Paramjit Bhatia

Biologic and Clinical Significance of Cytogenetic and Molecular Cytogenetic Abnormalities in Benign and Malignant Cartilaginous Lesions

Cartilaginous neoplasms are often histologically and therapeutically challenging. Predicting biologic behavior can be difficult. In this study, 120 nonneoplastic, benign, and malignant cartilaginous lesions from 103 patients were cytogenetically analyzed in a 6-year period after short-term culture. For selected cases, fluorescent in situ hybridization (FISH) techniques using chromosome-specific probes were performed on metaphase/interphase preparations and on paraffin-embedded tissue sections. Clonal abnormalities of chromosomes 2, 3, 5, 7, 8, and 12 were most frequently observed. Involvement of chromosomes 5, 8, and 12 may be etiologically significant because of the gene localizations for the human cartilage link protein, Langer-Giedion syndrome (a rare syndrome characterized by multiple exostoses), and type II collagen (a major component of normal cartilage) respectively, to these three chromosomes. That chromosome 7 abnormalities were observed only in malignant tumors is of diagnostic value. The identity of three marker chromosomes and the significance of trisomy 7 (a finding of controversial meaning), were determined with FISH. That the presence of chromosome aberrations and increasing histologic grade strongly correlated (p = 0.001) is of prognostic importance. Moreover, complex aberrations were observed nearly exclusively in high-grade tumors (p = 0.001). The data show that nonrandom chromosome loci are aberrantly affected in cartilaginous lesions and that these abnormalities may be of significant histopathogenetic consequence. In addition, these chromosome abnormalities appear to be diagnostically and prognostically valuable in classifying and grading chondromatous neoplasms.

Colonic mucosal mast cell distribution at line of demarcation of active ulcerative colitis

We examined the distribution of colonic mucosal mast cells in 25 patients with active ulcerative colitis, with a clear line of demarcation separating active inflammation from normal mucosa. Biopsies, at least one adjacent to the line of demarcation, one in inflamed mucosa, and one above were obtained during colonoscopy. Eight patients had elevated mast cells throughout the colon, and 12 had increased numbers at the line of demarcation of disease. Mean numbers of mast cells from these patients were 6.3 (±2.1sd) in active inflammation, 19.5(±7.1sd) at the line of demarcation and 15.8 (±8.4sd) in normal mucosa. Histologic inflammation decreased as mast cells increased. The accumulation of mast cells at the visible line of demarcation between normal and abnormal mucosa suggests mast cells play a critical role in either accelerating the process of inflammation or in suppressing continued extension of the disease.

Cytogenetic findings and biologic behavior of giant cell tumors of bone

Giant cell tumor of bone is a benign but often aggressive lesion with a distinct tendency toward local recurrence and, rarely, malignant transformation. Over a 3‐year period, 20 giant cell tumors from 14 different patients were cytogenetically characterized. Random chromosomal abnormalities were detected in 14 of the 20 specimens and clonal chromosomal abnormalities were detected in six. An unusual anomaly, telomeric fusion, was the most striking random chromosomal abnormality detected. A comparison of the presence or absence of cytogenetic aberrations and the clinical behavior of these neoplasms was studied as well as a comparison of the aberrations in the initial specimen with those in subsequent specimens. Chromosomal abnormalities were detected in all but one of the ten tumors shown to be locally aggressive, recurrent, or metastatic. (The abnormalities observed in five of these tumors were clonal.) There were no chromosomal abnormalities present in three of four tumors that behaved in an innocent fashion. These findings support the presence of chromosomal abnormalities in giant cell tumors (telomeric fusion in particular) and suggest that cytogenetic analysis may be useful in predicting the biologic behavior of these neoplasms.

Increased colonic mucosal mast cells associated with severe watery diarrhea and microscopic colitis

SummaryA patient with microscopic colitis, clearly identifiable by its histologic characteristics, is presented in whom the histology also revealed large numbers of mast cells. The patient was treated with H1 antagonists with prompt resolution of the diarrhea. The histologic and therapeutic findings in this case suggest the diarrhea and inflammation of microscopic colitis may be mediated by the degranulation of excessive numbers of mast cells in the colon and small bowel.

Establishment of a rat placental cell line expressing characteristics of extraembryonic membranes.

A cell line was derived from midgestation chorioallantoic placental explants of the outbred Holtzman rat. The cell line was found to express characteristics of extraembryonic membranes and to grow when introduced into allogeneic hosts. Growth in allogeneic hosts was detected following intraperitoneal injection of the cells but not following subcutaneous injection. The transplanted cells grew as cystic structures free in the peritoneum and as solid masses adhered to various abdominal organs. Cystic structures had a homogeneous morphology consisting of an epithelial-like cell layer surrounding a fluid-filled sac. Solid masses had a heterogeneous morphology, containing parts resembling normal components of the extraembryonic membranes (trophoblast, parietal, and visceral yolk sacs). Biochemical analysis of the placenta-derived cell line and transplanted structures derived from the cell line indicated that the cells had the potential to produce a variety of proteins characteristic of extraembryonic tissues. Cultured cells and both types of in vivo transplants produced the basement membrane protein, laminin. Peritoneal cystic structures also contained alpha-fetoprotein mRNA and very high levels of c-fos mRNA. Solid masses demonstrated elevated alkaline phosphatase activity, a marker of trophoblast cells. Cells grown in vitro expressed elevated c-myc mRNA levels, whereas, c-myc mRNA levels were reduced in the in vivo transplants. The behavior of the cell line in vitro and following in vivo transplantation suggests it contains elements capable of differentiation toward various components of the extraembryonic membranes. The results indicate that the rat placental cell line will be valuable for future studies on the differentiation of trophoblast cells and other components of the extraembryonic membranes.

Evaluation of antral mast cells in nonulcer dyspepsia

Two hundred twenty-five patients with the symptoms of nonulcer dyspepsia underwent clinical and endoscopic evaluation including histologic assessment of endoscopic biopsies. Mast cells were counted after special staining with low pH Alcian blue. Of 225 patients, 31 (13%) were found to have 11 or greater mast cells per high-power field. Endoscopic and routine histologic findings were similar between the subset of 31 patients with 11 or more mast cells and the entire group of 225. The 31 patients with increased antral mast cells had failed treatment with standard drug used for peptic ulcer disease. H1-antagonists improved symptoms in the majority of patients (79%) in whom we had adequate follow-up. Patients with increased mast cells on antral biopsy appear to be subset of patients with nonulcer dyspepsia amenable specific treatment with H1-antagonists.

Prevalence of aneuploidy, overexpressed ER, and overexpressed EGFR in random breast aspirates of women at high and low risk for breast cancer

SummaryBreast tissue biomarkers which accurately predict breast cancer development within a 10 year period in high risk women are needed but currently not available.We initiated this study to determine 1) the prevalence of one or more breast tissue abnormalities in a group of women at high risk for breast cancer, and 2) if the prevalence of biomarker abnormalities is greater in high risk than in low risk women. Eligible high risk women were those with a first degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. Low risk women were those without these or other major identifiable risk factors. Ductal cells were obtained via random fine needle aspirations and cytologically classified. Biomarkers included DNA ploidy, estrogen receptor (ER), and epidermal growth factor receptor (EGFR).The prevalence of DNA aneuploidy was 30%, overexpression of ER 10%, and overexpression of EGFR 35%, in the 206 high risk women whose median 10 year Gail risk (projected probability) of developing breast cancer was 4.5%. The prevalence of aneuploidy and overexpressed EGFR was significantly higher in the high risk women than in the 25 low risk controls (p < 0.002), whose median 10 year Gail risk was 0.7%. The difference in the prevalence of ER overexpression between high and low risk groups was not statistically significant (p = 0.095). This may be due to the low prevalence of overexpressed ER and the small number of controls. A significant difference was noted in the prevalence of one or more abnormal biomarkers between the high risk and low risk women (p < 0.001).A large prospective trial is needed to determine if one or more of these biomarkers, is predictive of breast cancer development.

Lymphoepithelioma-like carcinoma of the colon: report of a case with histologic, immunohistochemical, and molecular studies for Epstein-Barr virus.

We report a case of lymphoepithelioma-like carcinoma of the colon in a 62-year-old Hispanic male with multiple other tumors, including thyroid, breast, pharyngeal, and prostate carcinomas; a neurofibrosarcoma; and a meningioma. The association with Epstein-Barr virus infection and colonic lymphoepithelioma-like carcinoma was studied using immunohistochemical and polymerase chain reaction techniques.

Exacerbation of chronic ulcerative colitis with mesalamine

Activation of ulcerative colitis with mesalamine has rarely been reported. In case 1, a 34-year-old man was treated with oral mesalamine, resulting in an exacerbation of colitis that rapidly improved with glucocorticoids and mesalamine withdrawal. Oral cromolyn sodium and occasional low-dose prednisone therapy has maintained long-term remission. In case 2, a 28-year-old man receiving prednisone treatment developed chest pain and myalgias 1 week after initiation of mesalamine that resolved on mesalamine withdrawal. A lower dose of mesalamine with continued glucocorticoids resulted in clinical improvement, and both drugs were tapered. Mesalamine sensitivity was documented endoscopically and histologically by evaluating mucosal changes after two mesalamine enemas during a 24-hour period. There was dramatic progression from quiescent disease to active colitis in 24 hours. Mesalamine sensitivity must be included in the differential diagnosis of ulcerative colitis exacerbations. Concurrent steroid therapy can suppress systemic side effects, making the diagnosis even more elusive.

Secondary biliary cirrhosis as a consequence of graft-versus-host disease

A 9-yr-old white girl with acute monoblastic leukemia received an HLA-identical, mixed lymphocyte culture-nonreactive bone marrow transplant from her sister. Twelve days after the transplant, a diffuse, pruritic, maculopapular rash involving the entire body surface (including the palms and soles) developed. Subsequent skin biopsy was consistent with cutaneous graft-versus-host disease, and biopsy-proven hepatic involvement manifested by severe, unremitting cholestatic jaundice soon followed. The patients biliary status as monitored by serial liver biopsies demonstrated progression from chronic graft-versus-host disease to cirrhosis, culminating in death secondary to liver failure 25 mo after transplant.