Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatous, and perineuriomatous areas.

Soft tissue hybrid peripheral nerve sheath tumors (PNST), including schwannoma-perineurioma or neurofibroma-perineurioma, have recently been described. However, there are no reports on hybrid PNST arising in the nasopharyngeal area. In this article, we report such a case. A 58-year-old Japanese man presented with nasal obstruction and was found to have bilateral polypoid lesions in the middle meatus of the nose. Subsequently, nasal polypectomy was performed. Histologically, the tumor consisted of three components including schwannoma, neurofibroma, and perineurioma. Immunohistochemically, schwannoma, neurofibroma, and perineurioma components were positive for S-100 protein, CD34, and epithelial membrane antigen, respectively. In conclusion, this is the first case of hybrid PNST reported to occur in the nasopharyngeal area. Pathologists should be aware of the possibility that hybrid PNST may present outside soft tissue.

Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice.

Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration.

Dedifferentiated liposarcoma with rhabdomyoblastic differentiation in an 8-year-old girl.

The development of a liposarcoma during childhood is extremely rare. We report a case of dedifferentiated liposarcoma arising in the left thigh of an 8-year-old girl. Morphological and immunohistochemical studies revealed occasional rhabdomyoblastic differentiation in the dedifferentiated component. The identical cells were co-mingling with the well-differentiated liposarcoma component. This is the first description of such a case of liposarcoma occurring in a child.

Expression of fascin-1, an actin-bundling protein, in migrating hepatoblasts during rat liver development.

Fascin-1 is an actin-bundling protein localized at the core actin bundles within microvillar projections and filopodial extensions in migrating cells. It is expressed at a low level in normal epithelial cells, but at a high level in tumor cells, indicating its importance in the invasion and motility of tumor cells. In addition, fascin-1 is expressed in human and murine embryos, occurring at high levels especially in developing nervous tissues. In this study, we have investigated the expression patterns of fascin-1 immunohistochemically during the early stages of rat hepatogenesis. A high expression of fascin-1 was detected in the liver bud and hepatoblasts at embryonic day (ED) 10.5, ED11.5, and ED12.5. Expression fell by ED13.5 and was not detectable at ED14.5. These observations demonstrate that the expression of fascin-1 is correlated with the migration activity of hepatoblasts during the early stages of liver development in rats.

Spinal epithelioid hemangioendothelioma with epithelioid angiosarcomatous areas.

Epithelioid hemangioendothelioma is a distinctive vascular tumor rarely involving bones. We report a case of epithelioid hemangioendothelioma in the cervical spine with angiosarcomatous areas. A 50-year-old female presented with dizziness while walking. A mixed sclerotic and osteolytic or destructive lesion was radiographically disclosed in her upper cervical vertebrae. Histologically, a laminectomy specimen exhibited areas of ordinary epithelioid hemangioendothelioma together with foci of more atypical epithelioid cell proliferation, closely resembling epithelioid angiosarcoma. This phenomenon has been exceptionally described in cases with skeletal lesions, which are typically of low-grade malignancy.

Primary pulmonary synovial sarcoma: a clinicopathologic, immunohistochemical, and molecular study of 11 cases.

Primary synovial sarcoma (SS) of the lung is rare and may create diagnostic challenges. We reviewed 11 cases of pulmonary SS (PSS) confirmed by the presence of a tumor-specific SYT-SSX fusion gene to verify their clinicopathologic features including immunohistochemical and genetical profiles. The tumors occurred in 4 men and 7 women (age 29 to 81 years; mean age, 58; median age, 50), and ranged in size from 2 to 15.5 cm (mean, 9 cm). Of the 11 tumors, 10 were a monophasic fibrous type and 1 was a poorly differentiated type. Mitotic rate ranged from 8 to 43 per 10 high-power fields. All cases showed at least focal immunohistochemical positivity for AE1/AE3, CAM5.2 and/or epithelial membrane antigen. High proliferating cell nuclear antigen labeling index (>20%) was found in 8 of 10 cases (80%). Eight (90%) of 9 cases were negative for E-cadherin, and 1 case (10%) exhibited reduced expression of the molecule. The aberrant expression of beta-catenin within cytoplasm and/or nuclei was observed in 6 of 9 (67%) cases. SYT-SSX1 and SYT-SSX2 fusion gene transcripts were detected in 9 and 2 cases, respectively. In 10 patients with follow-up, 3 (30%) had local recurrences, and 4 (40%) developed distant metastases. Five (50%) patients died of the tumor 1 to 9 years after surgery, and 5 (50%) were alive and disease-free in the period ranging from 3 months to 5.5 years. In conclusion, PSS tends to occur in older patients and shows an aggressive behavior probably due to its anatomical location and large tumor often resulting in incomplete resection and high proliferative activity.

Coexpression of NOR1 and SIX3 proteins in extraskeletal myxoid chondrosarcomas without detectable NR4A3 fusion genes.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal tumor cytogenetically characterized by reciprocal translocations, such as t(9;22)(q22;q12) and t(9;17)(q22;q11), which result in EWSR1/NR4A3 and TAF15/NR4A3 fusion genes (alias EWS/NOR1, TAF2N/NOR1), respectively. NOR1 is an orphan nuclear receptor and acts as a transcription factor that can bind to its putative coactivator, SIX3. Although the NOR1 fusion protein has been implicated in oncogenesis of EMC, a small fraction of EMC lacks detectable rearrangements of the NR4A3 gene or 9q22. We report a case of EMC with no detectable NR4A3 gene alterations, as assessed with various molecular techniques including reverse transcription-polymerase chain reaction (RT-PCR), Southern blotting, interphase fluorescence in situ hybridization, and PCR single-strand conformation polymorphism-but with coexpression of native NOR1 and SIX3. In our survey of another 18 EMCs, we identified one more case expressing both NOR1 and SIX3 but lacking NR4A3 fusion. Fourteen tumors with detectable NR4A3 fusion genes (EWSR1-NR4A3; TAF15-NR4A3) expressed neither native NOR1 nor SIX3. SIX3 expression is normally confined specifically to the developing eye and fetal forebrain, although the expression of NR4A3 is largely ubiquitous. Our data suggest that aberrant coexpression of NOR1 and SIX3 is a potential alternative mechanism underlying the development of EMC.

Congenital (infantile) pseudarthrosis of the fibula associated with osteofibrous dysplasia.

We describe a recently noted association of congenital (infantile) pseudarthrosis of the lower leg with osteofibrous dysplasia. The patient was a 2-year-old boy who presented with a deformed left ankle joint and three cutaneous cafe-au-lait spots. Radiography demonstrated pseudarthrosis of the left distal fibula and a round lucent lesion adjacent to the proximal part of the pseudarthrosis. Histologically, the surgically removed fibula with pseudarthrosis showed a fibromatosis-like fibrovascular proliferation and nonspecific reparative changes. The focal lucent area demonstrated a fibro-osseous lesion, which was histologically identical to osteofibrous dysplasia. This case provides further evidence that osteofibrous dysplasia may be associated with congenital (infantile) pseudarthrosis of the lower leg.

Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitis-like lymphoma in Japan.

CD56 is an important marker for prospecting clinicopathologic features of cytotoxic T-cell and natural killer (NK)/T-cell lymphomas. We examined 22 cases of subcutaneous panniculitis-like lymphoma and classified these into CD56-positive and CD56-negative groups. The 11 CD56-negative cases were mainly in the younger age group and had systemic subcutaneous nodules without ulceration. They exhibited subcutaneous invasion by medium-sized lymphoma cells, scattered erythrophagocytosis, patchy necrosis, and little tumor invasion in the superficial dermis. Their lymphoma cells had characteristics of CD3 epsilon-, CD8-, TcR beta F1-, T-cell intracellular antigen (TIA)1-, and granenzyme B-positive cytotoxic T cells and were negative for apoptosis-promoting proteins CD95 (Fas), Bax, CPP32 (caspase 3), and p53 (DO7). Ten patients were alive despite clinical signs of hemophagocytic syndrome and relapses in 7 cases. The 11 CD56-positive cases had systemic ulcerative skin tumors composed of pleomorphic lymphoma cells with massive necrosis and little erythrophagocytosis involving the subcutis and also often the whole dermis. Their tumor cells were positive for CD3 epsilon, TIA1, granenzyme B, CD95, CD95L (Fas ligand), Bax, and CPP32. Three cases were of the TcR beta F1-positive phenotype, 1 was of the TcR gamma/delta-positive T-cell phenotype, and 6 were of the TcR beta F1- and TcR gamma/delta-negative NK/T-cell phenotype. Six cases were p53 (DO7) positive. Seven cases had complications of liver dysfunction and cytopenia, and 8 died of disease. One CD56-negative case and 3 CD56-positive cases had nuclear signals of Epstein-Barr virus-encoded RNA in their lymphoma cells. The 2 groups had significantly (P <0.01) different prognoses by Kaplan-Meier and log-rank methods. Patients with CD56-negative and CD56-positive groups had statistically different clinicopathologic, immunohistologic, and functional findings and prognoses.

Clinicopathologic analysis of 22 cases of subcutaneous panniculitis-like CD56- or CD56+ lymphoma and review of 44 other reported cases.

In 22 histologic cases of subcutaneous panniculitis-like lymphoma, we studied the clinicopathologic differences between CD56- and CD56+ cases (11 each). CD56- cases had skin ulcers (1 [9%]); tumor invasion in the superficial dermis (1 [9%]); erythrophagocytosis (10 [91%]); and medium-sized (11 [100%]), CD8+ (10 [91%]), T-cell receptor (TcR)betaF1+ (10 [91%]), and CD95 (Fas)- tumor cells. CD56+ cases had skin ulcers (9 [82%]); tumor invasion in the superficial dermis (8 [73%]); erythrophagocytosis (1 [9%]); and pleomorphic large (10 [91%]), CD8+ (2/10 [20%]), TcRbetaF1 + (3/10 [30%]), and CD95 (Fas)+ (7/10 [70%]) tumor cells. These 7 factors were significantly different between groups (P < .01). Median survival rates were 96 and 12 months for the CD56- and CD56+ groups, respectively. Age younger than 40 years, no skin ulcers, no tumor invasion in the superficial dermis, and CD8+, TcRbetaF1 +, CD95 (Fas)-, and CD56- tumor cells were significantly better prognostic factors (P < .01). The CD56- and CD56+ groups showed different tumor cell characteristics, clinicopathologic findings, and prognosis. In the CD56+ group, 1 was gamma/delta T-cell phenotype, 3 were alpha/beta T-cell, and 6 were TcRbetaF1- and gamma/delta- NK/T-cell, and 3 NK/T-cell cases had nuclear signals of Epstein-Barr virus-encoded RNA. Cases of CD56+ T- and NK/T-cell lymphoma had similar clinicopathologic findings and prognosis.

Microtubule-associated protein-2 and class III beta-tubulin are expressed in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma is a rare soft tissue sarcoma of uncertain histogenetic origin. Because recent reports have indicated neural-neuroendocrine differentiation in some extraskeletal myxoid chondrosarcomas, we investigated 25 tumors for expressions of microtubule-associated protein-2 and Class III beta-tubulin, which are major components of microtubules and specifically localized in neurons and their derivatives. Immunohistochemical expression of microtubule-associated protein-2 and Class III beta-tubulin was studied in extraskeletal myxoid chondrosarcomas using formalin-fixed, paraffin-embedded tissues. Cytoplasmic expressions of microtubule-associated protein-2 and Class III beta-tubulin were detected in 21 (84%) and 13 (52%) of the 25 extraskeletal myxoid chondrosarcomas, respectively, although the number of positively stained tumor cells varied. Expression of the Class III beta-tubulin gene was also assessed in two immunohistochemically positive cases by in situ hybridization using an oligonucleotide probe specific for its transcript, and both cases showed expression of Class III beta-tubulin transcript. Another case was examined with immunoelectron microscopy, and immunogold particles for Class III beta-tubulin were localized to microtubular aggregates. Our data indicate that microtubules in extraskeletal myxoid chondrosarcoma are similar to those found in neurons, further supporting the concept that neural-neuroendocrine differentiation occurs in a significant number of extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma arising in the finger.

Extraskeletal myxoid chondrosarcoma (EMCS) is a rare soft tissue sarcoma and usually occurs in deep soft tissues, especially of the proximal extremities and limb girdles. We present an unusual case of the tumor arising in the finger. The diagnosis was confirmed by molecular detection of a characteristic EWS-CHN/TEC fusion gene transcript. Molecular detection of the tumor specific fusion gene could be a valuable aid for the final diagnosis of EMCS, particularly in cases with unusual clinicopathological features.

Juxta-articular myxoma and intramuscular myxoma are two distinct entities. Activating Gs alpha mutation at Arg 201 codon does not occur in juxta-articular myxoma.

Juxta-articular myxoma is a rare myxoid tumor of soft tissue that bears a close histologic resemblance to intramuscular myxoma but is distinguished from the latter by its clinical setting and behavior. Activating missense mutations at the Arg 201 codon of the Gs alpha gene ultimately leading to increased levels of cyclic adenosine monophosphate have been implicated in McCune-Albright syndrome and sporadic fibrous dysplasia of bone. Recently, we have demonstrated that the same Gs alpha mutations occur in intramuscular myxomas associated with fibrous dysplasia of bone (Mazabraud's syndrome) as well as in sporadic intramuscular myxoma. The overlapping histologic appearances of juxta-articular myxoma and intramuscular myxoma prompted us to investigate whether there is a relationship between the two entities. We studied this possibility by looking for Gs alpha mutations in juxta-articular myxoma using polymerase chain reaction (PCR) to amplify appropriate genomic DNA fragments extracted from formalin-fixed, paraffin-embedded specimens of five juxta-articular myxomas, followed by single-strand conformation polymorphism analysis. Using these techniques, no aberrant bands were detected in any of the five juxta-articular myxomas, indicating that they lack Gs alpha mutations. Moreover, DNA sequencing of the PCR products of two JAMs showed no abnormalities. We conclude that juxta-articular myxomas, in contrast to intramuscular myxomas, do not involve Arg 201 mutations of the Gs alpha gene, indicating that they represent distinct entities with different underlying molecular mechanisms.