Premalignant Disorders Research Articles

Future directions in innovative minimally invasive surgery

Future directions in innovative minimally invasive surgery

Mast cells in colorectal neoplasias and premalignant disorders.

Mast cells have recently been found to be well correlated with the prognosis of patients with rectal cancer. This work aimed to characterize the role of mast cells in colonic premalignant conditions. Mast cells were quantified in various colonic disorders, particularly those with premalignant potential. Possible avenues of mast cell action were investigated using these tissue samples, by measuring basement membrane and collagen layer thickening. The mean number of mast cells in carcinoma sections was 0.967/0.9 mm2, in various colorectal neoplasias and related conditions it ranged from 1.36-3/0.9 mm2, and in normal histologic specimens it was 11.90/0.9 mm2. These data established statistically significant differences in mast cell numbers in the colonic disorders studied. The number of mast cells is greatest in the lamina propria level of the colon, a site often not examined because of the limited depth of samples obtained from endoscopic biopsies. Mast cell numbers were found to be correlated to the development from premalignancy to colonic malignancy. Mast cells may be useful as markers of colorectal neoplasia.

Oral epithelial dysplasia and the development of invasive squamous cell carcinoma

Oral epithelial dysplasia, the histopathologic marker of a premalignant disorder of the mouth mucosa, may present clinically as leukoplakia, erythroplakia, or leukoerythroplakia. Its presence in lesions of the oral mucosa is predictive by a variable rate (6.6% to 36%) of transformation to invasive squamous cell carcinoma. We studied the clinical features and microscopic slides of 308 case of oral epithelial dysplasia in our biopsy service and retrospectively evaluated 44 of these with follow-up data for transformation to invasive squamous cell carcinoma. Forty-four patients had follow-up of more than 6 months with a mean follow-up time of 18.4 months. Twenty (45%) were clinically free of disease and 15 (34%) had recurrence of the dysplasia. An additional two cases of lower grades of the disease recurred as carcinoma in situ. Invasive squamous cell carcinoma developed in seven (16%) in a mean transformation time of 33.6 months.

Absence of Epstein-Barr viral RNA in lymphomatoid papulosis.

Epstein-Barr virus (EBV) recently has been implicated in the pathogenesis of Hodgkin's disease (HD). Lymphomatoid papulosis (LyP) is a premalignant cutaneous lymphoproliferative disorder which shares several characteristics with HD. The hypothesis has been made that EBV may be associated with the pathogenesis of LyP. We therefore examined 17 skin biopsy specimens and two lymph nodes from nine patients with LyP for EBV RNA using the highly sensitive and specific EBER method. In all specimens, the large atypical cells were negative for EBV while poly T studies confirmed the presence of adequate RNA for detection of EBER. The negative EBER results were confirmed in seven LyP patients whose biopsies were also stained for latent membrane protein (LMP-1). Interestingly, one patient with clonally related LyP and HD had no EBV RNA detected in any specimen. We conclude that EBV is unlikely to be an important aetiological agent in LyP. If confirmed in other patients, HD associated with LyP may have a different aetiology from HD arising de novo.

Endoscopic Assessment of Premalignant Esophageal Disorders

Among the 10,000 Americans newly diagnosed with esophageal cancer in 1990, fewer than 700 are expected to survive until 1995. This dismal survival rate is due in part to the lack of early warning signs for tumors of the esophagus. The appearance of symptoms suggests that the esophageal cancer has already grown extensively and disseminated. Regular endoscopic surveillance has been proposed as a means to detect nascent neoplasms, thereby providing the opportunity to effect meaningful intervention and cure. This article focuses primarily on Barrett’s esophagus.

Chronic pure thrombocytopenia in elderly patients. An aspect of the myelodysplastic syndrome.

From a group of 276 elderly patients studied in the last 12 years in a department of nuclear medicine for investigating a chronic thrombocytopenia, 36 patients have an acquired disorder, with normal platelet life span, a normal megakaryocytic bone marrow count, and absence of any evident cause at the time of clinical evaluation. During the 2 to 10 subsequent years, 16 patients developed symptoms of the myelodysplastic syndrome, i.e., chronic aregenerative anemia, granulocytopenia, dysmyelopoiesis, and appearance of circulating blast cells; three of them died from acute myeloblastic leukemia. So a pure thrombocytopenia due to a platelet production defect, without any demonstrated functional platelet defect or morphologic dysmegakaryocytosis, may be a preleukemic syndrome. In the other 20 patients, with the same pure chronic thrombocytopenia, no malignant evolution has been seen with long follow-up delays, which is often also the case in pure refractory anemias. In the absence of objective criteria of a possible premalignant disorder, the classification of these cases is difficult, which it is also the case for the so-called refractory anemias. We suggest to individualize, in the classification of the myelodysplastic syndromes, a group of pure refractory thrombocytopenias. From a practical point of view such a diagnosis may be useful, at least to avoid inefficient and possibly harmful treatments.

Familial Adenomatous Polyposis: A Nutritional Intervention Trial

Familial adenomatous polyposis, a premalignant autosomal dominant disorder, is characterized by a multitude of adenomatous polyps and progression to cancer in almost 100% of patients if not treated. In this issue, DeCosse et al. (7) present the results of a successful nutritional intervention trial in a group of patients with familial adenomatous polyposis. The patients, 58 adults, were entered in a randomized study in which they were treated with ascorbic acid (vitamin C) and a-tocopherol (vitamin E) coupled with a high-fiber (wheat bran) supplement or a low-fiber placebo in a double-blind protocol. A limited degree of polyp regression, which commenced about 6 months after study initiation, was observed in the high-fiber group. The mean daily intake of dietary fiber by the high-fiber group was 22.4 g/day, compared with 12.2 g/day in the low-fiber placebo group. High doses of ascorbic acid (4 g/day) or a-tocopherol (400 mg/day) in combination with the low-fiber placebo had no effect. The theoretical antecedents of this trial are founded on an analysis of epidemiologic surveys in which dietary fiber intake is identified as a significant life-style factor associated with reduced colon cancer risk (2). Worldwide trends in fiber consumption are inversely correlated with colon cancer

Vitamin A derivatives in the prevention and treatment of human cancer.

Vitamin A is essential for normal cellular growth and differentiation. A vast amount of laboratory data have clearly demonstrated the potent antiproliferative and differentiation-inducing effects of vitamin A and the synthetic analogues (retinoids). Recent in-vitro work has led to the exciting proposal that protein kinase-C may be centrally involved in many of retinoids' anticancer actions including the effects on ornithine decarboxylase induction, intracellular polyamine levels, and epidermal growth factor receptor number. Several intervention trials have clearly indicated that natural vitamin A at clinically tolerable doses has only limited activity against human neoplastic processes. Therefore, clinical work has focused on the synthetic derivatives with higher therapeutic indexes. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, epidermodysplasia verruciformis, dysplastic nevus syndrome, and basal cell carcinoma. Several noncutaneous premaligancies, however, are currently receiving more attention in retinoid trials. Definite retinoid activity has been documented in oral leukoplakia, laryngeal papillomatosis, superficial bladder carcinoma, cervical dysplasia, bronchial metaplasia, and preleukemia. Significant therapeutic advances are also occurring with this class of drugs in some drug-resistant malignancies and several others that have become refractory, including advanced basal cell cancer, mycosis fungoides, melanoma, acute promyelocytic leukemia, and squamous cell carcinoma of the skin and of the head and neck. This report comprehensively presents the clinical data using retinoids as anticancer agents in human premalignant disorders and outlines the ongoing and planned studies with retinoids in combination and adjuvant therapy.

Nonsurgical treatments for skin cancer: retinoids and alpha-interferon.

Retinoids, the natural and synthetic analogs of vitamin A, and alpha-interferon have been used effectively in the treatment of certain cutaneous premalignancies and malignancies. Retinoids have shown impressive activity against premalignant disorders of the skin (actinic keratoses, keratoacanthoma, epidermodysplasia verruciformis) and of other epithelial sites (oral leukoplakia, cervical dysplasia). In established basal cell skin cancers, topical retinoid treatment has produced a complete response rate of 33%, and systemic retinoids have produced an objective response rate of 51%. In advanced squamous cell skin cancers, systemic retinoids have produced a response rate of over 70%. Intralesional alpha-interferon has produced impressive responses and systemic alpha-interferon has produced a 50% objective response rate in basal and squamous cell carcinoma. Retinoid therapy and alpha-interferon have produced modest overall results in melanoma, although striking individual responses have been reported. In cutaneous T-cell lymphoma, which is notably refractory to chemotherapy, retinoids and alpha-interferon have produced responses in 60%+ and 70%+ of cases, respectively. Retinoids and alpha-interferon, either alone or in combination, offer exciting prospects for primary and neoadjuvant therapy for advanced malignancy. Retinoids also show promise as relatively nontoxic preventive and adjuvant therapy. Researchers should focus on integrating these drugs with other biological response modifiers, differentiation agents, and cytotoxic drugs for treating advanced malignancy.

The myelodysplastic syndromes

The myelodysplastic syndromes constitute a fascinating model for monoclonal premalignant disorders. Haemopoiesis is ‘dysplastic’ with inefficient maturation of a slowly expanding or sometimes of a stable population, of blood cell precursors. About one third of the patients evolve into acute leukaemia, the result of either a progressive expansion of the original clone or a new mutation producing a more malignant subclone. The majority of patients suffer from the results of bone-marrow insufficiency, with pancytopenia and possibly immune deficiency. Characteristic karyotype anomalies involving mainly chromosomes 5, 7 and 8 are seen in half the patients. These same chromosomes are known to carry different oncogenes. The myelodysplastic syndrome occurs mainly in the aged and there is a moderate male preponderance. The incidence is still unknown but is probably similar to that of acute leukaemia. The etiology is also unknown; however, a secondary myelodysplastic syndrome precedes acute myeloid leukaemia, as a late consequence of chemo- and radio-therapy in treated Hodgkin's disease. This suggests that environmental mutagens might also be involved in primary myelodysplastic syndromes. Treatment remains highly unsatisfactory but a few recent developments improve prognosis, as least in the younger patient.

Selected therapeutic applications of topical tretinoin

Since topical retinoic acid was first used for acne in 1959, many additional uses have been described for lesions on the skin, oral mucosa, and ocular surface epithelia. The topical application of retinoic acid has been shown to be effective in the treatment of several disorders of keratinization, keloids and hypertrophic scars, and various infections and inflammatory, pigmentation, and malignant and premalignant disorders. This article briefly reviews the use of topical retinoic acid for selected cutaneous conditions.

The yield of diagnostic upper endoscopy: results of a prospective audit.

Because of its widespread availability and the generally increasing economic pressure, endoscopy needs critical scrutiny to establish appropriate clinical guidelines. We carried out a prospective evaluation of 200 consecutive upper gastrointestinal (GI) endoscopies to ascertain the frequency of abnormal findings when specific indications were the impetus to endoscopy. Those indications were esophageal complaints, upper GI bleeding, abdominal discomfort, known premalignant disorders and abnormal findings on barium meal. The overall frequency of abnormal findings for all indications was 66%. Abnormal endoscopic findings were most often present when upper GI bleeding or premalignant conditions (88 and 87%, respectively) were reasons for endoscopy. Endoscopic confirmation of lesions seen on barium meal was 64%. Only 37% of patients endoscoped for abdominal discomfort had abnormal findings. Moreover, as symptoms resolved in 70% of such patients within 1 to 9 weeks, the low yield of endoscopy suggests that our current threshold for endoscopy in this setting may be too low. Refinement of the indications for and reassessment of the timing of endoscopy are needed.

Searching for markers in the hereditary intestinal polyposes.

Oral abnormalities in the intestinal polyposes have been reported by numerous authors. Detection of occult osteomatous and other dental changes in the jaws before development of polyps would be of considerable importance in the early diagnosis of premalignant gastrointestinal disorders. More than 425 individuals from families in whom intestinal polyposis is segregating have received oral-facial examinations. The dental findings may permit early, noninvasive identification of individuals at risk for polyposis.

Beckwith-Wiedemann (Exomphalos-Macroglossia-Gigantism?EMG) syndrome and malignant lymphoma

Although the Beckwith-Wiedemann (Exomphalos-Macroglossia-Gigantism) syndrome is felt to be a pre-malignant disorder, its association with lymphoma has not previously been noted. In this report we describe a child with the EMG syndrome who developed a disseminated diffuse lymphoma. Incidentally, he was found to be chronically infected with cytomegalovirus.

Increased bone marrow mast cells in preleukemic syndromes, acute leukemia, and lymphoproliferative disorders.

Increased numbers of bone marrow mast cells were found in 45 (2.2%) of 2,000 bone marrow specimens obtained from patients who had hematologic disorders. Mast cells were most frequently seen in the marrows of patients who had preleukemic syndromes, lymphoproliferative disorders, and acute leukemia. The 16 patients who had preleukemic syndromes included those with refractory sideroblastic and megaloblastic anemia (with or without an excess of blasts), idiopathic pancytopenia or pure erythrocytic aplasia, paroxysmal nocturnal hemoglobinuria, idiopathic refractory neutropenia, agranulocytosis or thrombocytopenia, and persistent eosinophilia. Five of the seven patients who had acute leukemia had nonlymphoblastic leukemia; two had blastic crisis of chronic granulocytic leukemia. Of the 13 patients who had lymphoproliferative disorders, eight had chronic lymphocytic leukemia, three had macroglobulinemia, and two had non-Hodgkin's lymphoma. Three patients who had chronic renal failure associated with severe anemia and two who had chronic liver disease, splenomegaly, or hypersplenism were also encountered. In this study there appeared to be a consistent relationship between the presence of increased numbers of mast cells and the lymphocyte and plasma cell counts in the bone marrow. The significance of the presence of secondary mastocytosis in premalignant lesions, neoplasia, and, in particular, lympho- and myeloproliferative disorders, is still unclear.

Human Alpha-Fetoprotein in the Epidermal Cells of Bowen's Disease

Human alpha-fetoprotein (HAFP) was demonstrated in clusters of atypical cells of an extensive Bowen's disease involving the pubic area. Frozen sections were studied by indirect immunofluorescence using monospecific rabbit anti-HAFP antiserum or purified rabbit anti-HAFP antibody followed by staining with fluorescein isothiocyanate (FITC)-labeled goat anti-rabbit gamma-globulin and by a direct technique using FITC-labeled rabbit anti-HAFP Fab2 fragments. Sections of fetal liver served as positive controls and sections of adult human skin and liver were used as negative controls. Preabsorption of the anti-HAFP antibodies with purified HAFP blocked the fluorescence. This finding adds Bowen's disease to the list of premalignant disorders which possess HAFP as an oncofetal marker of their malignant potential. HAFP might possibly enhance malignant behavior through interference with cellular immunosurveillance mechanisms.

Cancer, heredity and genetic counseling.Xeroderma pigmentosum

Cancer control can be improved through the application of knowledge of the hereditary aspects of certain malignant and premalignant disorders. A concrete example of the effectiveness of the application of genetic knowledge has been demonstrated by study of a family wherein five of seven siblings manifested xeroderma pigmentosum. Knowledge of the hereditary aspects of this disorder and its discovery in one sibling led to the immediate detection of the disorder in other siblings. In turn, preventive measures were instituted toward the avoidance of exposure to the carcinogenic effects of sunlight. Genetic counseling alleviated anxiety and major misconceptions among the family members concerning the hereditary aspects of this disorder.