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Myeloid metaplasia associated with idiopathic myelofibrosis most commonly involves the reticuloendothelial organs, such as the spleen, liver and retroperitoneal lymph nodes. We report on a patient with myeloid metaplasia (extramedullary hematopoiesis) of the renal pelves, ureters and bladder. The pathogenesis, clinical characteristics, treatment and prognosis of this condition are discussed.
Papillary immature metaplasia (PIM) is a variant of human papillomavirus (HPV) 6 or 11 infection. PIM resembles an immature metaplasia but has filiform papillae, variable cytological atypia, and, frequently, extension into the endocervical canal. Because the unusual morphology and presentation of PIM may cause confusion between this and other benign and malignant papillary neoplasms, we conducted a clinicopathologic analysis of PIM and compared expression of Ki-67 between PIM, condyloma, and papillary carcinoma. Data on patient age, duration of the lesions, and procedures, including cone biopsy, were obtained. The distribution and intensity of staining for Ki-67 in the epithelium was recorded and compared with both condyloma and papillary carcinoma. HPV typing was performed by polymerase chain reaction (PCR) and restriction fragment length pleomorphism analysis (RFLP). Ten of 13 PIMs were HPV 6/11 positive. Three cases contained areas closely resembling condyloma. Eleven cone biopsies were performed on nine cases. Three were found to have a coexisting high-grade squamous intraepithelial lesion that was either HPV 6/11 negative or contained another HPV type. All PIMs displayed variable staining for Ki-67 with a low index of staining in the mid and upper epithelial layers. In contrast, areas of condyloma had significantly stronger staining in areas with viral cytopathic effect (koilocytosis). Six papillary carcinomas were analyzed and displayed moderate to diffuse staining, including staining of the superficial cell nuclei. PIM is a distinct pathological subset of cervical condyloma that frequently is managed by cone biopsy and may persist. The marked reduction in Ki-67 staining in superficial cell layers distinguishes PIM from some condylomata and most HSILs and papillary carcinomas. Immunostaining thus may be helpful in distinguishing PIM from papillary carcinoma, although the differentiation of the two is best made on morphological grounds.
BACKGROUND: Primary squamous cell carcinoma of the endometrium is exceedingly rare. It has been described in association with pyometra but its etiology is still unclear. CASE: The authors report the case of a 75-year-old woman who presented with pelvic pain and pyometra. No gross tumor was identified in the uterus; however, extensive epidermalization of the endometrial mucosa was noted. Microscopic findings were consistent with a primary in situ squamous carcinoma of the endometrium associated with extensive squamous metaplasia and areas of dysplasia. HPV antigen and DNA detection were negative in both the endometrial lesions and the cervix. CONCLUSIONS: These results support the sequence of change with squamous metaplasia, progressing through dysplasia to carcinoma as a possible pathogenetic process. HPV's role, however, remains uncertain.
Philadelphia chromosome-positive essential thrombocythaemia (Ph(+)-ET) and chronic granulocytic leukaemia (Ph(+)-CGL) constitute a separate malignant disease entity, whereas essential thrombocythaemia (ET), polycythaemia vera (PV) and chronic megakaryocytic granulocytic metaplasia (CMGM) belong to the Philadelphia chromosome-negative (Ph-) myeloproliferative disorders. The megakaryocytes in Ph(+)-ET and Ph(+)-CGL are abnormal and small with round nuclei, showing little lobulation. Both the number and size of megakaryocytes in Ph-ET, -PV and -CMGM are typically increased. Enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or slightly increased cellular bone marrow represent the hallmark of ET. In reactive thrombocytosis the size and morphology of increased megakaryocytes are normal. The characteristic increase and clustering of enlarged mature and pleomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses is the diagnostic hallmark of untreated PV. In secondary polycythaemia, in which increased cellularity of the erythroid cell line may be present, the number, size and morphology of megakaryocytes remain small and normal. CMGM, including early stages without myelofibrosis and advanced myelofibrotic stages of agnogenic myeloid metaplasia, appears to be a distinct neoplastic proliferation of neutrophilic granulopoiesis and megakaryopoiesis. The histopathology of the bone marrow in CMGM is dominated by atypical, enlarged and immature megakaryocytes with cloud-like nuclei which are not seen in ET and PV. Myelofibrosis in ET, PV and CMGM is graded in no reticulin fibrosis (MFO), early reticulin fibrosis (MF1), advanced reticulin sclerosis with minor collagen fibrosis (MF2) and advanced collagen fibrosis with or without osteosclerosis (MF3). Myelofibrosis is not a feature of ET, may occur in PV, and constitutes a prominent feature of CMGM during the natural history of the disease.
A 49 year-old female had been suffering from primary myelofibrosis since February 1987 without receiving any treatment. In 1994, a breast mass was detected. Breast tumor biopsy revealed tubular carcinoma with intraductal components and multinucleated giant cells in the loose and myxoid stroma. The giant cells were thought to be megakaryocytes because both Factor VIII and platelet glycoprotein GP IIIa were detected in their cytoplasm. While additional mastectomy specimens and the axillary lymph nodes also revealed prominent myeloid metaplasia, there was no proliferation of the cancer cells. Granulocytic series stained for chloroacetate esterase and very few erythrocytic series were observed. This is the first case in which breast carcinoma and myeloid metaplasia coexisted in the same breast tumor.
A 52-year-old man with agnogenic myeloid metaplasia had a sudden onset of pain and bleeding from the left ear and an associated decrease in hearing acuity on that side. Examination revealed a friable mass that filled the middle ear and protruded through a perforated tympanic membrane. Special staining of a tissue specimen of the mass revealed myeloid metaplasia. Otorhinolaryngologists should be aware of the fact that the ear can be involved in hematopoietic disorders.
We sought to determine if an immunohistochemical panel of p53, PCNA, and c-erbB-2 was a useful biomarker of transformation in Barrett's metaplasia. P53, PCNA, and c-erbB-2 immunohistochemistry was performed on resected Barrett's specimens selected to show discrete grades of dysplasia and then on prospectively obtained biopsies. In resection specimens, p53 was positive in 36% with no dysplasia, in 30% with low-grade dysplasia, in 85% with high-grade dysplasia, and in 90% of adenocarcinomas. While an evaluation of proliferation throughout the specimen did not differ between groups, surface proliferation was significantly higher in high-grade dysplasia than in low-grade or no dysplasia. All high-grade dysplasia specimens were positive for at least one marker, compared to 44% with no or low-grade dysplasia. C-erbB-2 was only seen in 31% with high-grade dysplasia and in 10% of adenocarcinomas. Prospectively, the panel had a sensitivity of 100%, a specificity of 81% and an overall accuracy of 83% in identifying patients who developed high-grade dysplasia or cancer. Thus, overexpression of p53 occurs early in the malignant transformation of Barrett's and increases with histologic progression, and proliferation at the surface of Barrett's epithelium increases with progressive grades of dysplasia. An immunohistochemical panel of p53 and PCNA is a useful biomarker for Barrett's metaplasia.
The presence or absence of intestinal metaplasia of the stomach was determined in 272 patients by direct vision biopsy of standardized intragastric sites using fiberoptic gastroscopy. Analysis of ABO blood groupings and Rhesus factor failed to reveal an association with metaplasia.
The FHIT gene, which spans the common fragile site FRA3B, has been shown to produce aberrant transcripts in a variety of tumor types. Homozygous deletions within the FHIT locus have been detected only in tumor-derived cell lines and LOH has been described in numerous primary tumors. Based on these findings and its location on 3p, FHIT has been proposed as a tumor suppressor gene. To further study the relationship of FRA3B to the findings regarding the FHIT gene and to determine the extent of FHIT mRNA alterations in early stages of tumor development, the status of the FHIT gene was evaluated in the premalignant condition of Barrett's esophagus and associated esophageal adenocarcinomas. FHIT expression was investigated by RT-PCR in normal esophageal, Barrett's metaplasia and adenocarcinoma tissues from 15 patients. Alterations of FHIT transcripts were observed in 12/14 (86%) of Barrett's metaplasia and in 14/15 (93%) of the adenocarcinomas from the same patients. Characterization of the altered transcripts revealed FHIT mRNA lacking one or more exons, with deletion of exons 5-7 being most frequent. Analysis of genomic DNA from 20 patients showed homozygous deletions involving exon 5 of FHIT in 4/20 (20%) esophageal adenocarcinomas, and 7/20 (35%) tumors demonstrated hemizygous loss. Genomic deletions also involved the BE758-6 locus, indicating that a large region is deleted. Fluorescence in situ hybridization (FISH) analysis demonstrated that this region of deletion is localized within FRA3B. Our results extend the range of tumor types in which altered FHIT transcripts have been demonstrated and show that these alterations can be seen in the premalignant stage of esophageal tumor development. These results indicate that the fragility and recombination-prone nature of FRA3B is related to tumor-specific chromosomal instability affecting the FHIT gene in esophageal adenocarcinoma development.
Clinical, hematological and morphological peripheral blood and bone marrow characteristics, in particular, megakaryopoiesis and bone marrow cellularity, reveal diagnostic clues and pathognomonic features, which enable a clear-cut distinction between essential thrombocythemia (ET), polycythemia vera (PV) and prefibrotic and fibrotic agnogenic myeloid metaplasia (AMM). The characteristic increase of enlarged mature megakaryocytes with mature cytoplasm and multilobulated nuclei and their tendency to cluster in a normal or slightly increased cellular bone marrow represent the hallmark of ET. The characteristic increase and clustering of enlarged mature and pleiomorphic megakaryocytes with multilobulated nuclei and proliferation of erythropoiesis in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses are the specific diagnostic features of untreated PV. ET may precede PV for many years to more than one decade. Prefibrotic and fibrotic AMM appears to be a distinct dual proliferation of abnormal megakaryopoiesis and myelopoiesis. The histopathology of the bone marrow in prefibrotic and fibrotic AMM is dominated by atypical enlarged and immature megakaryocytes with cloud-like immature nuclei, which are not seen in ET and PV at diagnosis and during follow-up. Myelofibrosis is not a feature of ET at diagnosis and during long-term follow-up. Myelofibrosis, which is secondary to the megakaryocytic/granulocytic myeloproliferation, and extramedullary myeloid metaplasia constitute a prominent feature and usually progress more or less rapidly during the natural history of PV and AMM. Life expectancy is normal in ET, normal in the first and decreased in the second decade of follow-up in PV, but significantly shortened in thrombocythemia associated with prefibrotic AMM as well as in the various fibrotic stages of AMM. These clinical and pathological characteristics of the Ph-negative MPDs, by including bone marrow histopathology, enable a clear-cut distinction between ET, PV and prefibrotic and fibrotic AMM. The use of established and new biological markers of MPDs, like spontaneous EEC, PRV-1 gene expression etc, should be validated in large prospective multicenter studies of newly diagnosed and previously treated MPD patients using the proposed European clinical and pathological (ECP) criteria as the only gold standard available for the proper diagnosis and differential diagnosis of ET, PV and AMM.
Agnogenic myeloid metaplasia is a rare indication for allogeneic bone marrow transplantation (BMT). We have retrospectively studied 12 patients allografted for this disease within the French BMT group. Prior to BMT, the mean age was 40 years (range 14-49). Diagnosis was based on the Polycythaemia Vera Study Group criteria. Before BMT, 10 patients had been splenectomized, eight required transfusions, and four had received at least two lines of chemotherapy. Cyclophosphamide and total body irradiation was the main conditioning regimen used (n=8). The donor was an HLA-identical sibling except in one case where there was one HLA-DR mismatch. Acute graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporine A. 11 patients engrafted with median times to achieve absolute neutrophil count > 0.5 x 10(9)/l and platelet count > 50 x 10(9)/l of 17 (range 12-44) and 29 (range 12-196) days respectively. One primary graft failure occurred. 10 patients developed grade II-IV acute GVHD, four developed extensive chronic GVHD. One patient relapsed 16 months post-BMT and was untreated and well 14 months later. Three patients died from the BMT procedure. In May 1996 the median follow-up was 25 months and the 4-year overall and event-free survivals were 71% and 59%, respectively. Thus, we conclude that extensive myelofibrosis is not associated with delayed engraftment, and that HLA-identical sibling allogeneic BMT can be considered in a small proportion of patients with agnogenic myeloid metaplasia.
Myelofibrosis with myeloid metaplasia (MMM) is uniquely characterized by macroscopic bone marrow stromal changes that are believed to be both reactive and cytokine mediated. Furthermore, a prognostically detrimental increase in bone marrow angiogenesis has recently been demonstrated. These observations suggest a potential therapeutic role for agents that are inhibitory to angiogenesis as well as cytokines that are pathogenetically implicated in MMM. In a prospective study of 15 patients with MMM, thalidomide treatment, starting at a dose of 200 mg/d, resulted in increased platelet counts (12 of 15 patients), increased haemoglobin level (3 of 15), a modest decrease in spleen size (3 of 12), increased bone marrow megakaryopoiesis (5 of 9) and decreased bone marrow angiogenesis (2 of 9). Undesirable haematological effects included pericardial extramedullary haematopoiesis in one patient, marked leucocytosis in two patients and extreme thrombocytosis in three patients. The thrombocytosis occurred in both patients with post-thrombocythaemic myeloid metaplasia (PTMM) and was also associated with higher baseline levels of circulating CD34+ cells. Previously described toxicities of thalidomide were seen in the majority of patients and dose escalation to 400 mg/d was permitted in only two patients. In contrast, toxicity-related dose reductions to 50 mg/d did not appear to lessen drug efficacy. We conclude that thalidomide has both beneficial and potentially adverse biological activity in MMM. A lower dose of the drug might be more tolerable without compromising therapeutic value. Patients with PTMM and/or markedly increased circulating CD34+ cell counts might be susceptible to thalidomide-induced thrombocytosis.
There are approximately 200 reported cases of breast tumors containing areas of bone. The majority of the neoplasms are sarcomas, phylloides tumors, or fibroadenomata. We present a case of osseous metaplasia mammographically detected by clustered heterogeneous calcifications. Stereotactic core biopsy revealed the presence of well-formed bone tissue without associated neolplasia. The case represents the first reported case of mammographically detected osseous metaplasia confirmed by core biopsy.
Overexpression and/or amplification of c-myc oncogene are known to occur in human breast carcinomas, particularly those of high grade. Apocrine metaplasia (APM) is a common finding within fibrocystic change, and in some cases appears to be associated with an elevated risk of subsequent breast cancer. It has been suggested that apocrine metaplasia within sclerosing adenosis of the breast, also called apocrine adenosis (AA), has a premalignant potential. Little, however, is known about cellular level genetic alterations in either APM or AA of the breast. Because of this, c-myc expression and amplification in APM and AA were studied. Fluorescence in situ hybridisation (FISH) is a methodological approach to detecting these genetic alterations. In this study, APM and AA were studied immunohistochemically to detect c-myc oncoprotein expression, and FISH was employed using a DNA probe for the c-myc gene in archival tissue sections of cases of APM and AA of the breast. Nuclear immunostaining for c-myc was seen in all APM and AA cases studied, but amplification of the c-myc gene was not seen in any cases with APM or AA. The results of this study indicate that c-myc overexpression appears to occur early in breast oncogenesis. Amplification of the c-myc gene does not occur in APM or AA of the breast, however, suggesting that this particular genetic alteration constitutes a late event in the pathogenesis of breast carcinomas.
BACKGROUND: Specialized intestinal metaplasia (SIM) in Barrett's esophagus (BE) is not identifiable by standard endoscopy. Acetic acid instillation enhances the ability to detect columnar epithelium at the squamocolumnar union. Enhanced magnification endoscopy involves the combined use of magnification endoscopy with acetic acid. This study assessed the value of enhanced magnification endoscopy in detecting SIM in patients with BE. METHODS: Patients undergoing endoscopic surveillance because of short segment BE without dysplasia underwent enhanced magnification endoscopy with 1.5% acetic acid instillation. Standard endoscopy was followed by magnification endoscopy and repeated after acetic acid spraying. Surface patterns were characterized prior to and after acetic acid spraying. The observed surface patterns were compared with histology results. RESULTS: Forty-nine patients, 9 women and 39 men, with a mean age of 50.5 years were studied. One was excluded because of unclear definition of the surface pattern. Enhanced magnification endoscopy detected 4 different mucosal surface patterns: I, round pits; II, reticular; III, villous; and IV, ridged. A total of 129 areas were examined. Standard endoscopy identified an endoscopic pattern in 1.5% of the areas, standard endoscopy and acetic acid in 8.5%, magnification endoscopy alone in 38%, and enhanced magnification endoscopy in all 129 endoscopic areas. The yields for detecting SIM according to endoscopic patterns were as follows: pattern I, 0%; II, 11% (odds ratio 0.5, p = 0.54); III, 87% (odds ratio 36, p = 0.001); and IV, 100% (odds ratio 14, p = 0.015). CONCLUSIONS: Enhanced magnification endoscopy is an accurate method of predicting SIM in BE. The simplicity of the technique and its ability to identify characteristic endoscopic patterns with outstanding clarity and resolution that correlate with histologic identification of specialized intestinal metaplasia make enhanced magnification endoscopy an excellent method for the evaluation of patients with BE.
BACKGROUND: Gastric intestinal metaplasia (IM) is seen mostly in association with chronic gastritis, induced either by Helicobacter pylori infection or autoimmune mechanisms. IM can be categorized into three subtypes, where type III is associated with gastric carcinoma of intestinal type. METHODS: Gastric biopsies from 475 subjects randomly selected from the general population and from 27 patients with autoimmune gastritis associated with pernicious anaemia were used. The criteria of Filipe & Jass were applied using different histochemical techniques in combination with haematoxylin and eosin stained material. RESULTS: Twenty-three percent (109/475) of the subjects from the general population and 88% (24/27) in the group with autoimmune gastritis had IM. Type III IM occurred in 4% in both populations. Type III IM was located in the antrum in 90% in the general population. In the group with autoimmune gastritis, only one patient had type III IM, which was located in the corpus. CONCLUSIONS: This study reveals for the first time the prevalence and distribution of subtypes of IM in a general population from the Western world. The comparatively high prevalence of type III IM in the general population (4%) indicates that its role as a precursor of gastric carcinoma may have been overemphasized. A similar prevalence of type III IM in patients with autoimmune gastritis may be considered low and suggests that mechanisms for gastric carcinogenesis other than the atrophy-metaplasia-dysplasia sequence could also operate in this condition.
OBJECTIVE: The Mongolian gerbil is considered as the model of choice when studying adenocarcinoma related to Helicobacter pylori infection. The purpose of this study was to compare two different H. pylori strains and elucidate whether adenocarcinomas developed in gerbils. MATERIAL AND METHODS: Male gerbils were separated into three groups: one control and two groups infected with two different strains of H. pylori, TN2GF4 and SS1. At 3, 6, 12 or 18 months after inoculation 5 animals from each group were sacrificed. The stomach was used for culture, and for histology. RESULTS: Inflammation was seen after 3 months in all the infected animals. In the controls no pathology was found at any time. Intestinal metaplasia was found in both the infected groups. Glands buried in the submucusal layer, changes that might be misinterpreted as adenocarcinoma, were found in 10% of the SS1 and in 65% of the TN2GF4 animals. Adenocarcinoma was not found in any of the gerbils. CONCLUSIONS: All studies claiming to have found H. pylori-induced adenocarcinomas in gerbils describe atypical glands penetrating into the muscularis propria and interpret these as invasive growths due to cancer. An alternative interpretation is that the deranged glandular structures grow in and below the submucosa. It is suggested that atypical glands in the muscularis layer are not enough as a diagnostic criterion for gastric adenocarcinoma. It is concluded that adenocarcinoma has not yet been shown convincingly to develop in Mongolian gerbils infected with H. pylori. Nevertheless, it is a model well suited for studying gastritis, gastric ulcer and premalignant changes such as metaplasia.
BACKGROUND: Helicobacter pylori infection is associated with gastroduodenal disease in humans. In this study we aimed to show this relationship directly in Mongolian gerbils. METHODS: The animals were challenged orally with H. pylori and killed 1, 2, 3, and 6 months after inoculation for histologic and anti-H. pylori antibody titer examination. RESULTS: The spiral bacteria were observed in the mucus and gastric pits of all infected animals. A severe infiltration of the lamina propria by polymorphonuclear and mononuclear cells was seen 1 month after H. pylori inoculation. The submucosa was infiltrated by mainly mononuclear cells with formation of lymphoid follicles. Erosion of the gastric mucosa appeared soon after inoculation, whereas gastric ulcers, gastritis cystica profunda, and atrophy with goblet cell metaplasia occurred between 3 and 6 months after inoculation. In the duodenal mucosa a mild inflammatory cell infiltration with ballooning and diminished number of duodenal glands was seen. The IgG anti-H. pylori antibody titer increased gradually after 2 months of inoculation. CONCLUSIONS: Since the gastritis, gastric ulcers, atrophic gastritis, and intestinal metaplasia that developed in Mongolian gerbils were similar to those observed in humans, this model may be useful to study the therapy of gastric ulcer and, with a longer observation period, to confirm a possible relationship between H. pylori and malignancy.