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rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach.

BACKGROUND AND OBJECTIVE: Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is slight up to now. We present our results of the treatment of 6 patients and a review of the literature in search of possible parameters predicting response to this treatment. DESIGN AND METHODS: From January 1994 to June 1996 all transfusion-dependent patients with MMM diagnosed in our hospital were included in this study. We established a minimum period of 4 weeks of treatment and a maximum of 12 if no response was observed. Initial dosages used were 100 U/kg s.c. 3 times weekly, increasing by 50 U/kg every 4 weeks where no response was observed. Response was defined as a reduction > or = 30% of the previous transfusional needs. The review of the literature was made using a MEDLINE search (January 1990-December 1996) on the keywords erythropoietin, myelofibrosis, and agnogenic myeloid metaplasia. A statistical study was made in search of possible parameters to predict response. The parameters studied include age, sex, hemoglobin, serum erythropoietin (sEPO) levels, transfusional dependency, transfusional requirements per month prior to treatment, maximum dosages used and dosage at which response was obtained. RESULTS: Only 2 of our 6 patients responded, both at a dosage of 600 U/kg/week (200 U/kg 3 times weekly s.c.). In addition to our 6 patients we have found only 28 other patients in the literature. For statistical calculation 2 of our patients were not considered as they did not complete the period of study. The overall rate of response was 17/32 (53.1%). In the univariate analysis comparing responders and non-responders we found a tendency to significance with respect to sex (p = 0.07), sEPO (p = 0.07) and transfusional needs in units of packed red blood cells per month (PRBC/m) (p = 0.13). In this way patients with low sEPO, females and those with low transfusional needs (< 3 PRBC/m) respond better. This better response in females could be explained by the fact that their disease situation was more stable (with both lower sEPO levels and transfusional dependency). The best cut-off point in the sEPO to predict response was 123 mU/mL. No important side-effects have been observed except three cases of aggravation of splenomegaly. In two cases this condition improved when the rHuEPO was discontinued. The association of rHuEPO with hydroxyurea or interferon does not seem to affect the response. INTERPRETATION AND CONCLUSIONS: Though the number of patients is low, our data suggest that some MMM patients, in particular females and individuals with low sEPO levels and with low transfusional needs, might benefit from rHuEPO in terms of elevation of hemoglobin levels. Unfortunately, transfusion dependent-patients, i.e. those in whom a beneficial effect of rHuEPO would be most welcome, are unlikely to respond, and more generally, treatment is not cost effective in medically responsive patients.

Aged↗

Submandibular gland squamous metaplasia mimicking recurrent squamous cell carcinoma: diagnostic dilemma.

New masses in the head and neck region of previously treated patients with cancer are considered suggestive of potential recurrence. Fine-needle aspiration is an excellent primary tool for evaluating these masses but may show atypical squamous cells that mislead clinicians to pursue aggressive treatment. We describe 3 patients in whom submandibular gland masses developed after radiation therapy for squamous cell carcinoma and for whom subsequent excisional biopsy findings showed benign squamous metaplasia. We review distinguishing clinical and histopathologic features that may allow these lesions to be identified. We also propose a treatment algorithm for this uncommon clinical scenario.

Aged↗

Determinants of intestinal metaplasia within the columnar-lined esophagus.

HYPOTHESIS: The clinical and physiological features of patients with short segments of columnar-lined esophagus (CLE) with and without intestinal metaplasia (IM) are distinct. DESIGN: Retrospective case series. SETTING: University tertiary referral center. PATIENTS: Sixty-five consecutive patients with a 2-cm or shorter length of endoscopically visible CLE. INTERVENTIONS: The type of CLE and the presence of Helicobacter pylori were determined by histopathologic examination of esophageal and gastric antrum biopsy specimens. All patients underwent esophageal manometry and simultaneous 24-hour pH and bilirubin monitoring. MAIN OUTCOME MEASURES: Clinical and physiological data were compared in patients with and without IM. RESULTS: Thirty-six patients had IM and 29 had cardiac-type mucosa without IM in biopsy specimens from the CLE. There was no significant difference in age or sex distribution, but the duration of symptoms was significantly longer in patients with IM (10 vs 5 years; P = .03). Abnormal esophageal acid exposure was found in 30 (83%) of 36 patients with IM and 23 (79%) of 29 patients without IM. The prevalence of abnormal bilirubin exposure was significantly higher in patients with IM (75% [27/36]) than in those without IM (41% [12/29]; P = .01). There was no significant difference in the prevalence of H pylori infection between the 2 groups (8% vs 10%; P >.99). CONCLUSIONS: Patients with short segments of CLE and IM have similar esophageal acid exposure but significantly higher frequency of abnormal bilirubin exposure and longer median duration of reflux symptoms than patients without IM. Therefore, CLE, regardless of histological type, is a manifestation of gastroesophageal reflux disease. The presence of duodenoesophageal reflux and the duration of reflux seem to be important in the pathogenesis of IM.

Barrett Esophagus↗

Previously undescribed syndrome of spondylometaphyseal dysplasia, osteocartilaginous metaplasia of long bones, and progressive osteolysis of distal phalanges.

We present the findings and clinical course of a Caucasian woman (now age 23 1/2) who has been treated since early childhood for a previously undescribed syndrome of painful osteocartilaginous metaplasia of long bone metaphyses and painful distal phalangeal osteolysis and soft tissue swelling. Despite extensive evaluations and attempts at effective treatment, the cause and pathogenesis of her unique musculoskeletal disorder remain elusive.

Abnormalities, Multiple↗

Role of Helicobacter pylori gastritis in gastric atrophy, intestinal metaplasia, and gastric neoplasia.

Helicobacter pylori is the major cause of chronic gastritis worldwide. With an estimated rate of infection of over one half of the world's population, it is responsible for extensive morbidity and mortality. Infection with this organism does not appear to spontaneously resolve. Instead it reaches a chronic stage from which a number of outcomes are possible. This article reviews those outcomes that have been linked to H. pylori and explores the pathogenesis while attempting to resolve the discrepant paths infection can take. The associations include duodenal and gastric ulcers and the majority of gastric lymphomas of B-cell type derived from the mucosa-associated lymphoid tissue (MALT). Chronic gastritis has also been shown to evolve into atrophy with intestinal metaplasia in certain populations. This change in the gastric epithelium has been linked with an increased risk of gastric adenocarcinoma. Microsc. Res. Tech. 48:313-320, 2000. Published 2000 Wiley-Liss, Inc.

Atrophy↗

The significance of squamous metaplasia in the development of low grade squamous intraepithelial lesions in young women.

BACKGROUND: The purpose of this study was to examine, prospectively, the presence and extent of cervical epithelial immaturity as well as the rate of squamous metaplastic activity as a risk for the development of low grade squamous intraepithelial lesions (LSIL). METHODS: The study was a nested case-control design that used subjects from an ongoing cohort study of human papillomavirus infection. Fifty-four sexually active young women who developed LSIL were matched for age and number of visits with 54 women who had never developed LSIL. The percent of cervical immaturity was interpreted from colpophotography using a computer-generated pixel count of delineated immature and total cervical areas. Activity of squamous metaplasia was interpreted as the percent change in the area of immaturity over a defined time period. Conditional logistic regression analysis examined risks for the development of LSIL. RESULTS: Baseline area of biologic immaturity was not a predictor of LSIL. However, women with the a high degree of metaplastic activity near the SIL event were more likely to develop LSIL (odds ratio = 3.01 [95% confidence interval, 1.3, 6.8] for every 10% unit change in area of immaturity). CONCLUSIONS: A rapid rate of metaplastic change within the transformation zone, rather than the initial area of biologic immaturity, is a significant risk factor for the development of LSIL.

Adult↗

Atypical immature metaplasia (AIM). A subset of human papilloma virus infection of the cervix.

Atypical immature squamous metaplasia (AIM) is a poorly understood lesion with uncertain biological and clinical significance. This report reviews 170 cases of cervical condylomata and 60 cases of high-grade cervical intraepithelial neoplasia (CIN II/III); AIM was found in association with 34% of condylomata and 16% of high-grade CIN. Thirty-seven cases of AIM alone were reviewed and nearly all presented with a cytologic diagnosis of CIN I or condyloma and a colposcopic appearance of white epithelium with or without punctation and mosaic structure. The mean ages of patients with condylomata, AIM, CIN II, and CIN III were 27, 27, 32, and 37 years, respectively. By immunoperoxidase techniques 75% of condylomata, 16% of AIM, and 0% of CIN lesions were positive. The histologic criteria for the diagnosis of AIM and it's morphologic distinction from CIN and relationship to condylomata, are outlined. AIM is a distinct histologic entity that shares similar epidemiologic, morphologic and biologic characteristics with condyloma. When AIM is found alone in biopsy material, careful correlation of cytology, and biopsy results should be performed and therapy should be based on the size and distribution of the lesion.

Adult↗

Histochemical characterization of different types of intestinal metaplasia in gastric mucosa.

The histochemical patterns of mucosubstances in 1.010 intestinal metaplasia (IM) foci in stomachs removed during surgery for benign ulcer and carcinoma has been studied. Two kinds of IM were characterized: the complete and the incomplete types, with the first one subdivided in Small intestine Type I, Small intestine Type II, and Colonic type, based on their similarity of mucosubstances, with those found in normal small intestine and colon, and the second one divided in two groups, depending on the presence or absence of sulfomucins. The incomplete type with sulfomucins was significantly more frequent in patients with carcinoma than in benign ulcer cases (P less than 0.001) as well as, in stomachs bearing intestinal type of carcinoma than in stomachs with diffuse type of carcinoma (P less than 0.005). The significance of the different types of IM, in relation to the gastric pathologic findings is discussed.

Gastric Mucosa↗

Atrophic chronic gastritis and intestinal metaplasia in gastric carcinoma. Comparison with a representative population sample.

The occurrence of chronic gastritis and intestinal metaplasia (IM) was studied in 257 patients with gastric carcinoma (GC). In all cases biopsies were available from the benign mucosal area adjacent to the tumor, and in 139 patients from the antrum and/or body mucosa outside the tumor. The results were compared with endoscopically and bioptically examined noncancer controls representing a large Finnish population sample. For every GC patient, a control subject was matched by age and sex. In addition, a mean age-adjusted score (AAS) of chronic gastritis, which expresses the progression of gastritis in GC patients as compared with that in the general population, was calculated for GC patients. The prevalences of chronic and atrophic gastritis in the antrum and body mucosa were similar in GC patients and controls when carcinoma cases were not more specifically classified according to histologic type or location of tumors. On the other hand, the location of the tumor showed a significant relation to gastritis: the progression of gastritis was more rapid (high mean AAS value) and the prevalence of atrophic gastritis was higher in the tumor-affected area (i.e., in the antrum in patients with antral [distal] tumors; in the body in patients with body [proximal] tumors), than in the general population, but were similar in the tumor-free area in both GC patients and controls. In the intestinal type of GC (IGC), the prevalence of chronic gastritis was higher and its progression was more rapid than in controls. In the diffuse type of GC (DGC), these correlations were less distinct. In GC patients, the IM adjacent to and outside the tumor area was significantly more common and extensive than in the corresponding area of controls, and a significant positive correlation was present between the location of the tumor and the distribution of IM. Like gastritis, the IM showed a closer relationship to IGC than to DGC. In all cases of GC and particularly of IGC, the antral mucosa tended to be more severely affected by gastritis and IM than the body mucosa, i.e., the prevailing type of gastritis found in this GC series was that morphologically corresponding to the so-called B-type of chronic gastritis.

Age Factors↗

Carcinoma of the breast with pseudosarcomatous metaplasia.

Twenty-six cases of breast carcinoma demonstrating pseudosarcomatous metaplasia are described, and their clinical and pathologic aspects are correlated. The metaplastic elements include mature and immature bone, cartilage, myxoid stroma, loose fibromyxoid and dense spindle-cell stroma, and anaplastic stroma with giant cell features. Light and electron microscopic examination demonstrated an orderly sequence of transformation and dedifferentiation of epithelial cells to become undifferentiated mesenchymal cells. These tumors are more aggressive than purely epithelial carcinomas. The overall survival rate was 44%. Five-year survival figures for TNM Stages I, II, and III lesions were 56%, 26%, and 18%, respectively. The incidence of lymph node metastasis was 25% despite the large size of many of these tumors. Systemic metastases replicated the range of metaplastic elements seen in the primary site. Patients with tumors composed predominantly of pseudosarcomatous elements had worse prognoses than those with predominantly epithelial components (28% versus 62%, 5-year survival).

Adult↗

Sulphomucin-secreting intestinal metaplasia in the human gastric mucosa. An association with intestinal-type gastric carcinoma.

Sixty-three gastrectomy specimens (21 with early intestinal type carcinoma, 21 with early diffuse carcinoma, and 21 with benign nonneoplastic lesions) were examined histochemically to determine the distribution of intestinal metaplasia (IM), particularly the sulphomucin-secreting type (Type IIB IM). The frequency and distribution of Type IIB IM were similar, irrespective of the disease, when age of the patient was matched and if the extension of the IM was similar. Type IIB IM was usually observed in the mucosa along the lesser curvature of the lower portion of the stomach, particularly in elderly patients and was mainly located in the deeper foveolae and intermingled with or transient to those in other types of IM. These findings suggest that a casual relationship between Type IIB IM and intestinal type carcinoma is dubious.

Age Factors↗

Expression of cyclin B1 in the metaplasia-dysplasia-carcinoma sequence of Barrett esophagus.

BACKGROUND: It is known that proliferation is deregulated progressively during carcinogenesis in Barrett esophagus (BE). Cyclin B1 is a key protein for the regulation of G2-M-phase transition during the cell cycle and is essential for initiation of mitosis. METHODS: Using immunohistochemistry, samples of Barrett metaplastic specialized epithelium (SE; n = 36 samples), low-grade dysplasia (LGD; n = 25 samples), high-grade dysplasia (HGD; n = 25 samples), and invasive adenocarcinoma (CA; n = 46 samples) derived from 50 esophagectomy specimens were investigated for the expression of cyclin B1. The number of cyclin B1 positive cells was determined semiquantitatively. In addition, in SE, LGD, and HGD samples, the pattern of cyclin B1 expression was assessed by determination of the presence of positive cells in four mucosal compartments: the deep glandular zone, the lower crypt zone, the upper crypt zone, and the luminal surface. RESULTS: Cyclin B1 expression was found in all lesions under investigation. Regarding the percentage of positive cells, a marked increase of cyclin B1 positive cells was observed in SE samples compared with LGD samples and in HGD samples compared with CA samples (chi-square test; P < 0.0001), nevertheless showing a broad overlap between the different lesions. Concerning staining patterns, in the majority of SE samples (72.2%), cyclin B1 positive cells were restricted to the glandular zone and the lower crypt zone. In contrast, an expansion of cyclin B1 positive cells to superficially located zones of the mucosa (the upper crypt zone and/or the luminal surface) was observed in the majority of LGD samples (96.0%) and HGD samples (100%; P < 0.0001). CONCLUSIONS: Overexpression of cyclin B1 is a frequent and early finding in the metaplasia-dysplasia-carcinoma sequence in BE. It may contribute to the loss of growth control and, subsequently, to the development of tumors in this location.

Adenocarcinoma↗

Atypical squamous metaplasia of seromas in breast needle aspirates from irradiated lumpectomy sites: a potential pitfall for false-positive diagnoses of carcinoma.

The presence of squamous metaplasic cells is an uncommon finding in fine-needle aspiration (FNA) biopsies of the breast. We report that FNA smears containing atypical squamous metaplastic cells derived from the lining of seroma-type cavities following lumpectomy and irradiation in patients with breast cancer can be a potential pitfall for a false-positive diagnosis of recurrent malignancy. Four fine-needle breast aspirates from two adult patients with previous histories of invasive breast carcinoma were retrieved. One specimen was from a 56-yr-old female, while the remaining three FNAs aspirates were from a 75-yr-old female. Both patients presented with indurated cystic lesions arising at irradiated lumpectomy sites. The cytospins from the 56-yr-old patient showed markedly atypical cells having enlarged, degenerating, hyperchromatic nuclei and surrounding dense cytoplasm with sharp borders that were suspicious for carcinoma. A mastectomy revealed irradiation changes and atypical squamous metaplastic cells lining a cystic cavity consistent with a seroma, but there was no evidence of residual cancer. After three aspirations yielded "atypical" diagnoses, the second patient underwent core needle biopsies that also revealed changes consistent with a seroma cavity lined by atypical squamous metaplastic cells. We believe this is the first report of squamous metaplasia occurring in a seroma cavity following lumpectomy and irradiation of the breast. The squamous metaplastic cells in aspirates of these cystic lesions may display significant cellular atypia that can potentially result in a false-positive diagnosis of malignancy.

Aged↗

Mucinous metaplasia in scar endometriosis. Diagnosis by aspiration cytology.

The clinicopathologic features of a case of scar endometriosis are presented. The lesion is unusual in that it occurred in a black woman following tubal surgery for ectopic pregnancy. The case appears to be unique in that the endometriotic focus was characterized by the presence of mucinous metaplasia. Diagnosis of this histopathologic curiosity was made by fine needle aspiration cytology.

Adult↗

Tubal metaplasia: a cytologic study with comparison to other neoplastic and non-neoplastic conditions of the endocervix.

Tubal metaplasia of the endocervix (TME), a condition that may be confused morphologically with glandular neoplasia, is frequently found in cone or hysterectomy specimens. To determine the frequency of detecting TME in cytologic smears, we retrospectively reviewed 28 Papanicolaou (Pap) smears from 22 women (mean age 39.1 yr; range 25-60 yr) with histologically proven TME. Our criteria for TME were the presence of two cell types in addition to endocervical secretory cells, i.e., peg cells (cells with dark and granular cytoplasm and elongate nuclei) and ciliated cells. All women had cervical cytology specimens obtained with an endocervical brush shortly before the procedures in which TME was diagnosed, and five also had at least one post-procedure smear. Of 20 smears with an adequate, non-neoplastic endocervical component, TME was found in 2 (10%). In these two, TME cells constituted 10% and < 5% of all the glandular cells, respectively, and the percentage of ciliated cells in the TME was approximately 25% and 75%. In conclusion, TME was noted infrequently (10%) on the cervical cytosmears of women with histologically-proven TME. This result corresponds to the histologic finding that TME typically involves the upper endocervix and glandular epithelium, with only 13% of the women having TME on the surface of the lower endocervix. Atypical glandular cells on cervical cytology are a problem for clinicians and pathologists alike. The differential diagnosis of such atypia, including TME, cells of the lower uterine segment, squamous intraepithelial lesion in glands and glandular neoplasia, is discussed.

Adult↗

Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer.

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.

Aged↗

Modification effects of GSTM1, GSTT1 and CYP2E1 polymorphisms on associations between raw salted food and incomplete intestinal metaplasia in a high-risk area of stomach cancer.

Incomplete intestinal metaplasia (IM) is a precursor of stomach cancer. To identify risk factors of incomplete IM, a 2-stage survey was carried out in 1995 among 1,485 residents in Matzu, an area with highest mortality from stomach cancer in Taiwan. There were 312 study subjects including 174 men and 138 women sampled for the gastroendoscopic examination of IM. Information on personal and familial history of stomach cancer, cigarette smoking, alcohol consumption and intake frequency of various salted food items were obtained by personal interview based on a structured questionnaire. Blood samples were collected from each participant. Four biopsies per subject were taken from all subjects at gastroendoscopic examination to diagnose the status of IM pathologically. The Helicobacter pylori in biopsies was detected by the histomorphological or immunochemistry method, and antibodies against H. pylori in serum by the enzyme-linked immunosorbent assay. Plasma level of selenium was determined by atomic absorption spectrometry, plasma level of retinol, alpha-tocopherol, alpha-carotene, and beta-carotene by high performance liquid chromatography, genotypes of glutathione S-transferase (GST) M1 and T1 and cytochrome P450 (CYP) 2E1 by polymerase chain reaction. The significant association between history of stomach cancer among first-degree relatives and incomplete IM was found (odds ratio [OR] = 2.50; 95% confidence interval [CI] = 1.15-5.43). There was no association between H. pylori infection and incomplete IM. Alcohol drinkers for >20 years had an elevated risk compared to non-drinkers (OR = 3.34; 95% CI = 1.19-9.39). No associations between incomplete IM and plasma levels of selenium, retinol, alpha-tocopherol, alpha-carotene and beta-carotene were found. Salted food including salted meat, dehydrated salted vegetables and raw salted seafood consumed at ages of </=15 and 16-30 years old was associated with an increased IM risk with OR ranging from 2-3. More striking associations between incomplete IM and salted food intake were observed among subjects with genotypes of GSTM1 null, GSTT1 non-null and CYP2E1 c1/c1. Our study suggests the importance of gene-environment interaction on the development of incomplete IM.

Adolescent↗

Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia.

Between 1967 and 1976, 1,525 Slovenian patients with a histological diagnosis of intestinal metaplasia (IM) were classified according to subtype of IM based on morphology and mucin staining; 518 cases were diagnosed with type I, 197 with type II and 275 with type III, but in 291 the diagnosis of IM was not confirmed. Patients who had developed cancer or died up to 1986 were identified by record linkage at the Slovenia Cancer Registry and the Central Population Registry in Slovenia. A total of 34 incident cases of gastric cancer occurring at least 6 months after the diagnosis of IM were identified. The standardised incidence ratio (SIR) for stomach cancer was 2.23 in the whole cohort. It was highest for IM type III, followed by type II and IM-unconfirmed, but not increased for type I. The relative risk (RR) of developing gastric cancer based on Cox's proportional hazards model was 2.14 for type II and 4.58 for type III, compared with type I. The RR was especially increased for a subgroup of type III secreting sulphomucins in their goblet cells in comparison with types I-II negative to sulphomucins. Our results confirm that subtyping of IM is useful for identifying individuals at high risk for gastric cancer.

Adult↗