Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis.

The in vivo function of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) was investigated in mice, carrying a null allele of the GM-CSF gene, that were generated by gene targeting techniques in embryonic stem cells. Although steady-state hematopoiesis was unimpaired in homozygous mutant animals, all animals developed the progressive accumulation of surfactant lipids and proteins in the alveolar space, the defining characteristic of the idiopathic human disorder pulmonary alveolar proteinosis. Extensive lymphoid hyperplasia associated with lung airways and blood vessels was also found, yet no infectious agents could be detected. These results demonstrate that GM-CSF is not an essential growth factor for basal hematopoiesis and reveal an unexpected, critical role for GM-CSF in pulmonary homeostasis.

Human breast carcinoma: fibrin deposits and desmoplasia. Inflammatory cell type and distribution. Microvasculature and infarction.

Study of 14 human infiltrating breast carcinomas revealed new features that shed light on the pathogenesis of tumor stroma formation and on host immunologic defense mechanisms. Fibrin deposits were observed in the stroma of all tumors, particularly at their growing edge. Fibrin may have contributed both to tumor angiogenesis and, with organization, to the formation of the fibrous stroma characteristic of these and other scirrhous carcinomas. We previously proposed similar mechanisms for several animal tumors. All breast carcinomas studied elicited some degree of lymphocytic response at the tumor periphery; lymphocytes penetrated the fibrous tumor stroma poorly, did not exit in significant numbers from central tumor vessels, and, even when greatly outnumbering tumor cells locally, appeared relatively ineffective at tumor cell killing. Microvascular endothelial cell damage was frequently observed and may have been responsible for zones of tumor infarction. Similar observations have been made in skin allografts and animal tumors where rejection was effected principally by microvascular damage and subsequent tissue infarction, not by lymphocyte contact with individual epithelial target cells.

A human pituitary tumor-derived folliculostellate cell line.

Pituitary cells have been used for the study of hormone synthesis, secretion, and regulation. However, the lack of human cell lines of pituitary origin has made such studies in humans very difficult. Activin, a member of the transforming growth factor-beta cytokine family, is secreted by the pituitary and serves, in addition to regulating hormone biosynthesis, as a regulator of cell growth and differentiation. In the human pituitary, folliculo-stellate cells secrete an activin-binding and -neutralizing protein, follistatin. However, the role of these cells in the autocrine/paracrine regulatory mechanisms of activin is poorly understood. We describe a human pituitary-derived folliculostellate cell line, designated PDFS, that was developed spontaneously from a clinically nonfunctioning pituitary macroadenoma. PDFS cells showed an epithelial-like morphology with long cytoplasmic processes. Electron microscopy revealed frequent intercellular junctions, including desmosomes, and cytogenetic analysis showed clonal characteristics with chromosomal abnormalities. These cells express vimentin and the nervous tissue-specific S-100 protein, specific markers of folliculostellate cells in the anterior pituitary, but no secretory pituitary cell markers. PDFS cells formed large colonies in an anchorage-independent transformation assay. They express follistatin and activin A and have an intact activin intracellular signaling pathway as determined by reporter assays. Therefore, this human cell line provides a useful model for studying the regulation of cell growth and cytokine production by factors endogenously produced in pituitary folliculostellate cells.

Relapsing central and peripheral demyelinating diseases. Unusual pathologic features.

We treated a patient who had a demyelinating peripheral neuropathy and a central nervous system inflammatory demyelinating disease. The unusual pathologic feature of dense infiltrates of atypical macrophages was observed in many areas of the brain; otherwise the process had several features in common with either multiple sclerosis or chronic relapsing experimental allergic encephalomyelitis. The illness followed "swine-flu" inoculation; exacerbation followed pneumococcal vaccination.

Subtypes of chromophobe cell renal carcinoma: an ultrastructural and histochemical study of 13 cases.

The Mainz classification of renal epithelial neoplasms has become accepted as a reproducible morphologic and cytogenetic classification of epithelial tumors of the kidney. Chromophobe cell renal carcinoma (CCRC) is a distinct type of renal epithelial neoplasm, first described by Thoenes et al. in 1985. Both a typical type of CCRC, composed of cells with pale reticular cytoplasm, and an eosinophilic variant (EVCCRC) have been identified. Both variants have been reported to show cytoplasmic staining with the Hale's colloidal iron method. Cytogenetic analysis has tended to confirm the Mainz classification. CCRC has been shown to have consistent chromosomal abnormalities that are not shared by other renal tumors. Ultrastructurally, CCRC is typically characterized by a cytoplasm containing scant numbers of mitochondria, which have tubulovesicular christae, and by the presence of innumerable 150-300-microm microvesicles scattered between the mitochondria. Erlandson et al. recently described two subtypes of EVCCRC. One subtype has sparse microvesicles and abundant mitochondria that have tubulovesicular christae, whereas the second type (described as an oncocytic EVCCRC) has no microvesicles and abundant mitochondria containing pseudovesicular or lamellar christae. This was believed to be more akin to the ultrastructural appearances of a renal oncocytoma. The authors believe that the phenotype of the EVCCRC shows a range of appearances at both the light microscopic and the ultrastructural levels, from features similar to the typical type CCRC through to a neoplasm that is phenotypically similar to renal oncocytoma. A series of 13 cases of CCRC from the files of the Massachusetts General Hospital for which ultrastructural examination was available is described. These cases include six cases of typical type CCRC and seven cases of EVCCRC. The authors confirm the findings of Erlandson et al. of two subtypes of EVCCRC and designate them as type 1 EVCCRC (with some microvesicles and mitochondria with tubulovesicular christae) and type 2 EVCCRC (with no identifiable microvesicles and mitochondria with pseudovesicular or lamellar christae).

Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases.

The clinical and pathological features of 125 juvenile granulosa cell tumors of the ovary were analyzed. The patients ranged in age from newborn to 67 years (average 13 years). Forty-four percent were 10 years of age or younger, 34% between 11 and 20 years, 18% between 21 and 30 years, and 3% over 30 years of age. Eighty-two percent of the prepubertal patients presented because of isosexual pseudoprecocity. In the remainder of the children and in most of the older patients, the presenting manifestation was usually abdominal pain or swelling. Fifteen patients in the reproductive age group had menstrual irregularities or amenorrhea, and one of the two postmenopausal women presented with uterine bleeding. Two patients had Ollier's disease and two had Maffucci's syndrome. Laparotomy revealed unilateral involvement in 122 cases and involvement of both ovaries in two cases; bilateral tumors were found at autopsy in one case. Two tumors were Stage IIb and one Stage IIc; the remainder were Stage I. In 13 cases (11%), rupture had occurred before or during operation and ascites was present in 11 cases (9%). The tumors ranged from 3 to 32 cm in diameter (average 12.5 cm). Forty-nine percent of them were solid and cystic, 37% solid, and 14% cystic. Microscopic examination disclosed diffuse and follicular patterns, with the former predominating in most of the cases. The follicles varied in size and shape and characteristically contained basophilic or eosinophilic secretion, which often stained positively for mucin. The granulosa cells were typically luteinized to varying degrees and had dark round nuclei without grooves; a theca cell component of variable extent was present in many of the cases. The mitotic rate ranged from less than 1 to 32/10 high-power fields, with an average of 7. Nuclear atypicality varied from Grade 1 to 4. Follow-up information of at least 1 year's and up to 21 years' (average 5 years') duration was available for 95 patients, 87 of whom (92%) were alive and free of disease. One patient with Maffucci's syndrome died of chondrosarcoma 11 years after removal of the ovarian tumor (corrected survival--93%). The seven remaining patients died as a result of their tumor from 7 months to 3 years postoperatively; one of the clinically malignant tumors was Stage Iai, one Stage Iaii, two Stage Ic, two Stage IIb, and one Stage IIc.(ABSTRACT TRUNCATED AT 400 WORDS)

Metanephric adenoma of the kidney. A clinicopathological, immunohistochemical, flow cytometric, cytogenetic, and electron microscopic study of seven cases.

We report seven examples of a distinctive adenomatous tubular cortical neoplasm of the adult kidney. The average age of the patients (six women and one man) was 48.6 years (range, 38-64 years). In six patients the tumor was discovered during investigation of unrelated conditions, and all were treated with total nephrectomy. One tumor was found at autopsy. The tumors were well-circumscribed, nodular, tan-pink masses localized to the kidney, ranging in size from 0.6 to 8 cm. Histological examination demonstrated orderly, closely packed, small round tubules lined by bland, darkly staining oval cells with little cytoplasm, merging with rounded nests of similar cells. Occasional branching, elongated tubules, and papillary infoldings of glomeruloid-like bodies were present but blastema was absent. The tumor cells were immunoreactive for Leu 7 (three of five cases) and vimentin (four of six cases), and a few tumors were immunoreactive for cytokeratin (two of six cases), epithelial membrane antigen (one of six cases), and muscle-specific antigen (one of six cases). Ultrastructural examination of two tumors revealed tubular and solid nests of epithelial cells surrounded by basal lamina, with prominent cell junctions, microvilli, and apical secretory granules. DNA content analysis by flow cytometry yielded diploid histograms (four of four cases). Cytogenetic analysis of one case revealed a normal male karyotype. Clinical follow-up, available for six patients, revealed no evidence of recurrence (mean follow-up, 60.8 months). We believe this is a benign tumor, best classified as a metanephric adenoma because of its embryonic architectural and cytological appearance, that can be recognized by its very characteristic pathological features.

Papillary carcinoma of the thyroid, oxyphil cell type, "clear cell" variant: a light- and electron-microscopic study.

A unique case of papillary carcinoma of the thyroid having the combined features of three morphological subtypes--tall cell, clear cell and Hürthle cell--has been studied by light and electron microscopy. The distinctive neoplastic cells had an oxyphilic basal zone, a mid-placed nucleus and a clear apical region. Ultrastructurally, the cytoplasm was virtually filled with mitochondria, characteristic of Hürthle cells, but the unusual finding was the marked distention and emptiness of those mitochondria located in the apical zone, accounting for the clear phenomenon noted by light microscopy. In contrast, the mitochondria in the basal, or oxyphilic, part of the cells were intact. While a few cases of clear cell and papillary clear-cell carcinoma of the thyroid have been studied by electron microscopy previously, the clear change has never been attributed to dilated mitochondria, but rather to the presence of glycogen. The reason for the mitochondrial swelling is not answered, but it is probably an in vivo effect. Some of the other characteristics of papillary carcinoma of the thyroid described previously, such as microvilli, absence of colloid, infolded nuclei and nuclear bodies, were also present in this case. However, ground-glass nuclei, a frequently reported feature, were not found.

Mixed tumors of the vagina. A clinicopathological analysis of eight cases.

Eight mixed tumors of the vagina are described. Seven of them were situated in or near the hymenal ring. All but one were well-circumscribed masses unconnected to the surface epithelium. They were composed of small stromal-type cells usually containing islands of mature squamous cells and glands lined by mucinous epithelium. Their histogenesis is not clear. Follow-up of 2--9 years in seven of the cases has revealed no evidence of recurrence or metastases after local excision.

Myxoid leiomyosarcoma of the uterus. A report of six cases.

Six myxoid leiomyosarcomas of the uterus are described. Four were located within the myometrium and two lay predominantly within the broad ligament but appeared to have arisen in the outer myometrium. These tumors were characterized grossly by a gelatinous appearance and an apparently circumscribed border. On microscopical examination, however, they were observed to invade adjacent tissue and in two cases the lumens of veins. All the tumors contained copious amounts of myxomatous stroma. Although it was difficult to establish the nature of the neoplastic cells in some areas of these tumors, both light- and electron-microscopical examination showed characteristic features of smooth muscle cells in other areas. The mitotic count varied from 0 to 2/10 high-power fields. Follow-up investigation for periods ranging from 1 to 11 years revealed that four patients died and two are living with disease.

A distinctive ovarian sex cord-stromal tumor causing sexual precocity in the Peutz-Jeghers syndrome.

Two distinctive ovarian tumors that caused sexual precocity in young girls with the Peutz-Jeghers syndrome are described. Each of the tumors varied in its histologic pattern, with diffuse areas, foci of tubular differentiation, microcysts and papillae, and contained two unusual cell types. The light-microscopic and ultrastructural findings were consistent with a hitherto undescribed form of sex cord-stromal tumor. The unique microscopic appearance of this tumor and its association with the Peutz-Jeghers syndrome in both cases suggest that it is a third type of gynecological neoplasm related to that disorder.

Sinonasal hemangiopericytoma. A reassessment with electron microscopy, immunohistochemistry, and long-term follow-up.

Sinonasal hemangiopericytomas are rare, occasionally misdiagnosed neoplasms that have often been considered distinct from hemangiopericytomas of other sites. Eleven cases were studied. Nine arose from the nasal cavity and two from the paranasal sinuses. The patients' mean age was 58 years. In nine cases there were no appreciable mitoses; in two, mitoses were frequent. Of 10 cases studied by immunostaining, all were positive for vimentin; two had faint focal staining for actin; one focally expressed S-100 protein; all were negative for cytokeratins, desmin, and Factor VIII-related antigen; and none bound Ulex europaeus agglutinin 1. Five cases were studied by electron microscopy. The most consistent features were basal lamina-like material partly surrounding tumor cells and completely separating them from endothelium, tapered cytoplasmic extensions, and orderly bundles of filaments. Intercellular junctions and pinocytotic vesicles were present in some tumors. Of nine cases with adequate follow-up, tumors recurred in four cases (44%) after a mean of 6.5 years, and none metastasized. A review of the literature showed that high local recurrence rates, late recurrences, and low rates of metastasis were features of tumors in this location. This might be a reflection of early presentation, small tumor bulk, and difficulty of complete resection, rather than evidence for a biologically distinct neoplasm.

Spindle-cell argyrophilic mucin-producing carcinoma of the breast. Histological, ultrastructural, and immunohistochemical studies of two cases.

We report two cases of neuroendocrine carcinomas of the breast displaying unusual histological features: numerous spindle cells and argyrophilic signet-ring cells. Both patients were older than 70 years, and both presented with a bloody nipple discharge. The tumor in both cases was predominantly intraductal. The tumor cells showed little pleomorphism or cytological atypia; because of the presence of spindle cells, benign diagnoses, such as ductal epithelial hyperplasia and intraductal papilloma, were considered for the in situ component. Recognition of the palisading arrangement of the peripheral cells, intracytoplasmic lumina, mitotic figures, and mucin permitted the diagnosis of intraductal carcinoma. Invasive nests composed of identical cells confirmed the diagnosis of malignancy in both cases. Our cases, along with those previously reported, suggest that neuroendocrine carcinoma with mucin production is a distinct breast tumor that usually occurs in older patients who experience bloody nipple discharge. The prognosis may be more favorable than that of the usual type of breast carcinoma. Common histological features include predominantly intraductal growth, an absence of desmoplasia, and low-grade atypia. Awareness of morphological variants of this tumor, such as those reported here, is necessary to avoid erroneous diagnoses.

Angiomyofibroblastoma of the vulva with sarcomatous transformation ("angiomyofibrosarcoma").

We report on a locally recurrent vulvar tumor in an 80-year-old woman that we believe represents the first example of malignant transformation of an angiomyofibroblastoma. The tumor was predominantly a typical angiomyofibroblastoma, composed of epithelioid or oval cells with eosinophilic cytoplasm that tended to cluster in small groups and around blood vessels. These areas merged imperceptibly with a high-grade sarcoma that resembled a myxoid malignant fibrous histiocytoma. The tumor cells in the benign areas were diffusely immunoreactive for vimentin; many cells were positive for smooth muscle actin, and focal positivity for muscle actin and desmin was observed. The tumor cells in the sarcomatous areas were diffusely positive for vimentin, but negative for smooth muscle actin, muscle actin, and desmin. No staining for keratin, S-100 protein, or CD34 was noted. Ultrastructural examination of the sarcomatous area showed that the cells had the features of fibroblasts. All previously reported cases of angiomyofibroblastoma have exhibited banal histologic features and have behaved in a benign fashion. This case shows that these tumors may rarely be associated with a malignant component, and the designation "angiomyofibrosarcoma" may be appropriate in such cases.

Solitary fibrous tumor of the orbit.

We report three cases of an orbital soft tissue lesion that fulfills the histologic, immunohistochemical, and electron microscopic criteria for solitary fibrous tumor, an entity previously described as a pleural tumor, but recently reported to occur in other locations. All three patients presented with proptosis. Two of the patients were cured by simple excision, and one patient had two recurrences, the last recurrence incompletely excised. The findings indicate that solitary fibrous tumor can occur in the orbit and, like solitary fibrous tumors of other anatomic sites, may behave in a nonaggressive or occasionally, locally aggressive fashion, with as yet no metastatic potential demonstrated in orbital lesions.

Chondroid lipoma, a tumor of white fat cells. A brief report of two cases with ultrastructural analysis.

Chondroid lipoma is a recently described variant of lipoma with unusual morphologic features. Although classified as a fatty neoplasm, its phenotype is uncertain because it has not been determined whether cartilage is a real component or only simulated by light microscopy and whether the adipocytes demonstrate white or brown fat differentiation, issues that can be resolved only by electron microscopy. We present two cases of chondroid lipoma that ultrastructurally showed abundant intracytoplasmic lipid and glycogen and numerous pinocytotic vesicles, characteristic of white adipocytes. These findings support the conclusion that these tumors are composed solely of fat without true cartilage differentiation.

Lipomatous hemangiopericytoma. A histologic, ultrastructural and immunohistochemical study of a unique variant of hemangiopericytoma.

We report three cases of a unique, previously undescribed soft tissue tumor composed of mature adipocytes and hemangiopericytomatous areas, for which we propose the term lipomatous hemangiopericytoma. The tumors occurred in adults and were located in the sinonasal area, the soft tissue of the shoulder, and the retroperitoneum. The tumors ranged in size from 4 to 10 cm in greatest diameter and grossly were solid and ranged from tan to yellow. Histologically, they were composed of a variable admixture of benign lipomatous and hemangiopericytomatous components. Immunohistochemically, they stained with antibodies to vimentin and not to alpha-smooth-muscle actin, muscle-specific actin, desmin, S-100 protein, glial fibrillary acidic protein, epithelial membrane antigen, or keratin. Ultrastructurally, the cells constituting the hemangiopericytomatous areas had the features of pericytes, and no lipoblasts or transitional forms between lipocytes and pericytes were found. The histologic differential diagnosis of this neoplasm includes spindle-cell lipoma, angiolipoma, liposarcomas, tumors showing smooth muscle and adipocytic differentiation, and hemangiopericytoma infiltrating fat. Because of the small number of cases and the limited follow-up, we cannot be certain of their biologic behavior, although we expect that they are benign. Lipomatous hemangiopericytoma represents a distinctive pathologic entity that should be recognized and studied further.

Retroperitoneal malignant meningioma. A light microscopic, immunohistochemical, and ultrastructural study.

Malignant meningiomas are uncommon and rarely occur outside the central nervous system. We describe herein a morphologically unusual malignant neoplasm that arose in the retroperitoneum of a 25-year-old woman. The tumor was composed of sheets of epithelioid cells that were frequently arranged in prominent whorls. By electron microscopy, the neoplastic cells had long, tapering cell processes that formed numerous interdigitations; many junctions including desmosomes; and abundant intermediate filaments. Immunohistochemistry showed that the tumor cells expressed vimentin, keratin, and epithelial membrane antigen. Based on these findings, the neoplasm was classified as a malignant meningioma. According to our review of the literature, this is the first reported occurrence of a primary retroperitoneal meningothelial neoplasm and the second reported case of an ectopic meningioma that was malignant.

Lipofuscin pigmentation (so-called "melanosis") of the prostate.

Although intraepithelial pigment in the prostate gland has been termed melanosis, the nature of the pigment is not entirely clear, and many pathologists are not aware of its existence. We examined 863 hematoxylin and eosin (H + E) stained slides from 150 surgical specimens of prostate (69 needle biopsies, 66 transurethral resections, 14 radical prostatectomies, and 1 suprapubic prostatectomy) from 149 patients (age range, 47 to 90 years; mean 70 years) in an effort to characterize this pigment. The 1-3 microns in diameter, predominantly subnuclear, yellow-brown to gray-brown granules with a dark blue rim (by H + E) stained positively with Fontana-Masson, periodic acid-Schiff with diastase, Congo red, luxol fast blue, and oil-red-O and exhibited yellow autofluorescence consistent with lipofuscin. H + E stained slides revealed pigment in the benign epithelium in 86 of 150 cases (57%), within stromal macrophages in eight cases, and in atypical epithelium in two cases of high-grade prostatic intraepithelial neoplasia. Ten cases of invasive adenocarcinoma without recognizable pigment in H + E stained sections were stained by the Fontana-Masson technique, and pigment was identified in malignant epithelium in three of these cases. Ultrastructural examination of intraepithelial pigment in KII-fixed tissue from three radical prostatectomy specimens demonstrated the typical appearance of lipofuscin. Although intraepithelial pigment in prostatic biopsy or resection specimens is usually considered characteristic of seminal vesicle epithelium, our study demonstrates that lipofuscin is commonly present in epithelial cells of benign prostatic hyperplasia and less frequently in those of prostatic intraepithelial neoplasia and adenocarcinoma. The recognition of this pigment is important in preventing diagnostic confusion with seminal vesicle epithelium and with melanocytic lesions.

Pulmonary blastoma with argyrophil cells and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal lung).

A tumor of the lung in a 35-year-old woman contained numerous complex, branching tubules resembling the developing fetal lung in its canalicular state. Some of the epithelial cells within the tubules were argyrophilic, and electron microscopy demonstrated the dense-core neurosecretory-type cytoplasmic granules. These characteristics support an endodermal origin for this neoplasm. Morphologically the tubules are similar to the epithelial component seen in pulmonary blastoma, but the tumor lacks the sarcomatous areas integral to the concept of blastoma. The designation pulmonary endodermal tumor resembling fetal lung may better describe this unusual neoplasm.