A model for human colon carcinoma evolution based on the differential response of cultured preneoplastic, premalignant, and malignant cells to 12-O-tetradecanoylphorbol-13-acetate.

Small colonic adenocarcinomas can be found in focal areas within benign tumors (adenomas), strongly suggesting an adenoma-to-carcinoma sequence. The induction of plasminogen activator (PA) secretion by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) has been used to order histologically distinct classes of human colonic adenomas in primary culture into a sequence from the most benign to the most advanced premalignant state. This ordering is based on the observation that each of five carcinomas examined in an earlier study by E. A. Friedman (Cancer Res., 41: 4588-4599, 1981) and each of seven carcinomas tested in this study released PA in response to TPA, inducing easily scored morphological alterations. Benign tumors either resembled carcinomas in their response to TPA or exhibited no morphological changes. The most benign adenomas by histopathology criteria were the small pure tubular adenomas without dysplasia. Six of seven of these adenomas did not secrete PA in response to TPA. We concluded that malignant cells had acquired the ability to respond to TPA by PA secretion, while tubular adenoma cells were not an advanced enough preneoplastic stage to so respond. TPA treatment of two cultured villous adenomas, one with infiltrating carcinoma and one with focus of moderately dysplastic cells, in the presence of low serum to decrease the plasmin concentration, demonstrated that only a subpopulation of cells secreted PA. Local areas of the monolayer were morphologically altered by the protease, forming clusters of cells loosely attached to the dish. The presence of such subpopulations within cultured adenomas was demonstrated by screening an additional five villous adenomas, 15 villotubular adenomas, and 11 tubular adenomas. The presence of dysplastic cells in 23 of 24 cases correlated with PA secretion. A subpopulation of villous cells, in the absence of dysplastic cells in each of three cases, also secreted PA. We conclude that, during tumor evolution, this villous subpopulation is the first preneoplastic cell type to acquire responsiveness to TPA by PA secretion. This property is maintained as the cells further evolve through premalignant dysplastic stages to carcinoma.

Expansion of the epithelial cell proliferative compartment and frequency of adenomatous polyps in the colon correlate with the strength of family history of colorectal cancer.

Expansion of the proliferative compartment of epithelial cells in colonic crypts and colonic adenomas have been described as phenotypic precursors to colon cancer in individuals affected with hereditary or sporadic colon cancer. This study measured the size of the proliferative compartment in colonic crypts and the frequency of adenomas in asymptomatic members of families having sporadic colorectal cancer. The subjects were divided into 2 groups according to the frequency of colorectal cancer in their families. A shift of the compartment of proliferating epithelial cells toward the lumenal surface of colonic crypts was seen in the group of subjects with a stronger family history of colorectal cancer, with significant differences in the numbers of proliferative cells in the upper and the lower crypt compartments (P < 0.05) and in the fraction of proliferative cells at the highest compartment at the lumenal surface of the crypts (P < 0.05). Cell proliferation patterns in normal-appearing mucosa of the 2 groups revealed no difference in whole crypt [3H]thymidine labeling index. Colonoscopic examination of the 56 subjects revealed an overall prevalence of adenomas of 21%; when stratified by frequency of colorectal cancer in their families, 3 of 22 subjects (14%) with a weaker family history had adenomas, while 9 of 34 (26%) with a stronger family history had adenomas. Thus, parallel abnormalities of colonic epithelial cell proliferation and neoplasia were seen in individuals with a family history of colorectal cancer, both of which were more pronounced with increasing strength of family history. This observation provides further evidence of relationships among these factors in the etiology of "sporadic" colorectal cancer.

Cis-diamminedichloroplatinum(II) nephrotoxicity and its relationship to renal gamma-glutamyl transpeptidase and glutathione.

To investigate the mechanism of cis-diamminedichloroplatinum(II) (cisplatin) nephrotoxicity, male Sprague-Dawley rats were given one injection of cisplatin (6 mg/kg i.v.). Urinary levels of amino acids and gamma-glutamyl transpeptidase were monitored for 8 days; kidney homogenate content of gamma-glutamyl transpeptidase was followed for 50 hr, and that of selenium-dependent glutathione peroxidase and total glutathione was followed for 4 hr. Peak urinary levels of amino acids and gamma-glutamyl transpeptidase occurred 4.5 hr after the i.v. dose. Glutamine, glycine, and ethanolamine were all elevated greater than 20 times that of the control at 4.5 hr and were still significantly elevated at 50 hr. Total renal glutathione content increased 51 +/- 17% (S.D.) of control values 20 min after cisplatin was given, before returning to base-line levels. No depletion of either renal glutathione or glutathione peroxidase was detected over the time interval studied. These results demonstrate an earlier physiological impairment than has hitherto been shown. Furthermore, depletion of glutathione and glutathione peroxidase does not occur in the rat kidney following therapeutic doses of cisplatin, in contrast to the changes observed in cardiac tissue following doxorubicin treatment.

Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma.

A combination of recombinant human interleukin 2 (rhIL-2) and mouse monoclonal antibody R24 (recognizing the ganglioside GD3) was evaluated in patients with metastatic melanoma in a phase I trial. rhIL-2 was given at a constant daily dose of 1 x 10(6) units/m2 i.v. over 6 h on days 1-5 and 8-12. R24 was given on days 8-12 at four dose levels (1, 3, 8, and 12 mg/m2 daily). Twenty patients were evaluable for toxicity and response, five at each dose level. The toxicity of the combination was not overlapping and generally mild. There was a rebound peripheral blood T-lymphocytosis at the end of treatment increasing with the dose of R24. The median lymphocyte count on day 12 of treatment was 3108 +/- 554/ml in patients treated at R24 doses of 8 and 12 mg/m2 versus 2239 +/- 672/ml at doses of 1 and 3 mg/m2. This evidence and other data suggested that R24 enhanced IL-2-mediated T-cell activation in vivo. Two patients demonstrated increases in R24-mediated antibody-dependent cellular cytotoxicity for GD3-expressing cells during treatment. rhIL-2 appeared to accelerate the development of human anti-mouse antibody; three patients developed human anti-mouse antibody by the fifth day of R24 treatment, earlier than observed in prior studies using R24 alone and one patient during the first week of rhIL-2 alone, prior to R24 treatment. One patient had a partial response in soft tissue sites lasting 6 months and two patients had minor responses. This clinical trial extends the previous observation that R24 enhances lymphocyte proliferation in vitro.

Unexplained persistent lymphadenopathy in homosexual men and the acquired immune deficiency syndrome.

Ninety-three homosexual men with persistent lymphadenopathy were followed at the Memorial Sloan-Kettering Cancer Center for a mean period of 20.8 months. Histories and serologic evidence of a number of previous infections were common, but the lymphadenopathy was not due to recognizable infections or neoplastic disease. Leukopenia, lymphopenia, granulocytopenia, monocytopenia, decreased ratios of T-helper to T-suppressor cells, decreased natural killer cell activity and increased serum immunoglobulin concentrations were common. Lymph node biopsies showed reactive hyperplasia without any unique histopathologic features. Antibody to the human T-lymphotropic virus-III (HTLV-III or LAV), a newly described retrovirus believed to be the etiologic agent of the acquired immune deficiency syndrome (AIDS), was detected in 91.4%. Over a 3-year period, 11 cases of AIDS were recognized in these patients: Kaposi's sarcoma developed in 7 and opportunistic infections in 4. The lymphadenopathy resolved in six patients and the others remained unchanged. Although most of these patients are asymptomatic and remain well, the risk of AIDS in this group of men was higher than in other groups of homosexual men in New York.

Outbreak of Kaposi's sarcoma with cytomegalovirus infection in young homosexual men.

Kaposi's sarcoma, a multicentric malignant neoplasm, occurs in certain geographic areas in the world. It is most common in Equatorial Africa and Eastern Europe. The annual incidence of Kaposi's sarcoma in the United States is between 0.021 and 0.061 per 100,000 persons. The appearance of an outbreak of Kaposi's sarcoma in young homosexual men in New York and California is a new and unique phenomenon. Certain differences are already recognized between the disease in these young men and the ordinary Kaposi's sarcoma. Herein we report our observations of the first 10 cases of Kaposi's sarcoma in young homosexual men. In these patients, the disease follows an aggressive clinical course characterized by widespread skin lesions with early involvement of the lymph nodes. In some of these patients, the result was death in a short period of time after initial diagnosis. In addition, cytomegalovirus infections were seen in these patients, which suggests at least a possible association between this viral and the disease.

Primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus is exceedingly rare. We identified six patients seen at Memorial Hospital for Cancer and Allied Diseases over a period of 35 years. All patients were Caucasian, with an age range of 30 to 74 years (mean: 60 years). There were three men and three women. No association was noted with tobacco or ethanol use, nor was there a personal or family history of malignant melanoma. Symptoms were related to obstruction or hemorrhage. All tumors were polypoid and had attained large size at the time of initial diagnosis. Histologically, the melanomas had epithelioid, spindle-cell, and pleomorphic areas with focal melanin production. An intraepithelial "in situ" component was present in five cases and melanosis of the non-neoplastic esophagus in five. All six neoplasms were immunoreactive for S-100 protein, and none reacted with anticytokeratins. Two cases examined ultrastructurally showed premelanosomes. All patients were treated by esophagogastrectomy. The mean survival for four patients was only 2.1 months. The two remaining patients are alive at 5.5 and 11 months.

Rhabdomyosarcoma of the liver associated with long-term oral contraceptive use. Possible role of estrogens in the genesis of embryologically distinct liver tumors.

We report a case of rhabdomyosarcoma arising in a 34-year-old woman with a 16-year history of oral contraceptive use. This is the first reported case of hepatic rhabdomyosarcoma associated with oral contraception. The tumor did not grossly or microscopically involve biliary structures or gall bladder. It was mostly comprised of undifferentiated spindle cells that were histologically similar to embryonal sarcoma. Foci of cells showing rhabdomyoblastic differentiation blended into poorly formed muscle bundles. No epithelial neoplasm was identified by either morphologic or immunohistochemical analysis. A review of the literature reveals that, although the incidence is low, mesenchymal neoplasms of the liver have been associated with oral contraceptive use. Furthermore, there is now evidence that a multipotential progenitor cell exists that can give rise to both epithelial and mesenchymal neoplasms. Thus, there may be a common precursor cell on which estrogens could act, and which could give rise to epithelial, mesenchymal, or mixed neoplasms. Finally, we suggest that embryonal sarcomas of the liver can undergo further differentiation to more well-defined mesencymal elements.

Giant myofibroblastoma of the male breast.

Myofibroblastoma of the breast is a rare, benign neoplasm, seen predominantly in men. The gross appearance is that of a well-circumscribed nodule, characteristically small, seldom exceeding 3 cm. We report a case of giant myofibroblastoma measuring 10 cm and weighing 169 g in the breast of an 83-year-old man. Light microscopic, immunohistochemistry, and electron microscopic features are described. Histologically, these neoplasms may exhibit a varied cellularity that can be misinterpreted as sarcoma. However, they lack marked cellular pleomorphism, tumor necrosis, and mitosis and are characteristically composed of plump and long bipolar, spindly cells arranged in swirling fascicles with intervening broad collagen bands. As we report, immunostaining is strongly positive for vimentin, desmin, and muscle common antigen and negative for cytokeratins and S-100-associated protein. Electron microscopy shows predominantly cells suggestive of myofibroblastic differentiation. The patient has remained free of disease 2 years after mastectomy.

Bursa formation in secondary chondrosarcoma with intrabursal chondrosarcomatosis.

Osteocartilaginous exostoses (osteochondromata) are rather common bone tumors. Although most are straightforward lesions, one may occasionally encounter one of a number of well-recognized complications. In the current case, secondary malignant transformation and bursal sac formation were present. Additionally, numerous malignant chondroid nodules were shed into the attached bursa, giving rise to a large soft tissue mass, a situation which we feel is both remarkable and, to our knowledge, unique.

Aggressive natural killer cell lymphoma/leukemia. A recently recognized clinicopathologic entity.

We report a comprehensive study of a case of aggressive natural killer cell lymphoma/leukemia, which is characterized by young male predominance, rapidly progressive clinical course, and presence of lymphadenopathy, hepatosplenomegaly, and bone marrow involvement. The leukemic phase is frequently preceded by pancytopenia. The diagnostic clues are the detection of cytoplasmic granules in tumor cells on Wright-Giemsa-stained tissue imprints or smears and a selective loss of T-cell antigens. Immunophenotyping is decisive in making the final diagnosis by showing positive natural killer cell markers (CD16, CD56, and/or CD57), CD2, CD11c, and Ia, but negative CD3, T-cell receptor heterodimers, terminal deoxynucleotidyl transferase, and B-cell markers. Genotyping always shows germline configuration in both immunoglobulin and T-cell receptor genes. The unique feature in this case is its presentation as a testicular lymphoma, which has not been previously reported. Polymerase chain reaction was performed in this case but failed to detect human T-cell leukemia virus type I/II provirus. It is important to recognize this new entity as it is a highly aggressive disease with a rapidly progressive clinical course and fails to respond to any chemotherapeutic regimen available.

Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years.

We summarize our experience with 238 cases of Langerhans cell granulomatosis (LCG), 198 of whom were followed for a median period of 10.5 years. Our patients did well unless overtreated, and no deaths were attributed to the disorder itself. The disease may appear in unifocal or multifocal form, and treatment is based on this fact. Virtually all patients recovered completely except for occasional residual orthopedic problems or residual diabetes insipidus. Several of the patients underwent subsequent pregnancies without difficulty. The granulomas primarily occur in bone, but lung, skin, and lymph nodal involvement is not uncommon. Involvement of thyroid, thymus, and other sites is rare. The hallmark of the disease is the accumulation of Langerhans cells (LCs). We review the pathology of LCG by histology, electron microscopy, and immunolabeling. LCs originally were identified in squamous epithelium, but these cells are part of the widespread system of dendritic cells. The latter cells, which arise from CD34+ progenitors, are specialized and efficient antigen-presenting cells for T-cell-mediated immunity. In LCG, however, the major associated cells are not T cells, but mature eosinophils: hence the original name eosinophilic granuloma. Confusion about terminology has been based upon the scanty and rather crude pathology reports in the original literature. The term histiocytosis X was meant to cover a spectrum of three diseases--eosinophilic granuloma, Hand-Schüller-Christian disease (HSC), and Letterer-Siwe disease (LS)--but HSC and LS have no basis in pathology and hence the terms are meaningless. The term HSC has become a synonym for multifocal eosinophilic granuloma (LCG). The term LS has been used in reporting a number of benign, malignant, or unknown conditions. We prefer the term LCG to avoid confusion with the term histiocytosis X because there is evidence that the LC is not a member of the mononuclear phagocyte system and hence not a tissue macrophage, and because the use of the term "histiocyte" has become a convenience in much of the literature when reporting incompletely understood diseases.

Histologic predictors of survival in acquired immunodeficiency syndrome-associated Kaposi's sarcoma.

The relationship between 22 histologic variables and survival was investigated in 93 patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). All the patients were homosexual men in whom KS was the initial manifestation of AIDS. All patients were followed for at least 12 months or until death. Histologic specimens of the initial KS biopsy were reviewed in a blind manner by two of the authors and were evaluated for the presence of a number of histologic features. In a univariate analysis nodular lesions of KS (upsilon patch or plaque lesions), the absence of hemosiderin, the absence of irregular vascular spaces, and the presence of spindle cell nodules were all significantly associated with increased length of survival. Two variables previously shown to be related to survival (CD4:CD8 cell ratio, initial lesion on lower extremities) were included in a multivariate analysis (Cox model) in addition to the histologic variables. Complete data were available from 85 patients. In the multivariate analysis a higher helper to suppressor T-cell ratio, initial lesion on lower extremities, presence of spindle cell nodules, and nodular histology (upsilon patch or plaque histology) were all significantly associated with increased length of survival. These data suggest that in AIDS-associated KS, as in reticuloendothelial neoplasms, histologic features may be useful in identifying prognostically different subgroups of patients.

Expression of Her2/neu oncogene product p185 in correlation to clinicopathological and prognostic factors of gastric carcinoma.

The expression of the Her2/neu gene product p185 was retrospectively analyzed in 58 patients with gastric carcinoma. The results were correlated to various clinicopathological and prognostic factors. Positive membrane staining for p185 could be detected in 38% of the patients (22/58). Membrane staining was significantly greater in well and moderately differentiated tumors of the intestinal type when compared with poorly differentiated lesions and carcinomas of the diffuse type (P less than 0.01). Positive membrane staining did not correlate with site and tumor stage, but T1 lesions had less membrane staining than more advanced primary tumors. Overall survival showed no difference between p185-positive and negative cases. Multivariate analysis defined a subgroup of curatively resected patients with stage III and IV disease that had a statistically significant poorer survival when p185 was overexpressed (P = 0.005). Overexpression of the Her2/neu product p185 appears to be associated with intestinal-type gastric carcinoma and may help in identifying a subset of patients at increased risk for shorter survival.

Subacute encephalitis in acquired immune deficiency syndrome: a postmortem study.

Thirty-one out of 40 patients with the acquired immune deficiency syndrome examined at autopsy had significant central nervous system disease. A subacute encephalitis, found in 19 patients, was the most frequent finding and was characterized by marked brain atrophy and a progressive dementing illness. This entity is linked to cytomegalovirus (CMV) by typical histopathology and association with systemic CMV infection with supportive evidence of positive immunohistochemical staining of tissue sections and, in one case, identification of CMV-type viral particles by electron microscopy. However, brain tissue cultures have been negative, making the etiology of subacute encephalitis not entirely clear.

Merkel cell carcinoma. Prognosis and management.

Seventy patients with Merkel cell carcinoma were treated at Memorial Sloan-kettering Cancer Center between 1969 and 1989. The overall estimated 5-year survival rate was 64%. Factors predictive of improved survival included head and neck site and negative lymph nodes at presentation. Local recurrence was seen in 18 patients (26%) and did not correlate with patient-, tumor-, or treatment-related variables. Nine patients with local recurrence (50%) were free of disease following aggressive reoperation. Regional nodes were involved at some point during the course of the disease in forty-six patients (66%). Regional lymph node involvement was apparent within 2 years of diagnosis in 40 (87%) of 46 patients in whom it occurred. Systemic disease was nearly uniformly preceded by the appearance of nodal metastases and was uniformly fatal regardless of subsequent therapy. This suggests an orderly "cascade" pattern of spread for this tumor, in which elective regional lymph node dissection may be justified. Our recommendations for treatment include a wide excision of the primary tumor and either elective or early therapeutic regional node dissection. The role of adjuvant radiotherapy or chemotherapy remains unproven.

Pancreatic cystadenoma. A clinicopathologic study.

A retrospective study of 19 patients with pancreatic cystadenoma included 15 patients with microcystic and 4 with mucinous cystadenomas. The typical clinical presentation was that of an elderly woman with an upper abdominal mass. An association with diabetes mellitus and extrapancreatic malignant disease was noted. Total tumor resection provided the best chance of cure and removed the risk of compression of adjacent organs and, in mucinous cystadenomas, the risk of malignant transformation.

Amplification of HER-2/neu gene in human gastric adenocarcinomas: correlation with primary site.

Adenocarcinomas of the proximal stomach including the gastroesophageal junction are extremely virulent cancers which are increasing rapidly in incidence. Stage-for-stage proximal gastric cancers have a worse prognosis than do tumors of the body or antrum of the stomach. To further explore biological differences based on site, we studied 80 patients with locally advanced primary tumours of the proximal (n = 40) and distal stomach (n = 40) for amplification of the HER-2/neu proto-oncogene. None of 40 patients with proximal lesions had overexpression of HER-2/neu, whereas four of 40 (10%) distal adenocarcinomas had a 16-24-fold gene amplification (P = 0.04). In the adenocarcinomas from two patients, gene rearrangements were found in addition to amplification. HER-2/neu gene product p185 over-expression was found only in the amplified cases. All four patients with distal tumors and amplification had rapid progression of disease (median survival: 4.3 months). While it is unclear why HER-2/neu amplification is seen only in distal tumors, these data further support the hypothesis that biological differences between proximal and distal lesions are present. As is the case for other tumours, HER-2/neu amplification is associated with a poor prognosis for the individual patient.

Recurrent deletions involving chromosomes 1, 5, 17, and 18 in colorectal carcinoma: possible role in biological and clinical behavior of tumors.

We have employed cytogenetic and restriction fragment length polymorphism (RFLP) analysis to identify a full spectrum of cytogenetic and molecular alterations associated with initiation and progression of "sporadic" colorectal cancer and also to correlate the alterations with biological and clinical behavior of the tumors. The study series included 63 colorectal cancers, 47 primary and 16 metastatic recurrences. Cytogenetic analysis was successful in 48 tumors (76%) of which 44 (91%) were abnormal. Of these 44 tumors, clonal abnormalities were identified in 43, whereas chromosomes from one tumor were unsuitable for complete analysis. Each of these abnormal tumors displayed heterogeneity with regard to extent and complexity of recurrent chromosomal abnormalities. Numerical losses of chromosomes 17 and 18 (20-34%) and gains of chromosome 7 (28%) were significantly higher. The four most frequent structural rearrangements on the other hand, involved specific regions of chromosomes 1p, 5q, 17p, and 18q. The shortest regions of overlap of these rearrangements or losses were located at 1p36, 5q21-22, 17p13 and 18q21- > ter. RFLP analysis directed at 1p, 5q, 17p and 18q identified allelic deletions of these regions in 39 tumors (64%) which included 17 normal and 11 cytogenetic failures. Of all the informative tumors, 32%, 37%, 31%, and 63% showed allelic losses at chromosomes 1p, 5q, 17p and 18q respectively. The two methods of analysis (cytogenetics and RFLP) employed to identify genetic alterations were complementary; probes for chromosome 1 and 18 showed the greatest degree of concordance, whereas probes for chromosomes 5 and 17 provided relatively higher rate of discordance with cytogenetic results. These differences could be attributed mainly to three reasons: 1) a limited number of probes used for RFLP analysis; 2) contamination of tumor cells with normal cells, and 3) either mutational inactivation or deletion of specific alleles not closely linked to the probes used. Regardless of these limitations, however, the combined use of cytogenetic and RFLP identified genetic alterations in a large number of tumors and help elucidate the role of hyperdiploidy and/or relative deficiency of a given chromosomal segment in expression of recessive mutations. In addition, alterations of either chromosomes 1 or 17 predicted poorer survival for the patients with primary colorectal cancer (p = 0.03).

Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results.

Epidermoid cancer of the anal margin should be distinguished from that in the canal because of its different clinical and pathologic characteristics, the suitability of local excision for its treatment, and its better overall prognosis. In addition, margin cancer rarely metastasises to visceral sites. Forty-eight patients with epidermoid cancer of the anal margin were reviewed. Two refused treatment, 4 had palliative therapy for advanced, inoperable disease, 31 had local excision, and 11 were treated by abdominoperineal resection. Local excision provided satisfactory results with a corrected 5 year survival of 88 percent, although locoregional recurrence developed in 46 percent of these patients during follow-up. A second local excision or inguinal lymphadenectomy provided good results in the patients with recurrence. Abdominoperineal resection did not provide better overall survival figures.