A search for cytomegalovirus and herpes viral antigen in brains of schizophrenic patients.

The peroxidase-antiperoxidase method was employed to search for evidence of cytomegalovirus (CMV) or herpes simplex virus (HSV) antigen in the brains of 25 patients with a diagnosis of schizophrenia, 25 nonschizophrenic neuropsychiatric patients, and 16 nonpsychiatric control subjects. Brain specimens from patients with acute CMV and herpes encephalitis served as positive controls. Although early results with low-titer CMV antisera suggested immunoreactivity in specific brain regions of a small number of schizophrenic and control cases, the present studies with high-titer anti-CMV IgG did not give a positive immunoperoxidase reaction in sections from the basal forebrain, hypothalamus, or midbrain. Scattered neurons in the lateral vestibular nucleus and hippocampus showed questionable staining with CMV IgG in one schizophrenic patient and none in control subjects. No schizophrenic or control cases demonstrated an immune reaction to HSV antisera.

Pigmented dermatofibrosarcoma protuberans (Bednar tumor). A pathologic, ultrastructural, and immunohistochemical study.

Described by Bednar as a "storiform neurofibroma," pigmented dermatofibrosarcoma protuberans is a rare neoplasm accounting for approximately 1-5% of all cases of dermatofibrosarcoma protuberans (DFSP). The lesion commonly presents as an exophytic, multinodular neoplasm of the dermis or subcutaneous tissue. It occurs predominantly in blacks. The majority are located on the trunk, and the remainder are more or less equally distributed in the upper and the lower extremities and the head and neck. Microscopically the lesion is characterized by spindled cells arranged in a tight storiform pattern and admixed with a small population of melanin-containing dendritic cells. The dendritic cells are the primary feature distinguishing this lesion from conventional DFSP. Three cell populations are identifiable by electron microscopy. The majority of cells resemble fibroblasts. A second population of cells exhibits long slender cell processes partially or completely invested by basal lamina. The third population of cells, also invested by basal lamina, contains both melanosomes and premelanosomes. The histogenesis of this neoplasm remains controversial. Although Bednar considered these lesions as variants of neurofibroma, S-100 protein could not be identified, and this finding contrasts significantly from the description of conventional neurofibroma, which almost always contains this antigen. Follow-up information available in nine cases indicates that this lesion may recur locally. Although distant metastases were not observed in our material, complete excision in conjunction with close follow-up care is indicated for this neoplasm of probable intermediate malignant potential.

Spindle-cell carcinoma of the aerodigestive tract. An immunohistochemical analysis of 21 cases.

Immunohistochemical analysis of 21 prototypic mucosal spindle-cell carcinomas of the aerodigestive tract was performed at the Armed Forces Institute of Pathology (AFIP) to establish the usefulness of selected immunohistochemical markers in distinguishing spindle-cell carcinoma from other mucosal spindle-cell neoplasms. Immunoreactive keratin could be demonstrated in only 13/21 (62%) of cases. Coexpression of keratin and vimentin was demonstrated in 10/17 (59%) of the tumors evaluated for both of these intermediate filaments. All spindle-cell carcinomas lacked S100 protein, which is an immunoreactivity we would expect to find in spindle-cell malignant melanoma, one of the principal considerations in a differential diagnosis. Both alpha-1-antitrypsin (AAT) and alpha-1-antichymotrypsin (ACT) were demonstrated in the tumor cells in all cases. However, albumin had a similar distribution in the tumors, which suggested that passive uptake was a serious confusing factor. The results of this study indicate that AAT and ACT are unreliable markers for distinguishing spindle-cell carcinomas from malignant fibrous histiocytomas.

Keratin in epithelioid sarcoma. An immunohistochemical study.

Intermediate-sized filaments have been noted in epithelioid sarcoma by previous investigators, two of whom have reported that the filaments represent vimentin. We utilized polyclonal antibodies directed against keratin and immunoperoxidase techniques (PAP) to stain 32 of the more than 300 cases accumulated at the AFIP . All of our material was formalin-fixed, paraffin-embedded. Seventy-five percent of our cases (24/32) showed positive immunoreactivity, a feature that may be of diagnostic help in distinguishing epithelioid sarcoma from modular fasciitis, benign and malignant fibrous histiocytoma, malignant melanoma, and necrotizing granuloma. In these cases, the reaction was enhanced using predigestion with trypsin. The immunoreactivity varied from tumor to tumor, perhaps due to formalin fixation. Since synovial sarcoma and mesothelioma may also be cytokeratin-positive, our findings indicate that keratin immunoreactivity is not confined to epithelial tumors and may also occur in neoplasms traditionally regarded as mesenchymal.

Kupffer cells in hepatocellular adenomas.

Hepatocellular adenomas are usually visualized as defects on technetium-99m-sulfur colloid liver scans, a fact which has been attributed to the absence of phagocytic Kupffer cells in the tumors. To determine whether this is true, seven hepatocellular adenomas were subjected to immunoperoxidase staining for lysozyme, a marker of mononuclear phagocytes. The Kupffer cells were counted in the tumors and surrounding non-neoplastic liver. All hepatocellular adenomas studied were found to contain Kupffer cells. Three tumors had fewer Kupffer cells than the surrounding liver. Three had about the same number as the surrounding liver, and one had more Kupffer cells than the non-neoplastic liver. Thus, the lack of phagocytosis of colloid in liver scans is probably due to something other than a deficiency of Kupffer cells in the hepatocellular adenomas.

Immunohistochemical localization of hepatitis B surface antigen and hepatitis B core antigen in tissue sections. A source of false positive staining.

The occurrence of apparent false positive immunoperoxidase staining for hepatitis B surface antigen (HBsAg) led to the evaluation of several commercial antisera for usefulness in the diagnosis of hepatitis B by immunohistochemistry. One commercial antibody to hepatitis B core antigen (HBcAg) was tested and found to give sensitive and specific staining, with only a few false negatives and no false positives. Of three antibodies to HBsAg, one gave good staining results that were consistent with serologic data; one had many false positive stains due to contaminating antibodies to plasma proteins; and one (a monoclonal antibody) had many false negatives, probably due to its restricted antigenic specificity. Diagnosticians should be aware of the problems with false positive and false negative immunohistochemical stains. False positives in particular can be a significant problem, causing frequent misdiagnosis of hepatitis B.

Differentiation of vascular prostheses in dogs with serial tests of in vivo platelet reactivity.

Three different vascular prostheses (standard weight knitted Dacron, double velour knitted Dacron, and expanded polytetrafluoroethylene) were implanted in the aortas of dogs, and serial determinations of platelet survival and platelet serotonin were monitored at 12-week intervals for 1 year. Prostheses were then removed and luminal coverage with endothelialized neointima and production of prostacyclin were measured. Changes in platelet survival were correlated with changes in platelet serotonin, and both measurements reflected in vivo platelet reactivity with the vascular prostheses. These changes were unique for each type of prosthesis and were dependent upon physical characteristics and the rate and degree of coverage of the prosthetic surface with endothelialized neointima that produced prostacyclin. Prostheses that reduced platelet survival and platelet serotonin the least as shown by serial evaluation were found at harvest to be the most completely paved with nonthrombogenic neointima. In dogs, these techniques allow differentiation of vascular prostheses and provide a useful animal model for their evaluation.

The antithrombotic nature of vascular prosthetic pseudointima.

Morphologic functional, and biochemical studies were performed on pseudointima obtained from woven Dacron aortic prostheses harvested from eight dogs 2 to 3 years after placement. In vivo platelet reactivity with prostheses was assessed by serial 51Cr-platelet survival measurements which documented that platelet survival returned towards normal but never attained preoperative levels. The extent of luminal coverage of prosthesis with pseudointima of the time of harvest was 60.3% +/- 2.4%. Morphologic techniques, including conventional light microscopy, immunoperoxidase light microscopy for endothelial factor VIII-related antigen, and scanning and transmission electron microscopy, demonstrated that pseudointima was composed of endothelial cells of varying maturity lining mesenchymal tissue. Areas of the prostheses with poorly formed pseudointima containing exposed Dacron fibers were covered with exuberant, platelet-rich thrombi. Ability of pseudointima to produce prostacyclin was assessed by bioassay of platelet antiaggregatory activity and radioimmunoassay of 6 keto PGF1 alpha, a metabolite of prostacyclin. These experiments confirmed that pseudointima produced abundant prostacyclin, although not as much as native aortic tissue. These studies document that vascular prosthetic pseudointima is nonreactive with platelets, presumably because of prostacyclin generation.

Lymphoid interstitial pneumonia: clinicopathological and immunopathological findings in 18 cases.

Eighteen patients with lymphoid interstitial pneumonia (LIP) were studied. The diagnosis was established by the microscopic finding of interstitial infiltrates of lymphocytes and plasma cells. Forty-seven% of patients also had germinal centres, while 72% showed interstitial giant cells. Cases studied by the immunoperoxidase technique showed the interstitial plasma cells to be polytypic. The median age of patients was 56 years; most had cough, dyspnea, or chest pain. Chest X-rays showed either patchy interstitial infiltrates (usually bilateral) or poorly defined nodules. Ten patients had hypergammaglobulinemia; one had hypogammaglobulinemia. Two patients had Sjögren's syndrome, two had biopsy-proven chronic active hepatitis, and two had a clinical diagnosis of primary biliary cirrhosis. Follow-up examination of 14 patients showed clearing of symptoms, X-ray infiltrates or stable infiltrates in 4 cases each. Five patients died (mean survival, 41 months), one of whom succumbed to disseminated lymphoma and a second to respiratory failure. Our results support the hypothesis that LIP is a non-neoplastic cellular proliferation in which lymphoma may supervene. The high incidence (22%) of chronic liver disease has not previously been noted.

Lymphomatoid granulomatosis: a clinicopathologic study of 42 patients.

We studied the histological and clinicopathological findings in 42 patients who had lymphomatoid granulomatosis (LYG). In addition to small round lymphocytes, small to intermediate lymphocytes with serpentine nuclei, large immature mononuclear lymphoid cells, abundant histiocytes, and vascular invasion by the cell infiltrate were observed in all cases. Fifty percent of lesions had occasional "atypical" cells with multi-lobed nuclei. Three of four follow-up autopsies showed large cell lymphoma, while one other autopsy and the single repeat biopsy showed increased numbers of large immature mononuclear lymphoid cells. Patients were most frequently men 40-60 yr old who had a history of pulmonary symptoms, such as cough or chest pain, and who showed multiple bilateral lung nodules without hilar adenopathy in the chest x-ray. Thirteen patients (38%) died of disease, 11 of them within 12 mth of initial diagnosis. The presence of neurological signs and symptoms, increased mitoses, or increased numbers of atypical multi-nucleated cells in the initial biopsy were not statistically significant predictors of survival.

Experimentally induced feline chlamydial infection (feline pneumonitis).

Cats exposed to aerosols of feline Chlamydia psittaci developed a disease characterized principally by conjunctivitis. Signs of conjunctivitis appeared between postexposure days (PED) 5 and 10, were often unilateral initially, and persisted for 22 to 45 days. Fever followed the onset of conjunctivitis (PED 11 to 15) and persisted for 3 to 8 days. Signs of mild rhinitis (occasional sneezing and mild serous nasal discharge) occurred in some cats between PED 8 and 37. Neither signs of lower respiratory tract disease nor significant pulmonary lesions were produced by the feline pneumonitis agent. Small foci of pneumonia were detected microscopically in 3 of 6 cats examined between PED 7 and 14. Chlamydiae were identified between PED 7 and 14 in the cytoplasm of epithelial cells in stained conjunctival smears. Conjunctivitis persisted for at least 18 days after chlamydiae no longer were detectable in conjunctival smears. Low levels of chlamydial infectivity, however, still were present in conjunctiva and lung on PED 45.

Ultrastructural morphogenesis of acute viral pneumonia produced by feline calicivirus.

The ultrastructural morphogenesis of acute viral pneumonia was studied in pathogen-free cats exposed to aerosols of a virulent strain of feline calicivirus. Electron microscopy and fluorescence microscopy indicated that the virus had a marked tropism for alveolar pneumocytes. Viral-induced necrosis of pneumocytes was observed as early as 12 hours after exposure and was associated with acute serofibrinous and neutrophilic inflammation in the distal air exchange tissue. The acute exudative phase abated by 168 hours after exposure. The regenerative phase that followed was characterized by hyperplasia of type II pneumocytes; influx of monocytes, lymphocytes, and plasma cells; and interalveolar and intraalveolar proliferation of fibroblasts. The decrease in pneumocyte injury coincided with the increase in alveolar macrophages and immunocytes. With minor exceptions, feline calicivirus-induced alveolar damage and the subsequent repair resembled toxic alveolar injury produced by oxidant gases. Feline caliciviral pneumonia, therefore, is a naturally occurring example of viral-induced diffuse alveolar damage.

Elaboration of chemotactic substances by alveolar cells: possible mechanisms for the initial neutrophilic response in feline caliciviral pneumonia.

In vitro experiments established that the interaction of feline calicivirus (FCV) with alveolar macrophages and pneumocytes results in the generation of chemotactic factors that produce directed migration of neutrophils in Boyden chambers. Factors were produced independent of immune mechanisms and of discernible serum factors. Lysates of noninfected alveolar macrophages and pneumocytes did not possess chemotactic activity, indicating that chemotactic factors were not preformed in these cells. Noninfected alveolar macrophages also elaborated neutrophil chemotactic factors in culture; however, activity was greater when macrophages were infected with FCV. The results of this study suggested that the neutrophilic response in the peripheral portion of the lung of cats exposed to aerosols of FCV was the result of the elaboration of complete chemotactic factors from FCV-infected alveolar cells.

Coexpression of keratin and desmin in a carcinosarcoma involving the maxillary alveolar ridge.

Immunohistochemical determination of the class of intermediate filaments (keratins, vimentin, desmin, neurofilaments, and glial fibrillary acidic protein) expressed by tumors has become an important diagnostic procedure for the histogenetic classification of neoplasms. A case of a poorly differentiated malignant neoplasm of the maxillary alveolar ridge which coexpressed keratin and desmin types of intermediate filaments is reported. These intermediate filaments have been associated with epithelial and muscle cell differentiation, respectively. The morphologic features of the tumor plus the expression of both these intermediate filaments indicate that this neoplasm represents a true carcinosarcoma.

Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant Schwann cell tumors.

Two hundred and two benign and malignant soft tissue lesions were studied for the presence of S-100 protein by means of the peroxidase-antiperoxidase technique on formalin-fixed, paraffin-embedded tissue. Virtually all benign nerve sheath tumors (neurofibroma, neurilemoma, and granular cell tumor) contained numerous immunoreactive S-100-positive cells. Only one-half (18 of 36) of malignant schwannomas contained the protein, suggesting that its presence is an expression of differentiation in Schwann cell tumors. S-100 protein was not identified within pure neuroblastic tumors (neuroblastoma, neuroepithelioma) but could be identified within rare cells of the ganglioneuroblastoma and within the Schwann cell component of ganglioneuroma. It was also identified within most melanocytic tumors (cellular blue nevus, clear cell sarcoma, and melanoma). In fact, its constant presence in melanoma indicates that it may prove to be an independently reliable method for diagnosing amelanotic forms. It is also sporadically present within a variety of mesenchymal lesions including lipoma, liposarcoma, synovial chondromatosis, chondrosarcoma, fibromatosis, histiocytosis X, and chordoma. Although S-100 protein is highly characteristic of neural crest-derived tumors, it is not restricted to them and, consequently, must be interpreted cautiously. It may prove helpful in select situations such as the distinction of (a) benign nerve sheath tumors from other benign mesenchymal tumors such as fibrous histiocytomas, (b) cellular neurilemomas from malignant schwannomas, (c) malignant schwannomas from conventional fibrosarcoma (d) malignant melanomas from many carcinomas, and, possibly (e) juvenile xanthogranulomas from histiocytosis X.

Malignant intraocular teratoid medulloepithelioma in three dogs.

Tumors derived from the fully differentiated ciliary epithelium include adenomas and adenocarcinomas. Many such tumors in animal eyes have been reported. Medulloepitheliomas derived from the primitive medullary epithelium of the optic cup have rarely been seen in animal eyes. A teratoid variant of medulloepithelioma, recently described in human eyes, has also been seen in canine and bovine eyes. These tumors contain tissues resembling brain, cartilage, rhabdomyoblasts, and primitive mesenchyme, in addition to the poorly differentiated neuroepithelial and neuroblastic elements characteristic of malignant medulloepitheliomas.