that were identifiable in routinely stained sections and four cases with morphologically uniform cell populations where the divergent differentiation was only detected immunohistochemically. The tumors occurred in adults (age range, 48-81; mean, 68); there were two men and three women. None of the patients presented with symptoms related to either enzyme or hormone liberation. Histologically, the tumors were very cellular; various combinations of solid, trabecular, acinar, and glandular growth patterns were noted. The cells contained d-PAS-positive granules and showed immunohistochemical positivity for pancreatic enzymes (trypsin, chymotrypsin, and lipase) and endocrine markers (chromogranin and synaptophysin); specific endocrine hormones were found in two cases. Double immunohistochemical staining for acinar and endocrine markers showed that most cells expressed only one line of differentiation. Ultrastructural study of two cases showed two populations of granules. Two of the patients died of their tumors (mean survival, 10.5 months), one with widespread metastases. Two patients were alive with disease at 12 months after diagnosis, and one patient was lost to follow-up after 3 months. This rare type of pancreatic neoplasm provides further evidence of the close histogenetic relationship between the exocrine and endocrine components of this organ.

Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2.

We studied the gross and microscopic pathology of the adrenal gland in 69 cases of sporadic phenochromocytoma in order to develop a profile of the neoplasm to compare with that of pheochromocytoma observed in the syndrome of multiple endocrine neoplasia, type 2 (MEN 2). The results showed that sporadic pheochromocytoma was a unicentric (93%), unilateral (100%) neoplasm, which was associated with normal extratumoral adrenal medulla (100%). The findings contrast with those encountered in the adrenal gland in MEN 2, in which the tumor involvement is frequently multicentric, usually bilateral, and associated with extratumoral medullary hyperplasia in cases of early involvement. Therefore, the interpretation of the results of pathologic examination of a pheochromocytoma should be immediately communicated to the surgeon.

Leiomyoblastomas and their relationship to other smooth-muscle tumors of the gastrointestinal tract. An electron-microscopic study.

Twelve cases of gastrointestinal leiomyoblastoma were studied by electron microscopy, and the findings were compared with those in 12 cases of leiomyoma and nine cases of leiomyosarcoma of the gastrointestinal tract. All of the "classic" ultrastructural features of smooth-muscle tumors, including subplasmalemmal dense patches, pinocytotic vesicles, cytoplasmic microfilaments and dense bodies, and focal basement membrane formation, were present in the leiomyoblastomas ; however, extensive sampling was commonly necessary to demonstrate such findings. In contrast, these features were more prominent in leiomyomas and leiomyosarcomas.

Thorotrast-associated hepatic leiomyosarcoma and cholangiocarcinoma in a single patient.

A 66-year-old man developed two distinct primary malignant hepatic neoplasms (leiomyosarcoma and cholangiocarcinoma) 50 years after Thorotrast administration. This is the first case report of Thorotrast-associated primary hepatic leiomyosarcoma. Ultrastructural and immunohistochemical studies are discussed.

Small cell undifferentiated carcinoma of the colon associated with hepatocellular carcinoma in an immunodeficient patient.

Small cell undifferentiated carcinoma (oat cell carcinoma) is a malignant epithelial neoplasm with neuroendocrine features. It can appear as a primary tumor in many organs besides the lung, including the colon. We report a case of primary small cell undifferentiated carcinoma of the left colon with omental metastases in a 23-year-old man with a history of X-linked hyper-IgM syndrome. The patient had a simultaneous primary hepatocellular carcinoma. A literature review of this rare colonic malignancy is presented together with a discussion of the possible relationship of this tumor with hepatic malignancy and immunodeficiency.

Multifocal choroidal melanoma in ocular melanocytosis.

A 29-year-old white women had ocular melanocytosis with scleral pigmentation and a diffuse choroidal nevus. The eye was enucleated because of two choroidal tumors. Light and electron microscopy showed two separate choroidal melanomas with differential cytologic characteristics. The extreme rarity of multicentric choroidal melanomas support the belief that ocular melanocytosis predisposes to malignancy.

Leiomyomatosis peritonealis disseminata. An ultrastructural study.

Electron microscopic features of the eighth documented case of leiomyomatosis peritonealis disseminata identify the main proliferative cell type as a mature leiomyocyte with all its associated ultrastructural features. The histogenesis of this neoplasm is considered to be a multicentric metaplastic change determined by an abnormal tissue response to the elevated hormonal levels occurring in pregnancy or ovarian functioning tumors. It is suggested that the cell of origin is the multipotent subcelomic mesenchymal cell, which retains the capacity to differentiate into several tissues, among them smooth muscle. To illustrate this possibility, myofibroblasts, cells with hybrid characters of fibroblasts and leiomyocytes, were observed; these may represent a transitional stage between the mesenchymal cell and the smooth muscle proliferating cell.

The significance of cytoplasmic chondrocyte inclusions in multiple osteochondromatosis, solitary osteochondromas, and chondrodysplasias.

Lesions from two patients with multiple osteochondromas and from three patients with solitary osteochondromas were studied. The histologic and ultrastructural features in both conditions were identical. The chondrocyte population in osteochondromas resembled those in normal hyaline cartilage but the cells in osteochondromas exhibited an accumulation of granular and filamentous materials within markedly dilated cisterns of ergastoplasm. These accumulations formed eosinophilic cytoplasmic inclusions which did not stain with Alcian blue, but were PAS positive after diastase digestion. Chondrocytic inclusions of similar or diverse morphology are found in a number of chondrodysplasias. The findings suggest that the solitary osteochondromas, like the lesions of multiple osteochondromatosis, share a common morphologic feature with the chondrodysplasias.