The respiratory epithelium. VII. Epidermoid metaplasia of hamster tracheal epithelium during regeneration following mechanical injury.

Regeneration was studied in female Syrian golden hamster tracheal epithelium. The epithelium was focally removed in vivo by scraping it with a blunt probe. At 2 hours, virtually all cells had sloughed from the injured area leaving a bare basal lamina. At 6 and 12 hours, flattened cells that migrated from adjacent uninjured epithelium partially covered the denuded basal lamina. Increased cell division did not occur at these times. Many of the simple squamous cells contained well-developed endoplasmic reticulum, Golgi apparatus, and mucous granules. Other cells resembled basal cells. At 24 hours the defect was covered by one or two layers of simple squamous cells. At that time, many of those cells were in division, and cell division was also greatly increased in mucous cells and basal cells in the uninjured epithelium distant from the defect. At 48 hours the epithelium was stratified, composed of four or five layers of polygonal to flattened cells, typical of nonkeratinizing epidermoid metaplasia. The cells contained many tonofilament bundles, a large Golgi apparatus, and many tiny mucous granules. Mitoses were seen in all cell layers. At 72 hours, the surface layer of cells was undifferentiated (indifferent cells) overlying an epithelium that otherwise retained its epidermoid character. Indifferent cells were characterized by an electron-lucent cytoplasm and a lack of tonofilament bundles, mucous granules, or cilla. Cells similar in other respects to indifferent cells were seen that possessed mucous granules or early signs of cilla formation. Some cells showed mucous granules and cilla developing in the same cell. By 96 hours, the regenerated epithelium was fully differentiated and was indistinguishable from the normal epithelium. These observations show that mucous cells have a significant role in the regenerative response. Mucous cells have a dual potential; they can undergo epidermoid metaplasia and still retain the ability to secrete mucus. The study explains the universal occurrence of mucosubstances in areas of epidermoid metaplasia and makes more understandable the previously reported fact that many bronchogenic carcinomas are combined epidermoid and adenocarcinomas. In the presence of a carcinogen, the hypothesis has been forwarded that initiation of mucous cells and basal cells occurs, which leads to malignant transformation and produces tumors that show active secretory activity and keratinization, often in the same cell.

The respiratory epithelium. III. Histogenesis of epidermoid metaplasia and carcinoma in situ in the human.

The histogenesis of epidermoid metaplasia and carcinoma in situ was analyzed in human bronchial epithelium. The conclusion is that epidermoid metaplasia and carcinoma in situ can result from conversion of mucous cells. This implies the direct transformation of one type of fully differentiated cell to another. The study therefore emphasizes the differentiation potentialities of the mucous cells that can divide and undergo goblet cell hyperplasia and epidermoid metaplasia. Epidermoid metaplasia is a common reaction to injury in the bronchus. In our series of cases it was especially frequent in patients without neoplastic disease who had undergone intratracheal intubation or tracheostomy and who had been maintained on a respirator in the Shock Trauma Unit, University of Maryland. Future studies will be required to distinguish the difference, if any, between epidermoid metaplasia destined to become malignant carcinoma and that which is not. One difference noted in this study was the absence of overt cornification in epidermoid metaplasia in patients without neoplastic disease.

Long-term organ culture of human uterine endocervix.

Explants of human endocervix have been maintained in organ culture for 24 weeks. The epithelium was viable for the entire duration of culture, as demonstrated by ultrastructural morphology and mitotic activity. The epithelium of the explants retained a near normal morphology for 2 to 4 weeks. The only changes observed were decreased mucus secretion in columnar cells, focal epidermoid metaplasia, and an increase in autophagic vacuoles. Subsequently, a slowly progressive transformation of the columnar epithelium into a metaplastic epithelium was observed, with loss of mucus-secreting columnar cells and ciliated cells and the appearance of cuboidal and flattened epidermoid cells, forming often two to three layers. Metaplasia began at the top of the papillae and ridges and extended progressively downwards into the clefts. Nevertheless, in a few areas deep in the clefts, columnar cells retained evidence of mucus secretion during the entire duration of culture. Epidermoid metaplasia appeared to develop in the explants by transformation of columnar mucous cells into cuboidal and flattened cells with epidermoid characteristics. This hypothesis is supported by ultrastructural observations that showed mucus secretion and early keratinization in the metaplastic cells. Mitotic figures were observed with transmission electron microscopy for up to 24 weeks, and all dividing cells contained mucous granules.

Identification and localization of 7B2 protein in human, porcine, and rat thyroid gland and in human medullary carcinoma.

The novel, highly conserved polypeptide 7B2, which belongs to a new protein superfamily, was isolated from human and porcine hypophysis. The availability of a specific antibody to a synthetic fragment enabled 7B2 localization in a number of neurocrine and endocrine tissues and revealed its secretory character. 7B2 was purified from thyroid homogenates by HPLC chromatography and characterized by gel permeation chromatography (dimeric mol wt, approximately 40,000) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (monomeric mol wt, 20,750). By immunocytochemistry 7B2 was colocalized with calcitonin in parafollicular cells and identified within secretory granules by electron microscopy. Three of nineteen human medullary carcinoma cases showed immunoreactive 7B2 within the early and late hyperplasia stages and neoplasia. Results suggest that 7B2 may play a role in endocrine function, possibly as a secretory substance, and may be a histochemical marker in addition to calcitonin for medullary carcinoma.

Myofibroblasts in the stroma of invasive and metastatic carcinoma: a possible host response to neoplasia.

After observing the presence of numerous stromal myofibroblasts in scirrhous mammary carcinomas, a series of invasive and metastatic carcinomas from diverse sites was examined by electron microscopy to determine whether myofibroblasts might also be present in their stroma. Myofibroblasts were identified in each instance and were most abundant in neoplasms which were hard, sclerotic, and retracted. This finding suggests that myofibroblasts represent a component of the stromal reaction to many carcinomas and contribute to the desmoplasia and retraction which characterize many of these neoplasms. The host commands several responses to neoplasia. As a result of the expression of tumor-associated antigens, the immune system contributes lymphocytes, macrophages, and antibodies, a reflection of immunologic surveillance against neoplasia. In contrast to experimental systems tumor neoantigens are poorly expressed or even lacking in many human neoplasms; thus, the immune system may be weakly stimulated or not activated at all. Tumor neovascularization induced by a tumor-angiogenesis factor represents a second host response, possibly deleterious, for it may facilitate tumor dissemination. The stromal myofibroblast reaction to many invasive and metastatic carcinomas may constitute a third, albeit more primitive response. The density of collagen produced and contractile state of such tissue may signify an attempt by the host stroma to contain the neoplasm and impede vascular invasion. If so, myofibroblast induction may complement immune surveillance or constitute a separate mechanism of response to invasive neoplasia in man.

Glycogen-rich clear cell rhabdomyosarcoma of the mediastinum. Potential diagnostic pitfall.

A 63-year-old black man of Caribbean origin, seropositive for human T-cell lymphoma virus type I (HTLV-I), presented with a 4-week history of progressive dyspnea, and was found to have a tumor of the anterior mediastinum. Incisional biopsy revealed a malignant neoplasm with a solid pattern of glycogen-rich clear cells. Diffuse expression of vimentin was observed, whereas only rare cells were immunoreactive for muscle-specific actin and desmin. Ultrastructure revealed a large amount of mono-particulate glycogen in most cells and features of rhabdomyogenic differentiation in occasional cells. The autopsy revealed a 23 x 14-cm (1,345 g), soft and white mediastinal neoplasm bulging in the right thorax with right pleural metastases. HTLV-1 proviral genome was not detected within tumor cells by polymerase chain reaction. This rhabdomyosarcoma is best classified as the solid subtype of the alveolar variant, with an unusually large amount of cytoplasmic glycogen. Clear cell rhabdomyosarcoma could be potentially confused with more commonly encountered clear cell tumors, particularly in the mediastinum.

Pleomorphic soft tissue myogenic sarcomas of adulthood. A reappraisal in the mid-1990s.

325 diverse sarcomas, 39 rhabdomyosarcomas (RMS), including all histologic variants, and 135 leiomyosarcomas (LMS) were identified. Within these two groups, 18 (46%) of the RMS and 14 (10%) of the LMS represented pleomorphic variants. These neoplasms were studied by morphology (histology and ultrastructure) and by immunohistochemical methods employing antibodies to intermediate filaments (vimentin and desmin) and actin isoforms [alpha-smooth (sm) and alpha-sarcomeric (sr) actins]. Twenty-four pleomorphic malignant fibrous histiocytomas (MFH) and eight pleomorphic liposarcomas (LS) were examined in a similar fashion. By light microscopy, the pleomorphic RMS, LMS, and MFH were indistinguishable, as each was dominated by pleomorphic cells disposed in a haphazard growth pattern; moreover, many featured fascicular, storiform, and sclerotic zones. The distinction between these neoplasms became apparent only following immunohistochemistry and/or ultrastructural study. All pleomorphic RMS disclosed rudimentary sarcomeres and exhibited the following cytoskeletal profile: vimentin (+) (18 of 18), desmin (+) (14 of 18), alpha-sr actin (+) (18 of 18) and alpha-sm actin (+) (five of 18). All the pleomorphic LMS featured smooth-muscle differentiation of variable degrees in the form of cytoplasmic bundles of microfilaments and associated dense bodies; their cytoskeletal profile was vimentin (+) (14 of 14), desmin (+) (seven of 14), alpha-sr actin (+) (none of 14), and alpha-sm actin (+) (eight of 14). The latter was demonstrated in all moderately differentiated, but absent or only focally expressed in poorly differentiated variants. All pleomorphic MFH and LS were devoid of myogenic (skeletal or smooth) ultrastructural features and expressed vimentin solely. This combined morphological and immunohistochemical study illustrates the following: First, these pleomorphic sarcomas are often indistinguishable by histologic growth pattern alone; thus, an accurate diagnosis requires study with all of these techniques. Second, pleomorphic myogenic sarcomas are restricted to adults and are not uncommon neoplasms among pleomorphic sarcomas: RMS (28%), LMS (21%), MFH (38%), and LS (13%). Third, the study defines desmin-negative and alpha-sm actin-positive pleomorphic RMS, and desmin-negative and alpha-sm-actin-negative pleomorphic LMS.

Hypertension with renal arterial stenosis: humoral, hemodynamic and histopathologic factors.

In 46 hypertensive patients with unilateral renal arterial stenosis, peripheral and renal venous plasma renin activity, juxtaglomerular cell count and granularity and systolic pressure gradient across the stenosis were determined. After corrective surgery and a mean postoperative observation period of 4.3 years, 18 patients were completely relieved of hypertension (good responders), 14 had a substantial reduction in arterial pressure (fair responders) and 14 remained hypertensive (poor responders). Analysis of plasma renin activity in both renal veins indicated that a ratio (stenotic/nonstenotic side) greater than 2.0 correctly predicted a favorable surgical result in all cases. Peripheral plasma renin activity was greater than normal in 65 percent of good responders, in 50 percent of fair responders and in one nonresponder. The prognostic accuracy of a pressure gradient greater than 40 mm Hg was 78 percent; no patient with a gradient of less than 40 mm Hg benefited from surgery. An increased juxtaglomerular cell count on the affected side predicted a successful operative result in 88 percent, as did increased granularity in 85 percent of cases. Renal venous renin ratio correlated positively (r =0.738, P less than 0.001) with the pressure gradient across the stenosis. The renal venous plasma renin activity of the affected side also correlated positively (r = 0.771, P less than 0.001) with the absolute count of granular cells in the juxtaglomerular apparatus. Plasma renin activity in both renal veins is the most reliable predictor of operative outcome. The addition of juxtaglomerular cell count or pressure gradient across the stenosis increases prognostic accuracy only slightly. The close mutual correlations between renal venous renin ratio, pressure gradient and juxtaglomerular cell count support the experimental evidence of a causal relation between the hemodynamic effects of the arterial lesion and the humoral and histologic changes observed in hypertension with renal arterial stenosis.

Renal and vascular effects of chronic endothelin receptor antagonism in malignant hypertensive rats.

The effect of the combined ETA/ETB endothelin receptor antagonist bosentan on blood pressure, vascular hypertrophy, and pathologic renal changes was investigated in a model of malignant hypertension, severe vascular hypertrophy, and enhanced vascular expression of endothelin-1, the deoxycorticosterone acetate (DOCA), and salt-treated spontaneously hypertensive rat (SHR). DOCA-salt treated SHR received 100 mg bosentan per kilogram weight per day mixed with their food. Systolic blood pressure of untreated DOCA-salt SHR rose to 241 +/- 1.5 mm Hg, whereas that of bosentan-treated rats rose to 221 +/- 5.1 mm Hg (P < .01). Cardiac and conduit artery mass were not affected by treatment. Small arteries from the coronary, renal, and mesenteric circulations showed a smaller media width and cross-sectional area of the media in rats treated with bosentan than in untreated rats. The kidneys showed the presence of fibrinoid necrosis in a high percentage of afferent arterioles and glomeruli of untreated DOCA-SHR. Some kidneys of treated rats exhibited less severe vascular hypertrophy and lesser extent of vascular or glomerular fibrinoid necrosis, but the renal injury score of bosentan-treated DOCA-SHR was only at the limit of significance from that of untreated rats (P = .06). These results suggest a role for endothelin-1 in blood pressure elevation and the severe vascular hypertrophy of small arteries of the coronary, renal, and mesenteric vasculature, but not of the heart or larger conduit vessels in the malignant hypertension that SHR develop after treatment with DOCA and salt. Although some bosentan-treated rats showed fewer renal lesions, a significant effect on renal pathology could not be unambiguously demonstrated. Further studies will be necessary to determine whether endothelin antagonists may indeed offer some degree of renal protection and have therapeutic potential in severe or malignant hypertension.

Lymphoproliferative lesions in BB Wistar rats.

Fifteen percent of long-term diabetic BB Wistar rats developed abdominal B cell lymphoproliferative lesions which ranged from minute mesenteric aggregates of plasma cells and lymphocytes to malignant lymphoma with features of immunoblastic sarcoma or plasma-cell lymphoma. Lymph nodes in younger BB Wistar rats, both diabetic and nondiabetic, demonstrated variable degrees, often extensive, of paracortical and medullary replacement by plasmacytoid lymphocytes and/or plasma cells. This study documents morphologic abnormalities in lymph nodes of BB Wistar rats, thus providing additional evidence of altered immunity in this model.

Cutaneous Endosalpingiosis.

Endosalpingiosis is the aberrant growth of Fallopian tube epithelium outside of its normal location. This phenomenon has long been recognized by gynecologists, since it most often occurs in the pelvic cavity after salpingectomy. We describe a 30-year-old woman with cutaneous columnar ciliated cysts of the umbilicus and adjacent skin that developed shortly after salpingectomy. Evidence is presented that these cysts are cutaneous endosalpingiosis.

Medullary thyroid carcinoma: localization of a mediastinal metastasis with I-131 MIBG.

An I-131 metaiodobenzylguanidine (MIBG) scan was performed in a patient with a familial history of multiple endocrine neoplasia (MEN) type 2 and recurrent medullary thyroid carcinoma (MTC). The scan revealed a mediastinal metastasis from her MTC and there was also an imaging pattern of bilateral adreno-medullary hyperplasia. Although the literature indicates that I-131-MIBG scanning is not sufficiently sensitive for the detection of MTC, this procedure has proven to be of value in the management of chosen patients with MEN-associated MTC.

[Polypoid pseudosarcomatous carcinoma. Histogenesis with evidence of myofibroblastic response (author's tranls)]. / Carcinoma polypoïde pseudosarcomateux. Histogenèse. Evidence d'une résponse myofibroblastique.

Three polypoid pseudosarcomatous carcinomas (PPSC) of the oesophagus, larynx, and urinary bladder were studied by electron microscopy to determine their histogenesis and the cellular associations which might contribute to their relative clinical benignity. In addition to a polypoid, exophytic growth, the three shared similar light microscopy features : surface ulceration, a minimal invasive epithelial component and prominent spindle-cell proliferation in association with reticulin and collagen. Three cell types were identified ultrastructurally : 1. - spindle and polygonal cells demonstrating tonofilaments and plasma membrane specialization, denoting an epithelial origin; 2. - cells identical to the first type, but with cytoplasm containing intracellular collagen ; and 3. - myofibroblasts characterized by a rough endoplasmic reticulum, prominent Golgi complexes and well formed bundles of myofilaments. The latter constituted the principal cellular component of the tumors. These findings demonstrate that the stroma of the PPSC is dominated by myofibroblasts, which probably synthesized much of the collagen associated with these neoplasms. It is suggested that the myofibroblasts signify an expression of host reactivity to the invasive carcinoma and constitute a beneficial response which contains and restricts local and vascular invasion by neoplastic cells, this contributing to the relative benignity of the neoplasms.

Evaluation of a preemptive strategy for BK polyomavirus-associated nephropathy based on prospective monitoring of BK viremia: a kidney transplantation center experience.

INTRODUCTION: BK polyomavirus-associated nephropathy (BKPVAN) is a major cause of renal failure early after kidney transplantation. The present study reports the preliminary results of prospective monitoring including a preemptive strategy for BKPVAN during the first year after kidney transplantation. METHODS: We monitored BK virus DNA in blood at months 1, 2, 3, 6, 9, and 12 among 92 subjects who received induction therapy (basiliximab or antithymocyte globulin), and maintenance immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. Patients with two or more consecutive measurements of viral load >10(4) copies/mL were treated with a stepwise approach including dose reduction or discontinuation of mycophenolate mofetil eventually followed by reduction of tacrolimus and introduction of leflunomide. RESULTS: Within 1 year, seven (7%) patients displayed sustained BK viremia at a median of 92 days after transplantation. Among 68 patients who underwent a renal allograft biopsy, seven were diagnosed as BKPVAN at a median of 15 weeks after transplantation. The diagnosis was achieved by a surveillance biopsy in four patients with stable renal function. BKPVAN was preceded by asymptomatic viremia except for two cases in whom BK viremia occurred at 6 or 11 months, after the histological diagnosis. At 12 months, six patients had cleared their viremia. Serum creatinine levels had stabilized in six recipients with BKPVAN estimated renal function was 43.7 ± 16.3 mL/min in patients with viremia and/or BKPVAN versus 61.3 ± 20.1 mL/min among patients who never became viremic (P = .03). None of the patients with viremia and/or BKPVAN lost the allograft. CONCLUSION: BKPVAN may occur early after kidney transplantation, at a low or undetectable viremia or at some weeks after the first positive viremia. Intensive monitoring during the first 4 months after transplantation together with early protocol biopsies or interventions prompted by BK viremia may optimize BKPVAN diagnosis at a subclinical stage, thus avoiding renal dysfunction.

Ciclosporin in Goodpasture's syndrome.

We report the case of a 39-year-old male patient with Goodpasture's syndrome. Despite therapy with prednisone, cyclophosphamide and plasma exchanges, serum creatinine (Scr) progressively increased up to 10.3 mg/dl (936 mumol/l) and hemoptysis recurred 3 months after initiation of treatment. Ciclosporin (CS) starting at 6 mg/kg/day was given. Scr began to decrease 2 weeks later and eventually stabilized at approximately 2.0 mg% (182 mumol/l). This case illustrates one of the potential uses of CS in human glomerular disease.

B cell lymphoproliferation in spontaneously diabetic BB Wistar rats.

Ninety-six spontaneously diabetic BB Wistar rats were maintained for their natural life span and, at death, were autopsied together with 86 age-and sex-matched non-diabetic BB control rats. A 15% incidence of abdominal B cell lymphoproliferative lesions was documented in the diabetic rats compared with 1% incidence in the non-diabetic rats (p less than 0.005). The B cell lymphoproliferative process included minute mesenteric and omental aggregates of plasma cells and small lymphocytes (one rat), atypical partially fibrotic lymphoproliferative mesenteric nodules (three rats), and malignant lymphoma with features of immunoblastic sarcoma (eight rats) or plasma cell lymphoma (two rats). Cytoplasmic immunoglobulin was demonstrated in two of the four lymphomas examined by the peroxidase-antiperoxidase technique, thus confirming their B cell derivation. The striking incidence of B cell lymphoproliferation in this diabetic population is additional evidence of altered immunity in this animal model of insulin-dependent diabetes mellitus.