Markku Miettinen

Gastrointestinal stromal tumors: Recent advances in understanding of their biology

Gastrointestinal stromal tumor (GIST) is the preferred term for mesenchymal tumors specific for the gastrointestinal tract (60% in stomach, 30% small intestine, 10% elsewhere). GISTs include most tumors previously designated as leiomyoma, cellular leiomyoma, leiomyoblastoma, and leiomyosarcoma. However, in the esophagus, leiomyoma is the most common mesenchymal tumor. GISTs are composed of spindle (70%) or epithelioid (30%) cells, and 10%-30% are malignant showing intra-abdominal spread or liver metastases. They are immunohistochemically positive for c-kit (CD117), CD34, and sometimes for actin but are almost always negative for desmin and S100-protein. The malignant GISTs especially show activating mutations in the c-kit gene. GISTs and gastrointestinal autonomic nerve tumors (GANT) overlap. The cell of origin is not fully understood, but resemblance to the interstitial cells of Cajal, expression of some smooth muscle markers, and occurrence outside of the GI-tract suggest origin from multipotential cells that can differentiate into Cajal and smooth muscle cells.

Postirradiation sarcoma. Analysis of a nationwide cancer registry material.

Thirty‐three cases of postirradiation sarcoma (PIS) from the files of the Finnish Cancer Registry were analyzed. The most frequent first primary tumors were cancers of the breast (seven cases) and female reproductive organs (13 cases). Five patients had a childhood cancer. The median total radiation dose at the site of the PIS was 3600 cGy (1600 cGy to 11200 cGy). The median interval from start of radiation therapy to detection of PIS was 13.2 years (3.4 to 22.8 years). The PIS was of soft tissue origin in 25 of 33 cases. The most frequent histologic types were osteosarcoma (ten cases, including four extraskeletal tumors), malignant fibrous histiocytoma (ten cases), and fibrosarcoma (six cases). The overall crude 5‐year survival rate was 29% (calculated from the start of treatment for PIS), and for patients initially treated with either radical surgery or combined marginal surgery and postoperative irradiation it was 67%. The authors conclude that there is a chance for cure for radically treated patients with postirradiation sarcoma that emphasizes the importance of regular long‐term follow‐up of cancer patients.

Diagnostic Application of Monoclonal Antibodies to Intermediate Filamentsa

Most of the histopathologic practice in pathology laboratories is based on histochemical staining techniques that reveal the major components common to most tissues or cells, or on more specific staining reactions, that reveal structural components or products typical of certain tissues or cells. The assortment of the utilizable specific stains is, however, narrow and therefore the correct identification of the specific nature of a given lesion is critically dependent on the personal experience of the pathologist. In order to improve the accuracy and reliability of the histopathological diagnostics, much effort has been devoted to develop new and more specific techniques that could be used to reveal specific compositional features of cells and tissues. The most successful approach has been the use of antibodies-either conventional polyclonal or monoclonal antibodies raised against specific tissue components that, combined with immunohistochemical techniques, can be used to retrieve more specific information on the compositional features of a lesion, e.g. tumor, which may allow its identification. Such new reagents include, for instance, antibodies that enable us to identify specific cell types in tissue sections, such as endothelial cells, histiomonocytic cells, different types of lymphatic cells, epithelial cells, neuronal cells, and muscle-type of cells.’32

Antibodies to Intermediate Filament Proteins in the Diagnosis and Classification of Human Tumors

Immunohistochemistry of intermediate filaments (IF) is a new and important way to evaluate the epithelial, mesenchymal, muscular, glial, or neural differentiation in tumors. This is based on the stable cell-type-specific expression of IF proteins in normal and neoplastic tissues. Immunohistochemical studies with antibodies to intermediate filaments have also given new perspectives in the histogenesis and biologic nature of many tumors. This article reviews both the recent findings and the authors experience in the use of intermediate filament antibodies in tumor diagnosis and classification.

Hodgkin's disease, lymphocytic predominance nodular. Increased risk for subsequent non-Hodgkin's lymphomas.

Fifty‐one cases of Hodgkins disease, of lymphocytic predominance type, nodular subtype (HDLPN) were singled out from three sources: lymph nodes originally diagnosed as malignant lymphoma, nodes suspected of lymphoma and nodes suspected of toxoplasmosis. Two thirds of the 51 patients were men, and the median age was 42 years. The disease was characteristically unilocular and cervical and axillary nodes were most often involved. Local recurrences were common (in 13 cases). Oncological treatment (irradiation, cytostatics, or both) was given to 20 patients, whereas 31 patients remained untreated as the original histological diagnosis was not malignant. Despite the lack of treatment, the prognosis was good. Relative actuarial survival for the whole material was 93% at five years and 80% at ten years. During follow‐up, five patients developed a diffuse large–celled non‐Hodgkins lymphoma 4–11 years after the onset of HDLPN. The majority of the subsequent lymphomas cannot be therapy‐induced as only one of these patients had previously been treated (irradiated). Transition to other types of Hodgkins disease was observed only in two cases. It is concluded that HDLPN is a clinicopathological entity with a good prognosis, but that it may sometimes change into a more malignant lymphoma of the Hodgkins or non‐Hodgkins type.

Demonstration of laminin, a basement membrane glycoprotein, in routinely processed formalin-fixed human tissues.

SummaryLaminin was demonstrated by immunoperoxidase and immunofluorescence staining in sections of normal human tissues fixed in formalin and routinely processed in paraffin. Exposure of the sections to a solution of pepsin (Burns et al. (1980) Histochemistry 67∶73–78) revealed the antigenicity of this basement membrane glycoprotein. Sections from paraffin blocks stored for years at room temperature could be stained with this procedure. Normal human tissues, developing fetal tissues and tumors could be stained with this method. The staining patterns were similar to those seen in unfixed frozen sections. It thus appears that basement membrane components can be detected by immunohistological means from routinely processed histological samples, once the sections are pretreated with proteases. Staining for laminin could be used in embryonic studies and in histopathology to study the relation of cells to basement membranes and for the visualization of normal and abnormal vascularization.

Keratin in the epithelial-like cells of classical biphasic synovial sarcoma

SummaryFour cases of classical biphasic synovial sarcoma were studied for intermediate filaments of keratin and vimentin type. Epithelial-like cells lining gland-like slits were strongly positive for keratin but negative for vimentin, whereas the spindle cell stroma was negative for keratin but positive for vimentin. The observations indicate epithelial differentation in the glandular elements of biphasic synovial sarcomas, and are consistent with earlier ultrastructural observations suggesting epithelial properties of these cells.

Intravascular bronchioloalveolar tumor

A 17‐year‐old girl was operated for a solitary well‐circumscribed pulmonary parenchymal tumor and reoperated ten times for multiple recurrent similar pulmonary tumors during 24 years. Histologic examination revealed the so‐called intravascular bronchioloalveolar tumor (IVBAT) in all instances. The patient died from pneumonia superimposed on decreased respiratory function 24 years after the onset of disease. This is the longest survival so far reported in IVBAT. The treatment was surgical in all phases of the disease, and the patient did not receive radiotherapy or cytostatic drug therapy. Mediastinal and pleural tumor nodules were removed 17 years from the first pulmonary operation, and 24 years after the first operation a fibrous tumor was removed from the retroperitoneal space. Immunohistologically, the tumor cells were positive for vimentin‐type of intermediate filaments, in line with their mesenchymal nature. Endothelial markers, Factor VIII‐related antigen and Ulex europaeus I lectin binding, were not found in convincingly neoplastic cells, and Schwann cell, epithelial cell, muscle cell, and histiocytic markers were absent. Thus, IVBAT appears to be a low‐grade malignant mesenchymal neoplasm, composed of poorly differentiated mesenchymal cells, whose exact nature remains undefined with the currently used cell‐type markers.

Histogenesis of Ewing’s sarcoma

SummaryFour cases of Ewing’s sarcoma, three in bone and one from an extraskeletal site, were studied immunohistologically using monospecific antibodies against intermediate filament proteins of keratin, vimentin, desmin and neurofilament types. All cases were also evaluated for the presence of Factor VIII-related antigen (FVIIIR:Ag) and for the binding of Ulex europaeus I lectin (UEA I), both of which are endothelial markers. In all cases the tumor cells contained vimentin but not keratin, desmin or neurofilaments. The tumor cells could not be decorated with either anti-FVIIIR:Ag or UEA I, whereas the vascular endothelium was positive for both markers. The vimentin-positivity indicates a mesenchymal derivation of Ewing’s sarcoma, while the lack of endothelial markers argues against the proposed endothelial origin of this tumor.

Glomus tumor cells: evaluation of smooth muscle and endothelial cell properties.

SummarySix cases of glomus tumor in superficial soft tissues were investigated immunohistochemically for the presence of different types of intermediate filaments, myosin, laminin, a basal lamina glycoprotein, and the endothelial cell markers, factor VHI-related antigen (FVIIIR:Ag) and Ulex europaeus I lectin (UEA I) binding sites. The tumor cells appeared to contain only vimentin, the fibroblast-type of intermediate filament protein. They were also positive for myosin, and were invested by laminin-positive basal lamina-like material, but did not express endothelial cell markers. Ultrastructural studies revealed prominent arrays of both intermediate filaments and microfilaments, the latter resembling the myofilament bundles seen in smooth muscle cells. The results show that glomus tumor cells resemble smooth muscle cells in their content of myosin and in some ultrastructural features. In their lack of desmin, however, they differ from most types of smooth muscle cell, although they are similar in this respect to some vascular smooth muscle cells.