Tadashi Hasegawa

Extrathoracic solitary fibrous tumors. Their histological variability and potentially aggressive behavior

The histological variability of solitary fibrous tumors may contribute to the difficulty in diagnosing these neoplasms, especially when they arise in extrathoracic sites. Like intrathoracic lesions, the behavior of extrathoracic solitary fibrous tumors is currently unpredictable because these types of tumor have only recently been recognized. This study therefore was undertaken to examine the clinical behavior and histological, immunohistochemical, and ultrastructural features of 24 extrathoracic solitary fibrous tumors with long-term follow-up. The patients comprised 10 men and 14 women, between 30 and 85 years of age (mean, 51 years). Ten tumors were located in the retroperitoneum or pelvis, 5 in the trunk, 4 in the extremities, 2 in the orbital region, and 1 each in the kidney, uterine cervix, and meninges. All of the tumors showed a classic morphological appearance, diffuse and strong immunoreactivity for both vimentin and CD34, and variable reactivity for bcl-2. All 7 cases examined ultrastructurally contained fibroblasts and myofibroblasts. Six tumors contained multinucleated giant cells, and in 4 cases these lined pseudovascular spaces with mononuclear cells, thus resembling giant cell angiofibroma and giant cell fibroblastoma. Other potentially similar spindle cell neoplasms mixed with adipose tissue, such as dendritic fibromyxolipoma, lipomatous hemangiopericytoma, cellular angiofibroma, and spindle cell lipoma, were considered in the differential diagnosis. One tumor displayed atypical histological features in the form of increased cellularity and nuclear pleomorphism, but this patient has remained free of disease for 14 years. Another 2 patients developed local recurrences at 6 months and 5 years, and a further patient developed pulmonary metastases that were diagnosed after 7 years. These tumors lacked any atypical histological features in the primary lesions. No patient has so far died of the disease. In conclusion, most extrathoracic solitary fibrous tumors appear to pursue a benign course, although, because some have the potential to recur or metastasize, careful long-term follow-up is necessary for all patients.

Proximal-type epithelioid sarcoma: a clinicopathologic study of 20 cases.

We studied the clinicopathologic and immunohistochemical features of 20 cases of proximal-type epithelioid sarcoma to identify prognostic factors. The 20 patients ranged in age from 13 to 80 years (mean, 40 y); 12 patients were male and 8 were female. The tumors presented as deep soft-tissue or subcutaneous masses on the inguinal region in five, the thigh in four, the vulva in three, the axilla in three, and one each in the flank, chest wall, back, hip and perineum. The tumors ranged from 2 to 16 cm at their greatest diameter (mean: 7.8 cm). Histologically, 12 tumors (60%) were classified as the large-cell subtype, characterized by sheets of large cells with prominent nucleoli resembling poorly differentiated carcinoma, and a frequent rhabdoid phenotype, six (30%) were classified as the conventional subtype, and two (10%) as the angiomatoid subtype. The numbers of tumors exhibiting immunoreactivity for various markers were: vimentin (20 cytokeratin (20 [100%]); epithelial membrane antigen (17 [85%]); CD34 (9 [45%]); CD99 (5 [25%]); muscle markers, either desmin or α-smooth muscle actin (3 [15%]), other markers such as S-100 protein, neurofilament, neuron-specific enolase, synaptophysin and CD56 (12 [60%]); and p53 (16 [80%]). Fourteen lesions (70%) exhibited an MIB-1 index of 30% or more and, by a system of histologic grading using the MIB-1 score, 16 tumors (80%) were classified as high-grade (Grade 3). Thirteen patients (65%) developed local recurrence and 15 (75%) had metastases, primarily to the lymph nodes. At the last follow-up, 13 patients (65%) had died of their disease. A large tumor size and early metastasis were independently associated with a poor outcome. We conclude that proximal-type epithelioid sarcomas are rare, undifferentiated soft-tissue sarcomas of adults, with epithelioid features and a frequent rhabdoid phenotype. These tumors, when arising in proximal locations, have a much worse prognosis than those arising in distal locations.

Malignant peripheral nerve sheath tumors : an immunohistochemical study in relation to ultrastructural features

The constituent cells in malignant peripheral nerve sheath tumors were examined by studying the expression of immunohistochemical markers for Schwann cells and perineurial cells in relation to ultrastructural features in 12 malignant peripheral nerve sheath tumors. Ultrastructural studies demonstrated mixed proliferation of Schwann cells, perineurial cells, fibroblastic cells, and primitive cells in many malignant peripheral nerve sheath tumors. Expression of S-100 protein was well correlated with Schwann cell-like differentiation of tumor cells. However, Leu-7 and epithelial membrane antigen, which have been considered to be specific to Schwann cells and perineurial cells, respectively, were common to Schwann cells, perineurial cells, and primitive cells. The common immunophenotypic expression suggests a close relationship among these cell types. The unusual expression of cytokeratin could be explained by the plasticity of intermediate filament expression.

Immunophenotypic heterogeneity in osteosarcomas

Eighteen osteosarcomas were studied immunohistochemically. The tumors were classified into the following six histologic subtypes: five osteoblastic, four chondroblastic, four malignant fibrous histiocytoma-like, two telangiectatic, two low-grade central, and one giant cell-rich. Variable amounts of osteocalcin immunoreactivity were found in all tumors. Factor XIIIa-positive cells, which may be of fibrohistiocytic lineage, were present in three tumors of the malignant fibrous histiocytoma-like type, one of the telangiectatic type, one of the low-grade central type, and the tumor of the giant cell-rich type. One tumor of the osteoblastic type showed cytokeratin and epithelial membrane antigen immunoreactivities. The positive reactions for desmin in four tumors, for alpha-smooth muscle actin in 11 tumors, and for type IV collagen in one tumor seemed to indicate myofibroblastic differentiation of some tumor cells. S-100 protein-positive tumor cells were detected not only in all four tumors of the chondroblastic type, but also in three of the osteoblastic type, one of the low-grade central type, and in the tumor of the giant cell-rich type. These immunohistochemical results suggest that osteosarcomas are composed of heterogeneous cell populations, such as those of the osteoblastic, chondroblastic, myofibroblastic, and fibrohistiocytic types, and occasionally also of cells with epithelial features.

Mechanism of pain in osteoid osteomas: an immunohistochemical study.

Osteoid osteoma is a benign bone tumour characterized by pain which is relieved by non‐steroidal anti‐inflammatory drugs (NSAIDs), such as aspirin. To clarify the mechanism of the pain, five osteoid osteomas were studied immunohistochemically using polyclonal antibodies against prostaglandin E2 (PGE2), S‐100 protein and protein gene product 9.5 (PGP 9.5). In all five cases, the pain had been relieved by NSAIDs. Nerve fibres positive for S‐100 protein and PGP 9.5 were observed in the fibrous zone, especially close to the blood vessels, around the nidus in all the lesions and also within the nidus in three lesions. PGE2 immunoreactivity was variably positive in the nidus of three lesions. In one case a large number of actively proliferating osteoblasts reacted with this antibody. The other cases showed unevenly distributed PGE2 positivity which tended to be prominent in the plump osteoblasts. As control material we examined fibrous dysplasia (3 cases), osteosarcomas (3) and giant‐cell tumours of bone (3). The plump osteoblastic tumour cells of three osteosarcomas and the bone‐forming cells in two cases of fibrous dysplasia gave a positive reaction for PGE2. No S‐100 or PGP 9.5 immunoreactive nerve fibres were seen in these lesions. It is concluded that the presence of nerve fibres alone might play a more important role in mediation of pain in osteoid osteomas than some effects of osteoblast‐produced PGE2 on the nerves and proliferated blood vessels.

Cytoskeletal characteristics of myofibroblasts in benign neoplastic and reactive fibroblastic lesions

The characteristics of the cytoskeleton of myofibroblasts were examined immunohistochemically in 10 extra-abdominal desmoid tumours, 3 palmar and 2 plantar fibromatoses and 5 nodular fasciites; in the cultured cells of one desmoid tumour, and also ultrastructurally in 3 desmoid tumours. Polyclonal anti-desmin antibody reacted with the cells in 7 extra-abdominal desmoid tumours, 1 palmar fibromatosis, 1 plantar fibromatosis and 3 nodular fasciites. Monoclonal antidesmin antibody reacted with cells in only 2 desmoid tumours. Desmin-positive spindle cells were scattered throughout these lesions. There were no marked ultrastructural differences between desmin-positive and desmin-negative desmoids. All specimens except one specimen of nodular fasciitis showed immunoreactivity for alpha-smooth muscle actin and vimentin. Muscle actin-positive cells were observed in all specimens. Cultured cells gave positive reactions with polyclonal desmin antibody as well as to vimentin antibodies and two preparations of actin antibodies, whereas the original tumour did not react with desmin antibody. The present studies suggested that the cytoskeleton of some myofibroblasts in both neoplastic and reactive lesions resembles that of smooth muscle cells.

Expression of intermediate filaments in malignant fibrous histiocytomas

The expression of intermediate filaments (IFs) in 34 malignant fibrous histiocytomas (MFHs) was studied immunohistochemically and ultrastructurally. Using the avidin-biotin-peroxidase method, positive reactions were detected as follows: for desmin in 12 tumors, for neurofilament in two tumors, for cytokeratin in one tumor, and for vimentin in 30 tumors. Desmin immunoreactivity was found in tumors of all four histologic subtypes and cytokeratin immunoreactivity was found in one tumor of the myxoid type. Because of the cross-reactivity of anti-neurofilament antibody with reactive histiocytes, the immunoreactivity for neurofilament seemed to be non-specific. Ultrastructurally, five of 13 tumors studied contained some tumor cells showing myofibroblastic or smooth muscle cell differentiation. A few tumor cells in one cytokeratin-positive tumor had tonofilaments in their cytoplasm. Desmin expression in some MFHs seemed to be due to myofibroblastic or smooth muscle cell differentiation of some tumor cells. Cytokeratin expression seemed to indicate epithelial differentiation in some MFHs. This varied expression of IFs in MFHs may reflect the heterogeneous nature of MFHs, and suggests that MFHs represent the final stages of dedifferentiation of several different types of sarcomas or, alternatively, represent forms of poorly differentiated sarcoma with the potential of developing into more differentiated sarcomas of heterogeneous origin.

Epithelioid angiosarcoma of bone

Angiosarcoma of bone is a rare, high-grade sarcoma of vascular origin. This article describes an epithelioid angiosarcoma in the humerus of a 48-year-old man. A multilocular osteolytic lesion with undefined margins and destroyed cortical and medullary bone, associated with a large soft tissue mass was demonstrated radiologically in the proximal metaphysis of the right humerus. The tumor, resected by amputation, was composed mostly of proliferating malignant cells with an epithelioid morphology. It had a predominantly sheet-like growth pattern, and an occasional pseudoglandular or alveolar arrangement, mimicking an adenocarcinoma. The dilated anastomotic vascular spaces lined by epithelioid endothelial cells and the intracytoplasmic lumina/vacuoles that sometimes contained erythrocytes suggested focal endothelial differentiation. On immunohistochemical investigation, many neoplastic cells expressed cytokeratin and endothelial markers: factor-VIII related antigen, CD31, and UEA-I. The ultrastructure of the tumor was consistent with that of an angiosarcoma. Our patient died of disease shortly after the diagnosis, implying an aggressive clinical course. Awareness of the existence of skeletal epithelioid angiosarcoma, combined with the identification of intracytoplasmic lumina, or at least small vasoformative foci, and immunohistochemical positivity for endothelial markers provide the best guide for distinguishing this tumor from metastatic carcinomas.

Differentiation and proliferative activity in benign and malignant cartilage tumors of bone

To assess the histological grade in benign and malignant cartilage tumors of bone by more objective methods, we examined the differentiation and proliferative activity of tumor cells in six enchondromas, five chondroblastomas, and 13 chondrosarcomas immunohistochemically. A variable number of cells in all tumors showed S-100 protein and vimentin immunoreactivity. In fully differentiated cartilage of enchondromas and low grade chondrosarcomas, tenascin, which is an extracellular matrix glycoprotein, was present in small amounts or absent but was increased at the periphery of tumor lobules and even in the matrix throughout the high grade chondrosarcomas. Higher rate and intensity of proliferating cell nuclear antigen (PCNA) reactivity were found in chondrosarcomas, especially in spindle-shaped cells of high grade tumors, than in enchondromas. The distribution of PCNA-positive cells almost corresponded to the regions with tenascin reactivity. One tumor of high grade chondrosarcoma showed p53 protein immunoreactivity. Aberrant expression of cytokeratin was observed in four chondroblastomas. The expression of desmin was identified in relatively large proportions of enchondromas and chondrosarcomas, regardless of their benign or malignant nature and histological grade. Smooth muscle or muscle-specific actins also were present in a smaller number of tumors. Based on these findings, it is concluded that unusual staining characteristics were present, in addition to those of a chondroblastic nature, in the cartilage tumors of bone. Tenascin and PCNA positivity of various degrees in all chondroblastomas may suggest that they are chondrogenic tumors having a relatively high proliferative activity, albeit their benign clinical course. Proliferative activity of tumor cells in enchondromas and chondrosarcomas correlated well with their histological grade. Tenascin may play a role in promoting tumor cell proliferation of cartilagenous neoplasms and, on the other hand, the alterations of extracellular matrix involving tenascin synthesis seem to be a result of tumor development.

Dual‐colour fluorescence in situ hybridization analysis of synovial sarcoma

Mounting cytogenetic evidence indicates that synovial sarcomas, regardless of histological conformation, share the specific reciprocal chromosomal translocation t(X;18)(p11.2;q11.2). Application of dual‐colour fluorescence in situ hybridization (FISH) on interphase nuclei isolated from archival paraffin‐embedded material to identify the specific translocation is of diagnostic importance for pathological practice and retrospective study. Five cases of well‐characterized biphasic synovial sarcomas, two monophasic fibrous synovial sarcomas, one embryonal rhabdomyosarcoma, one fibrosarcoma, and one malignant peripheral nerve sheath tumour were analysed. To visualize the translocated chromosomal fragments and their topographic relationships with centromeres of chromosomes X and 18, nuclei from each case were hybridized concurrently with chromosome X centromeric and chromosome 18 painting probes, and chromosome 18 centromeric and chromosome X painting probes, respectively. Six out of seven synovial sarcomas showed chromosomal alterations consistent with t(X;18). One biphasic synovial sarcoma had trisomy 18 and lacked the chromosomal translocation t(X;18). The other three spindle cell sarcomas and the normal control tissues showed the normal numerical and structural composition for chromosomes X and 18. It is indicated from the present study that when histological differential diagnosis is difficult, FISH would be a crucial aid in detecting a known specific chromosomal alteration and that dual‐colour FISH is an efficient stable diagnostic tool for pathological research and daily diagnosis. The results also suggest that rare synovial sarcomas may lack the chromosomal translocation t(X;18).