Immunohistochemical and Ultrastructural Investigation of Neural Differentiation in Ewing Sarcoma/PNET of Bone and Soft Tissues

The authors evaluated the role of immunohistochemistry and electron microscopy in defining neural differentiation in 28 cases of Ewing sarcoma/ PNET. The panel of primary antibodies used included vimentin, MIC-2, NSE, S-100 protein, leu7, neurofilaments, GFAP, and chromogranin A. Cases were considered undifferentiated when neural markers were absent, poorly differentiated if one neural marker was present, and well differentiated if two or more markers were observed. Cases were also evaluated for the presence of cytoplasmic processes, microtubules, and neurosecretory granules as ultrastructural features of neural differentiation: the tumor was classified as well differentiated if two of these features were present; and poorly differentiated if one was evident; all other cases were considered undifferentiated. According to immunohistochemistry, 10 cases (35.7%) were undifferentiated, 12 cases (42.9%) were poorly differentiated, and 6 (21.4%) were well differentiated. According to the ultrastructural analysis, 10 tumors were undifferentiated (35.7%), 14 poorly differentiated (50%), and 4 well differentiated (14.3%). The overall concordance between the two techniques was low (35.7%), and both modalities were concordant in classifying only 1 well-differentiated, 5 poorly differentiated, and 4 undifferentiated tumors. In conclusion, the authors suggest that investigations devoted to test the prognostic significance of neural differentiation in these neoplasms should employ both immunohistochemistry and electron microscopy, separately and in combination, to assess what is the most effective choice for predicting the clinical course.     

GANT-like gastrointestinal pacemaker cell tumours with oncocytic features

We describe two cases of gastrointestinal stromal tumours with prominent oncocytic features. Both had features consistent with differentiation towards the interstitial cells of Cajal (CC). They were composed of nests and bundles of cells with abundant, deeply granular, eosinophilic cytoplasm. Immunohistochemical investigations revealed positivity with c-kit, vimentin and CD34 antibodies in both neoplasms. Ultrastructurally the neoplastic cells showed characteristic features of CC; they had synapse-like structures and dense core cytoplasmic granules. Oncocytic features were confirmed by immunohistochemistry using anti-mitochondrion antibody in both cases and by electron microscopy in one case (case 1). Although the CC are frequently described as mitochondrion-rich cells, oncocytic changes have not previously been reported as a feature of gastrointestinal autonomic nerve tumour (GANT)-like stromal tumours. Received: 5 March 1999 / Accepted: 12 March 1999     

Inflammatory abdominal aortic aneurysms: does an early stage exist?

Inflammatory aneurysms are characterised by a peculiar clinical (i.e. abdominal-lumbar pain, weight loss and increased ESR) and morphological picture (whitish wall, adhesion to the surrounding organs and thickness greater than 0.5 cm). The lymphomonoplasmacellular infiltrate and the interstitial deposits of collagen define the histological picture of these lesions. The authors describe three abdominal aortic aneurysms macroscopically characterised by parietal edema, hyperemia and hypertrophy of the preaortic lymphnodes. Histological study revealed a conspicuous and widespread lymphomonoplasmacellular infiltrate and interstitial edema. The abdominal-lumbar pain, the increase in ESR and the reactive C protein defined the clinical and laboratory aspects. Serological tests for syphilis, rheumatoid arthritis and lupus erythematosis were negative. The question which arises from these observations is whether these forms represent separate entities or an early stage in the evolution of inflammatory abdominal aortic aneurysms with fibrosis.     

Solitary fibrous tumor of the central nervous system: a 15-year literature survey of 220 cases (August 1996-July 2011)

We reviewed the world literature on solitary fibrous tumors of the central nervous system from August 1996 to July 2011, focusing on both clinicopathological features and diagnostic findings. The anatomical distribution of the 220 cases reported so far reveals that most are intracranial and just over one-fifth are intraspinal. In decreasing frequency, intracranial tumors involve the supratentorial and infratentorial compartments, the pontocerebellar angle, the sellar and parasellar regions, and the cranial nerves. Intraspinal tumors are mainly located in the thoracic and cervical segments. Although most solitary fibrous tumors of the central nervous system are dural based, a small subset presents as subpial, intraparenchymal, intraventricular, or as tumors involving the nerve rootlets with no dural connection. Preoperative imaging and intraoperative findings suggest meningioma, schwannoma or neurofibroma, hemangiopericytoma, or pituitary tumors. Immunohistochemistry is critical to establish a definitive histopathological diagnosis. Vimentin, CD34, BCL2, and CD99 are the most consistently positive markers. The usual histologic type generally behaves in a benign manner if complete removal is achieved. Recurrence is anticipated when resection is subtotal or when the tumor exhibits atypical histology. The proliferative index as assessed by MIB1 labeling is of prognostic significance. Occasionally, tumors featuring conventional morphology may recur, perhaps because of minimal residual disease left behind during surgical extirpation. Rare extracranial metastases and tumor-related deaths are on record. Surgery is the treatment of choice. Stereotactic and external beam radiation therapy may be indicated for postsurgical tumor remnants and for unresectable recurrences. Long-term active surveillance of the patients is mandatory.     

Overexpression of the S-phase kinase-associated protein 2 in thyroid cancer

Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1-Cullin-F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours. Immunohistochemistry analysis showed that Skp2 was overexpressed significantly in thyroid carcinomas (26 out of 51) compared with goitres (0 out of 12, P<0.001) or adenomas (1 out of 10, P<0.05), and that high Skp2 expression was detected more often in anaplastic thyroid (ATC; 83%, n=12) than follicular thyroid (FTC; 40%, n=20) or papillary thyroid (PTC; 42%, n=19) carcinomas (P<0.05). Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05). In most cases, the observed overexpression of Skp2 protein was paralleled by an increase in the levels of Skp2 mRNA, and we observed Skp2 gene amplification at 5p13 in 2 out of 6 cell lines and in 9 out of 23 primary tumours (six out of eight ATCs, two out of nine PTCs and one out of six FTCs) using Q-PCR and/or fluorescence in situ hybridization analysis. Finally, in vitro experiments demonstrated that suppression of Skp2 expression drastically reduced proliferation of thyroid cancer cells and, conversely, forced expression of Skp2 circumvented serum dependency and contact inhibition in Skp2-negative cells by promoting p27 degradation. These findings indicate that Skp2 plays an important role for the development of thyroid cancer.     

Fibrohistiocytic tumors containing zebra body-like inclusions and fibripositors

Plexiform fibrohistiocytic tumor (PFH) and cellular neurothekeoma (CN) are dermal neoplasms that present many histological and immunophenotype similarities as well as unknown histogenesis. Recently, the ultrastructural detection of zebra body-like inclusions in lesional histiocytes has been considered crucial to favor the diagnosis of PFH over that of CN. Here we report two examples of dermal tumors that were diagnosed as CN. Electron microscopy revealed cytoplasmic collections of myelin and zebra body-like inclusions in tumor cells; these inclusions focally merged together or with multivesicular bodies; tumor cells also showed collagen secretion granules and fibripositors, i.e., channels containing single, double or multiple copies of collagen fibrils. These observations support the view that PFH and CN have a common histogenesis and consists of cells sharing phagocityc and fibrillogenic abilities.     

Mixed Tumors, Myoepitheliomas, and Oncocytomas of the Soft Tissues Are Likely Members of the Same Family: A Clinicopathologic and Ultrastructural Study

Four diagnostically unusual soft tissue tumors are presented. All lesions were of consistent size and long duration. Histologically, one lesion was analogous to mixed tumors of the usual sites (i.e., salivary glands), one lesion was totally spindled, and the two other lesions both had oncocytic appearances ( epithelioid and spindle biphasic pattern in a case, purely epithelioid in the other). Immunohistochemically, the mixed tumor was positive for vimentin, cytokeratins, S-100 protein, and focally for EMA. The purely spindled tumor exhibited immunoreactivity for vimentin, actins, S-100 protein, EMA (focally), and GFAP. The oncocytic biphasic tumor was positive for mitochondrial antigen, vimentin, and actins. The purely epithelioid oncocytic neoplasm was immunoreactive only for mitochondrial antigen and vimentin. Ultrastructurally, in the epithelial-like portion of the first (mixed) tumor, peripheral arrays of contractile filaments were detected along with well-developed desmosomes. In the second (spindled) case, peripheral contractile filaments and attenuated desmosomes were also seen. In the third case, a huge number of mitochondria, some desmosomes, and actin-type microfilaments were found. In the fourth case, desmosomes and punctate subplasmalemmal densities, in addition to numerous mitochondria, were documented. In all cases an external basal lamina were present, which was discontinuous in the first three cases and almost continuous in the fourth. These tumors were respectively designated as mixed tumor, myoepithelioma of the classic type, myoepithelioma of oncocytic type with biphasic cell architecture, and true oncocytoma. So far, all tumors have followed benign clinical courses (median follow up: 12 months). Comparisons with similar tumors of other sites are drawn, and suggestions for considering all of them as members of the same myoepithelial-derived tumor family are given.     

Necrobiotic Xanthogranuloma Without Periorbital Involvement: An Ultrastructural Investigation

A case of necrobiotic xanthogranuloma without typical periorbital involvement is described at the ultrastructural level. The patient, a 58-year-old Italian man, presented in 1995 with a brief history of nodulo-papular lesions commencing on the lower limbs, and mild paraproteinemia. During 6 years of follow-up, anemia, neutropenia with marked lymphopenia, and increased ESR were found, while serum cholesterol and triglyceride levels decreased from hyper to hypo values. Systemic diseases, such as diabetes, malignancy, or extracutaneous lesions, often associated with NXG, have not developed. Conventional histology was distinctive for NXG, and immunohistochemistry confirmed that dermal histiocytes were not of Langerhans cell lineage. At ultrastructure, regeneration and degeneration (regen-degen) features were observed in some individual deep dermal histiocytes, which have not been previously documented in the literature. Identification of giant histiocytes showing regen-degen aspects might prove to be a useful ultrastructural diagnostic marker for NXG.