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PubMed2000

Problems in the differential diagnosis of endometrial hyperplasia and carcinoma.

The differential diagnosis of endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma is complicated not only by the resemblance of these lesions to each other, but also by their tendency to be overdiagnosed (particularly hyperplasia) on the background of polyps, endometritis, artifacts, and even normally cycling endometrium. Atypical hyperplasia may also be overdiagnosed when epithelial metaplastic changes occur in simple or complex hyperplasia without atypia. Low-grade adenocarcinomas are best recognized by architectural evidence of stromal invasion, usually in the form of stromal disappearance, desmoplasia, necrosis, or combinations of these findings between adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers associated with manifestations of endogenous or exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and the estimation and reporting of myometrial invasion are presented.

Carcinoma, Endometrioid↗
PubMed2000

p27kip1 expression distinguishes papillary hyperplasia in Graves' disease from papillary thyroid carcinoma.

In most cases, the histopathologic and cytologic distinction between Graves' disease and papillary thyroid carcinoma is relatively easy, but on occasion Graves' disease may simulate a thyroid papillary carcinoma. For example, papillary fronds with fibrovascular cores may be present in both Graves' disease and papillary carcinoma. p27kip1 (p27) is a cyclin-dependent kinase inhibitory protein that has been shown to be an independent prognostic factor in a variety of human tumors. Our previous studies of p27 expression in hyperplastic and neoplastic endocrine lesions showed that the level of p27 was quite different in these two conditions. To determine if this distinction could also be made between Graves' disease and papillary carcinoma, we analyzed expression of p27 and other cell cycle proteins in a series of cases of Graves' disease with papillary hyperplasia and a series of papillary thyroid carcinomas. Formalin-fixed paraffin-embedded tissues from 61 randomly selected patients with thyroid disease, including 29 cases of Graves' disease with papillary architectural features and 32 cases of papillary carcinoma, were analyzed for expression of p27, Ki-67, and DNA topoisomerase II alpha (topo II alpha) by immunostaining. The distribution of immunoreactivity was analyzed by quantifying the percentage of positive nuclei that was expressed as the labeling index (LI) plus or minus the standard error of the mean. The papillary hyperplasia of Graves' disease had a p27 LI of 68.2 +/- 3.1 (range, 24 to 88), whereas papillary carcinomas had a LI of 25.6 +/- 2.5 (range, 12 to 70) (P < .0001). No significant differences in Ki-67 or topo II alpha expression were identified between papillary hyperplasia in Graves' disease and papillary carcinoma. These results indicate that p27 protein expression is significantly higher in papillary hyperplasia of Graves' disease compared to papillary carcinoma, which may be diagnostically useful in difficult cases.

Adult↗
PubMed1999

Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycaemia.

1. We examined whether endogenous inhibitors of NO synthesis are involved in the augmentation of intimal hyperplasia in rabbits with hyperglycaemia induced by alloxan. 2. Four weeks after the endothelial denudation of carotid artery which had been performed 12 weeks after alloxan, the intimal hyperplasia was greatly augmented with hyperglycaemia. The degree of hyperplasia was assessed using three different parameters of histopathological findings as well as changes in luminal area and intima: media ratio. 3. There were positive and significant correlations between intima:media ratio, plasma glucose, and concentrations of N(G)-monomethyl-L-arginine (L-NMMA) and N(G), N(G)-dimethyl-L-arginine (ADMA) in endothelial cells, that is, the intima:media ratio became greater as plasma glucose and endothelial L-NMMA and ADMA were increased. Furthermore, endothelial L-NMMA and ADMA were increased in proportion to the increase in plasma glucose. 4. In contrast, there were inverse and significant correlations between cyclic GMP production by carotid artery strips with endothelium and plasma glucose, between cyclic GMP production and endothelial L-NMMA and ADMA, and between the intima:media ratio and cyclic GMP production. 5. Exogenously applied L-NMMA and ADMA inhibited cyclic GMP production in a concentration-dependent manner. IC50 values were determined to be 12.1 microM for the former and 26.2 microM for the latter. The cyclic GMP production was abolished after the deliberate removal of endothelium from the artery strips. 6. These results suggest that the augmentation of intimal hyperplasia with hyperglycaemia is closely related to increased accumulation of L-NMMA and ADMA with hyperglycaemia, which would result in an accelerated reduction in NO production/release by endothelial cells.

Alloxan↗
PubMed1999

Effect of an angiotensin II receptor antagonist, candesartan cilexetil, on canine intima hyperplasia after balloon injury.

The roles of angiotensin (Ang) II as produced by two different enzymes, angiotensin-converting enzyme (ACE) and chymase, were investigated in a canine experimental model where intima hyperplasia was induced by balloon catheterization in the common carotid and femoral arteries. The animals received oral candesartan cilexetil (3 mg/kg) or enalapril (10 mg/kg) twice a day for 5 weeks. After 1 week of active drug therapy, the common carotid and femoral arteries were unilaterally injured by balloon catheterization. In the common carotid arteries, both ACE and chymase activities were increased by the injury, with the increase in chymase activities being greater than that in ACE activities. In the femoral arteries, ACE, but not chymase, activities were significantly increased by the injury. Both candesartan cilexetil and enalapril reduced blood pressure almost equally. Enalapril increased plasma renin activity more strongly than did candesartan cilexetil, and significantly decreased vascular and plasma ACE activities. Candesartan cilexetil significantly suppressed the formation of intima hyperplasia in both the carotid and femoral arteries, while enalapril significantly suppressed intima hyperplasia in the femoral, but not in the carotid arteries. These results indicate that local Ang II production by ACE and chymase is involved in the hyperplasia seen in injured intima, and the difference in the inhibitory action of candesartan and enalapril reflects the extent of contribution of each enzyme. The effect of the ACE inhibitor, enalapril, depended on the activity of ACE, whereas that of the Ang II receptor antagonist, candesartan, was independent of ACE activity.

Angiotensin Receptor Antagonists↗
PubMed1999

Conditional expression of the ErbB2 oncogene elicits reversible hyperplasia in stratified epithelia and up-regulation of TGFalpha expression in transgenic mice.

The ErbB2 receptor tyrosine kinase (RTK) is expressed in basal cells of squamous epithelia and the outer root sheath of hair follicles. We previously showed that constitutive expression of activated ErbB2 directed to these sites in the skin by the keratin 14 (K14) promoter produces prominent hair follicle abnormalities and striking skin hyperplasia in transgenic mice. However, perinatal lethality precluded the establishment of a transgenic line for analysis of ErbB2 function in adult animals. To investigate the significance of ErbB2 signaling in epithelial tissues during and post development, we developed a K14-rtTA/TetRE-ErbB2 'Tet-On' bitransgenic mouse system. These mice were normal until the ErbB2 transgene was induced by exposure to doxycycline (Dox). Prenatal induction resulted in perinatal death. Postnatally, ErbB2 transgene expression was observed at 4 h after the initiation of Dox, and reached a plateau at 24 h. Skin hyperplasia followed after 2 days and these changes reverted to normal upon Dox withdrawal. In adults, as in the neonates, prolonged ErbB2 induction caused prominent skin and hair follicle hyperplasias. Severe hyperplasias in the cornea, eye lids, tongue and esophagus were also observed. ErbB2 transgene induction was accompanied by increased expression of TGFalpha, a ligand of epidermal growth factor receptor (EGFR), and to a lesser extent, EGFR, further enhancing RTK signal transduction. We conclude that ErbB2 plays important roles in both development and maintenance of hair follicles and diverse squamous epithelia and that this ligand-inducible and tissue-specific 'Tet-On' transgenic mouse system provides a means to study transgenes with perinatal toxicity.

Animals↗
PubMed2003

Activation of beta-catenin in prostate epithelium induces hyperplasias and squamous transdifferentiation.

The Wnt/beta-catenin signaling pathway is critical for normal mammalian development, the specification of epidermal cells and neoplastic transformation of intestinal epithelium. However, precise molecular information regarding cell-specific responses to beta-catenin signaling has been limited. This question was addressed using a mouse model in which exon 3 of the beta-catenin gene was deleted in several cell types with loxP-mediated recombination utilizing a Cre transgene under control of the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). The stabilization of beta-catenin in prostate epithelium resulted in hyperplasias and extensive transdifferentiation into epidermal-like structures, which expressed keratins 1 and 6, filaggrin, loricrin and involucrin. The cell-specific loss of NKCC1 protein and reduced nuclear Stat5a is further suggestive of a loss of prostate epithelial characteristics. In addition to the prostate, hyperplasias and squamous metaplasias were detected in epithelia of the epididymis, vas deferens, coagulating gland, preputial gland and salivary gland. However, and in contrast to a recent study, no lesions reminiscent of high-grade prostate intraepithelial neoplasia were detected. Since beta-catenin was activated in several cell types and impinged upon the viability of these mice, it was not possible to evaluate the cumulative effect over more than 3 months. To assess long-term consequences of beta-catenin activation, mutant and control prostate tissues were transplanted into the mammary fat pads of wild-type males. Notably, squamous metaplasias, intra-acinous hyperplasia and possible neoplastic transformation were observed after a total of 18 weeks of beta-catenin stimulation. This suggests that the transdifferentiation into squamous metaplasias is an early response of endoderm-derived cells to beta-catenin, and that the development of intra-acinous hyperplasias or neoplastic foci is a later event.

Adipose Tissue↗
PubMed2005

Human Cripto-1 overexpression in the mouse mammary gland results in the development of hyperplasia and adenocarcinoma.

Human Cripto-1 (CR-1) is overexpressed in approximately 80% of human breast, colon and lung carcinomas. Mouse Cr-1 upregulation is also observed in a number of transgenic (Tg) mouse mammary tumors. To determine whether CR-1 can alter mammary gland development and/or may contribute to tumorigenesis in vivo, we have generated Tg mouse lines that express human CR-1 under the transcriptional control of the mouse mammary tumor virus (MMTV). Stable Tg MMTV/CR-1 FVB/N lines expressing different levels of CR-1 were analysed. Virgin female MMTV/CR-1 Tg mice exhibited enhanced ductal branching, dilated ducts, intraductal hyperplasia, hyperplastic alveolar nodules and condensation of the mammary stroma. Virgin aged MMTV/CR-1 Tg mice also possessed persistent end buds. In aged multiparous MMTV/CR-1 mice, the hyperplastic phenotype was most pronounced with multifocal hyperplasias. In the highest CR-1-expressing subline, G4, 38% (12/31) of the multiparous animals aged 12-20 months developed hyperplasias and approximately 33% (11/31) developed papillary adenocarcinomas. The long latency period suggests that additional genetic alterations are required to facilitate mammary tumor formation in conjunction with CR-1. This is the first in vivo study that shows hyperplasia and tumor growth in CR-1-overexpressing animals.

Adenocarcinoma↗
PubMed1987

Cardiac and renal hyperplasia in newborn spontaneously hypertensive rats.

Cardiac hyperplasia in newborn spontaneously hypertensive rats (SHR) has been noted by our group as well as by other investigators. The present study was designed to establish whether early (neonatal) hyperplasia is confined to the heart or is a generalized phenomenon in this hypertensive model. The ventricles, kidney and liver of newborn SHR, Wistar and Wistar-Kyoto (WKY) rats were analysed for their protein and DNA content. Total organ weight and the organ/body weight ratio of the heart and kidney but not of the liver were significantly greater in the SHR than in the control rats, irrespective of total body weight. The higher relative DNA content (per 100 mg of tissue or 100 g body weight) indicated that hyperplasia rather than hypertrophy was responsible for the enlarged heart as well as the kidney of newborn SHR. The cause of this selective cardiac and renal hyperplasia is not yet known: it may be due to putative 'haemodynamic growth stimuli', an intrinsic genetic abnormality of cells in the heart and kidney, circulating growth-promoting factors, or innervation.

Animals↗
PubMed2001

Heparin-binding epidermal-growth-factor-like growth factor activation of keratinocyte ErbB receptors Mediates epidermal hyperplasia, a prominent side-effect of retinoid therapy.

Sun-protected human skin was maintained in organ culture and treated with all-trans retinoic acid in the presence or absence of reversible or irreversible pharmacologic antagonists of c-erbB receptor tyrosine kinase activity. In the absence of these inhibitors, all-trans retinoic acid induced epidermal hyperplasia comparable to that induced in intact skin by all-trans retinol or all-trans retinoic acid itself. There was a strong correlation between inhibition of epidermal hyperplasia in organ culture and inhibition of epidermal-growth-factor-dependent keratinocyte growth in monolayer culture. In additional studies it was shown that all-trans retinoic acid could overcome the known inhibitory effects of calcium on expression of HB-EGF-like growth factor mRNA in organ-cultured skin. Further, it was shown that an antibody to HB-EGF-like growth factor inhibited retinoid-stimulated epidermal hyperplasia in organ culture and reduced proliferation in cultured keratinocytes. In contrast, the c-erbB receptor tyrosine kinase antagonists and the neutralizing HB-EGF-like growth factor antibody were ineffective in inhibiting all-trans-retinoic-acid-dependent survival and proliferation of human dermal fibroblasts. Taken together, these data indicate (i) that retinoid-induced epidermal hyperplasia in human skin proceeds through c-erbB, and (ii) that HB-EGF-like growth factor is one of the c-erbB ligands mediating this effect.

Adult↗
PubMed1997

Pheochromocytoma due to unilateral adrenal medullary hyperplasia.

We describe two male patients, aged 17 and 47 years, with clinical and biochemical features of pheochromocytoma. Both patients had normal-sized adrenal glands on abdominal CT scan and abnormal unilateral uptake of I-123 metaiodobenzylguanidine (MIBG) on scintigraphy. The surgical adrenalectomy revealed normal macroscopic glands in both patients. Histological examination showed adrenal medullary hyperplasia with adrenal cortico-medullary ratios of 2:1 and 4:1. Unilateral adrenalectomy resulted in amelioration of symptoms and normalization of catecholamines excretion. DNA examination for RET protooncogene revealed no mutations in exons 10, 11, 13, 14 and 16. Our results suggest that diffuse adrenal medullary hyperplasia may be the initial pathological change in the adrenal gland leading, subsequently, to the development of nodular hyperplasia and adrenal medullary tumor. These results indicate that the syndrome of pheochromocytoma may occur as an unilateral adrenal medullary hyperplasia in patients without evidence for multiple endocrine neoplasia.

Adolescent↗
PubMed1997

Epithelial hyperplasia of usual type expresses both S100-alpha and S100-beta in a heterogeneous pattern but ductal carcinoma in situ can express only S100-alpha in a monotonous pattern.

Immunohistochemical identification of myoepithelial cells using alpha-smooth muscle actin provides little information about the nature of solid or quasi-solid portions of epithelial hyperplasia and ductal carcinoma in situ (DCIS) because actin-rich myoepithelial cells are usually demonstrated only in the stromal-epithelial junction of both lesions. We studied the differential distribution of alpha-subunit (S100-alpha) and beta-subunit (S100-beta) of S100 protein in actin-negative areas of usual epithelial hyperplasia and DCIS by employing the streptavidin method with monospecific rabbit antibodies against each subunit. All usual epithelial hyperplasias (n = 17) were composed of heterogeneous epithelial cell types; cells expressing S100-alpha and/or S100-beta were intermingled with non-expressing cells, resulting in a mosaic-like pattern. On the contrary, DCIS (n = 32) uniformly lacked immunoreactive S100-beta; S100-alpha was diffusely expressed in 24 (68.8%) DCIS (three solid/comedo, 13 cribriform, four endocrine, one micropapillary, three papillary variants) and negative in the remaining eight (31.2%) DCIS (one cribriform, two micropapillary, four papillary and one apocrine variants). In conclusion, in contrast to usual epithelial hyperplasia that expresses both S100-alpha and S100-beta in a heterogeneous pattern, DCIS can express only S100-alpha in a monotonous pattern, possibly signifying unidirectional differentiation toward secretory glandular epithelium.

Adult↗
PubMed1996

'Undifferentiated progenitor cells' in focal nodular hyperplasia of the liver.

Focal nodular hyperplasia is a tumour like lesion, characterized by a central fibrous scar with irradiating fibrous septa that surround hyperplastic nodules and contain multiple bile ductules. The origin of the bile ductular structures is not clear. Recently, we found evidence for the existence of human counterparts of rat oval cells (potential stem cells) that have the ability of differentiating towards both bile duct cells and hepatocytes. These cells were found in regenerating human liver as well as in chronic cholestatic conditions. Because cholestatic features are seen in focal nodular hyperplasia, we initiated an immunohistochemical study on 23 surgical specimens using antibodies specific for cytokeratins 7 and 19 (bile duct type cytokeratins), OV6 (rat oval cell marker), chromogranin-A (shown to be positive in reactive bile ductules and human oval-like cells) and neural cell adhesion molecule--NCAM (shown to be positive in reactive bile ductules) to investigate whether 'undifferentiated progenitor cells' are also present in focal nodular hyperplasia. Electronmicroscopy was applied in five cases. Bile ductules invariably showed immunoreactivity for CK7 and 19, OV6, chromogranin-A and NCAM. In addition, small individual cells with an oval nucleus and a small rim of cytoplasm, in the vicinity of the septa, were immunoreactive for chromogranin-A, CK7 and 19 and OV6. These cells were hardly recognizable on routine light microscopy. Clusters of periseptal hepatocytes, seemingly in continuity with bile ductular structures, had a transitional phenotype: they stained positive for chromogranin-A, CK7 and OV6 and sometimes formed liver cell rosettes. The number of OV6-positive hepatocytes was greater than the number of chromogranin-A and CK7 positive hepatocytes. This indicates that, in human liver, OV-6 is not purely a marker of progenitor cells. Ultrastructurally, small immature cells, highly resembling rat oval cells, were recognized in the vicinity of septa. In addition, transitional cells displaying characteristics both of hepatocytes and bile duct cells were also present. These results confirm the presence of 'undifferentiated progenitor cells' in focal nodular hyperplasia and suggest that the ductular reaction in these lesions results, at least partly, from activation of these cells.

Animals↗
PubMed1997

Multifocal alveolar hyperplasia associated with lymphangioleiomyomatosis in tuberous sclerosis.

Multifocal alveolar hyperplasia associated with pulmonary lymphangioleiomyomatosis is reported in a 21-year-old woman with tuberous sclerosis. Beside the cystic lesions of lymphangioleiomyomatosis, the tomography showed nodules up to 8 mm in both upper lobes. A proliferation of type II pneumonocytes and Clara cells lining the alveolar walls in an adenoma-like pattern was observed. Nuclear atypia, mitoses and necrosis were not observed, providing evidence against multicentric bronchioloalveolar carcinoma or micronodular atypical alveolar adenomatous hyperplasia. Whereas the lymphangioleiomyomatosis lesions showed strong positivity for HMB45 and expressed oestrogen and progesterone receptors, the alveolar hyperplasia was negative for these markers as it was for carcinoembryonic antigen, p53 and MIB1 antibodies. Multifocal alveolar hyperplasia in tuberous sclerosis is probably a benign hamartomatous lesion in our case without progression on a 2-year follow-up. Its histogenesis is unknown, but is possibly related to chromosome instability.

Adult↗
PubMed2002

Significant role of Fas ligand-binding but defective Fas receptor (CD95) in lymph node hyperplasia composed of abnormal double-negative T cells.

The functional differences between two mutations of the Fas (CD95) locus, Faslpr (lpr) and Faslprcg (lprcg), were investigated using bone marrow (BM) transplantation on the C3H mouse background. Both lpr/lpr and lprcg/lprcg BM transferred caused lymph node (LN) hyperplasia in lpr/+ and lprcg/+ recipients, although it was clearly smaller than that in lpr/lpr and lprcg/lprcg recipients of lpr/lpr and lprcg/lprcg BM. In addition, both BM induced significantly larger LN hyperplasia in lprcg/+ than lpr/+ recipients. Appearance of CD4- CD8-[double negative (DN)] T cells in the periphery is the most consistent phenotype of Fas mutations. Importantly, the proportion of DN T cells was higher in larger LN hyperplasia in the order of lpr/+, lprcg/+ and lpr/lpr or lprcg/lprcg recipients. On the other hand, both lpr/lpr and lprcg/lprcg BM transferred into wild-type (+/+) mice caused marked LN atrophy. The former, but not the latter, induced wasting syndrome. Faslg1d (gld)-homozygous lpr/lpr BM transferred into +/+ mice elicited LN hyperplasia of the same extent as that in lpr/lpr mice transferred with lpr/lpr BM, but not wasting syndrome. Taken together with the fact that DN T cells massively express Fas ligand (FasL), this study implied that FasL overexpressed on DN cells may be involved in the accumulation of DN T cells in LN, LN atrophy and wasting syndrome, and that lprcg Fas, which can bind to Fas ligand but not transduce apoptosis signal into cells, may modulate these pathological conditions by interfering with the binding of FasL to Fas.

Animals↗
PubMed2003

Is oral azithromycin effective for the treatment of cyclosporine-induced gingival hyperplasia in cardiac transplant recipients?

Anecdotal evidence suggests that azithromycin is effective for the treatment of cyclosporine-induced gingival hyperplasia in solid-organ transplant recipients. We present the cases of two heart transplant patients who insidiously developed gingival hyperplasia, likely because of immunosuppression with cyclosporine, which was treated with azithromycin. Evidence supporting the efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in solid organ transplant recipients was searched for, identified, and then critically assessed. While no data were found specifically evaluating azithromycin in cardiac transplant patients, there were nine pertinent papers identified that evaluated the clinical question of interest in the renal transplant population [Wahlstrom et al. (1995) The New England Journal of Medicine 332, 753; Boran et al. (1996) Transplantation Proceedings 28, 2316; Gomez et al. (1997) Nephrology Dialysis Transplantation 12, 2694; Ljutic (1997) Dialysis & Transplantation 26, 787; Puig et al. (1997) Transplantation Proceedings 29, 2379; Nash et al. (1998) Transplantation 65, 1611; Nowicki et al. (1998) Annals of Transplantation 3, 25; Wirnsberger et al. (1998) Transplantation Proceedings 30, 2117; Citterio et al. (2001) Transplantation Proceedings 33, 2134]. These studies and case reports are summarized. While more evidence is required to support routine use of azithromycin for the treatment of cyclosporine-induced gingival hyperplasia in cardiac transplant recipients, preliminary published evidence from renal transplant patients is certainly favourable.

Administration, Oral↗
PubMed2000

Benign prostatic hyperplasia-associated prostate-specific antigen (BPSA) shows unique immunoreactivity with anti-PSA monoclonal antibodies.

We previously identified a modified molecular form of prostate-specific antigen that is significantly elevated in the nodular transition zone tissue of prostates with benign prostatic hyperplasia. This prostate-specific antigen form, designated BPSA, is inactive and contains clipped polypeptide bonds at amino-acid residues Lys145-146 and Lys182-183. BPSA is not elevated in prostate cancer tissues and may therefore be a prostate-specific antigen marker to better discriminate benign prostatic hyperplasia from early prostate cancer. In this work we characterize the immunoreactivity of BPSA in competition assays with prostate-specific antigen using anti-prostate-specific antigen mAb recognizing six different epitopes on the prostate-specific antigen molecule. One mAb showed > 50% loss of immunoreactivtiy with BPSA compared with prostate-specific antigen, while the binding of two mAbs was largely unaffected and three mAbs had intermediate reactivity. BPSA purified from prostate tissue and seminal plasma, as well as BPSA generated in vitro by mild trypsin-treatment were found to have a similar pattern of reactivity to the six mAbs. However, other forms of inactive seminal plasma prostate-specific antigen, either intact or clipped at Lys145 only, had immunoreactivity similar to total prostate-specific antigen. These results demonstrate that BPSA has unique immunological properties from other forms of prostate-specific antigen, which should allow the development of BPSA-specific mAbs for the study of benign prostatic hyperplasia. Measurement of BPSA levels in the serum may help discriminate benign prostatic hyperplasia from early prostate cancer.

Animals↗
PubMed2000

Leukemia inhibitory factor induces epidermal hyperplasia in patients with amyotrophic lateral sclerosis.

We investigated the biochemical and morphologic alteration in skin of amyotrophic lateral sclerosis patients. We found an obvious high expression of leukemia inhibitory factor and distinct epidermal hyperplasia in the skin of amyotrophic lateral sclerosis patients compared with disease controls. The thickness and cell density, as well as the leukemia inhibitory factor immunostain density, of the epidermis in amyotrophic lateral sclerosis patients correlated positively with duration of illness. The striking fact was the significant epidermal hyperplasia correlating with leukemia inhibitory factor expression in amyotrophic lateral sclerosis patients (r = 0.94, p < 0.001). In vitro experiments revealed that leukemia inhibitory factor stimulated keratinocyte proliferation in primary keratinocyte culture and induced epidermal hyperplasia in skin organ culture. These findings lead to the hypothesis that a high expression of leukemia inhibitory factor is closely associated with epidermal hyperplasia in amyotrophic lateral sclerosis patients.

Adult↗
PubMed2003

Frequency of microsatellite instability in unselected sebaceous gland neoplasias and hyperplasias.

Sebaceous gland neoplasias are the cutaneous manifestation of the Muir-Torre syndrome, which is known to be a phenotypical variant of hereditary nonpolyposis colorectal cancer. Both hereditary nonpolyposis colorectal cancer and Muir-Torre syndrome are caused by inherited DNA mismatch repair defects. As a prominent molecular genetic feature, all tumors associated with a DNA mismatch repair defect exhibit high microsatellite instability. So far, the frequency of DNA mismatch repair defects in patients selected solely on the basis of a sebaceous gland tumor has never been determined. In order to estimate this frequency, we assessed microsatellite instability with up to 10 microsatellite markers in a newly collected unselected series of 25 sebaceous gland neoplasias (six sebaceous adenomas, 16 sebaceous epitheliomas, three sebaceous carcinomas) in comparison to 32 sebaceous gland hyperplasias from unrelated patients. As many as 15 of the 25 sebaceous gland neoplasias (60%), but only one of the 32 sebaceous gland hyperplasias (3%), exhibited high microsatellite instability. Thus, in our study, the majority of patients with a sebaceous gland neoplasia in contrast to patients with a sebaceous gland hyperplasia are highly suspicious for an inherited DNA mismatch repair defect. On the basis of the subsequently collected tumor histories, nine of the 15 patients with a high microsatellite unstable sebaceous gland neoplasia were identified to have Muir-Torre syndrome. In none of these cases, however, were the clinical Amsterdam criteria for diagnosing hereditary nonpolyposis colorectal cancer fulfilled. In the sebaceous tumors of the remaining six patients, high microsatellite instability was an incidental finding. In two of these six patients, single relatives were known to be affected with internal cancer; however, their family histories were not suggestive of Muir-Torre syndrome or hereditary nonpolyposis colorectal cancer. In comparison with microsatellite instability screening studies in a variety of other randomly selected tumors, our study identifies sebaceous gland neoplasias as tumors with the highest frequency of high microsatellite instability reported so far, whereas sebaceous gland hyperplasia rarely exhibits high microsatellite instability. Therefore, screening for microsatellite instability in sebaceous gland neoplasias will be of great value in the detection of an inherited DNA mismatch repair defect, which predisposes to various types of internal cancers.

Adult↗