Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.

Does malignant hibernoma exist?

The authors present a case of a highly atypical, possibly malignant, hibernoma. It presented as a deep-seated tumor in the retropharynx of a 57-year-old male. A review of possible similar cases is presented. The patient is without recurrence 4 years after complete excision and radiation therapy. The tumor must be differentiated from liposarcoma. The clinical potential must await the accumulation and observation of additional cases.

Barrett's metaplasia and adenocarcinoma of the esophagus and gastroesophageal junction.

Most previous studies of Barrett's metaplasia have used biopsy material to document cell, gland, and architectural types, leading to inaccurate or incomplete conclusions. The present study presents data from eight esophagogastrectomy specimens of Barrett's metaplasia with associated neoplasia, which were evaluated topologically by use of dissecting microscopy, specimen radiography, scanning electron microscopy, and routine histologic examination. Barrett's metaplasia was found to be mosaic of cell, gland, and architectural types, showing variable degrees of atrophy and maturation toward intestinal and gastric epithelium. Zonation was not found. Surface mucous, goblet, absorptive, mucous neck, mucous gland, and neuroendocrine cells were found in all cases; Paneth, chief, and parietal cells were found in approximately half. The presence of villar architecture with lining goblet and absorptive cells is unique and can be used to make a biopsy diagnosis. In one case, only a minute residual focus of Barrett's metaplasia was found, suggesting that the pathogenesis of some cases of adenocarcinoma of the lower esophagus and gastric cardia unassociated with Barrett's metaplasia may be the same. Nine cases of adenocarcinoma of the gastroesophageal junction unassociated with Barrett's metaplasia, studied during the same time period, had similar epidemiologic characteristics including mean age, age range, and sex distribution. Multifocal dysplasia and carcinoma in situ were found in all but one case. In two of eight cases adenomatous change was present; one of these resembled a villous adenoma of the colon with malignant degeneration. Barrett's metaplasia thus appears to be important as a precursor of adenocarcinoma in the region of the lower esophagus and gastroesophageal junction. The significance of these findings in relation to previous reports is discussed.

Significance of proliferative epithelial lesions of the uterine tube.

Proliferative epithelial lesions of the oviduct have been called adenomatous hyperplasia or carcinoma in situ. In order to assess the incidence and significance of these lesions, we sectioned entire oviducts from 124 nonselected hysterectomies. We found 23 cases (18.5%) with lesions corresponding to those described in the literature. We have found no justification for diagnosing and treating these lesions as carcinoma in situ. There appears to be an association with salpingitis.

Phase II evaluation of dibromodulcitol, ICRF-159, and maytansine for sarcomas.

Patients with objectively measurable soft tissue sarcomas, osteosarcomas, chondrosarcomas, and mesotheliomas were treated with dibromodulcitol (DBD) (180 mg/m2 p.o. days 1-10 q4 wks.). ICRF-159 (300 mg/m2 p.o. tid days 1-3 q4 wks), or maytansine (MAYT) (1.5 mg/m2 I.V. q3 wks.). Forty-five evaluable patients received DBD, 47 MAYT, and 37 ICRF-159. Only patients who had had their histopathologic diagnoses confirmed by a pathology reference panel were included in the final analysis. Two patients had objective partial responses: a patient with osteosarcoma who responded to DBD and a patient with fibrosarcoma who had a partial response of brief duration to ICRF-159. Approximately 70% of the patients treated with each drug were of ECOG performance status 0 or 1, and over half had moderate or worse toxicity. It seems unlikely that these drugs have significant therapeutic activity for common mesenchymal malignancies.

Tumors of striated muscle.

Three benign forms of muscle tumors and three variants of rhabdomyosarcoma are discussed from the point of view of their histology and behabior. Recent combined modality therapy has significantly improved the prognosis in at least the embryonal form of rhabdomyosarcoma.

Pathologist and histotechnologist: a marriage in need of counseling.

The general level of histotechnology in this country is alarmingly low. Surgical pathology, a difficult field, is made doubly so by poorly prepared sections. The blame for this must rest in part on the pathologist because of his ignorance of histologic procedures, his acceptance of shoddy work, and his lack of interest in seeing that bright young people are enticed into the field and that adequate training facilities and career opportunities are available to them. Today we are asked to perform increasingly complex procedures, and if we are to meet this challenge, as well as perform our duties in pathologic anatomy to the best of our ability, it is essential that we rapidly change our attitude.

Gastric pseudolymphoma. Its three subtypes and relation to lymphoma.

Three separate histologic types of gastric pseudolymphoma (GPL) are described: (1) the common "inflammatory" type usually accompanied by ulceration and extensive fibrosis; (2) the entity known as "nodular lymphoid hyperplasia," which was associated with multiple intestinal lesions; and (3) the third reported case of angiofollicular lymphoid hyperplasia of the stomach (one with nodal involvement). Criteria for the common type were developed and, in general, confirm previous studies. However, the importance of evaluating nuclear cytology and mitotic rate are stressed. Organ infiltration by chronic lymphocytic leukemia should be excluded by the absence of an absolute peripheral lymphocytosis. In addition to the ten cases presented, the literature on 175 previous cases is summarized. GPL is estimated to account for 10-15% of all gastric lymphoid tumors. In comparison to gastric lymphoma, GPL is usually smaller in size and occurs a decade earlier on the average. Since an associated focal lymphoma was documented in an additional five cases, this study proposes that pseudolymphoma be considered a precursor lesion with malignant potential. Extensive pathologic sampling and total surgical excision are recommended.

Primary gastric lymphomas. A clinicopathologic study of 58 cases with long-term follow-up and literature review.

A large series of primary gastric lymphomas with long-term follow-up (average, 12.8 years) is reported. A number of factors known to affect nodal lymphoma were examined. Five- and ten-year survival rates were 57 and 46%, respectively. Statistically significant favorable prognostic variables were smaller tumor size (less than or equal to 7 cm), superficial mural invasion (submucosal only), and pathologic Stage I disease; these variables were intimately interrelated. A favorable influence on survival was discerned concerning histologic type and nodular histology, although still below statistical significance. No significant relation to survival was observed concerning clinical weight loss or palpable mass, vascular invasion, mode of therapy, or histologic subtypes of "histocytic" lymphoma. Of patients who succumbed to disease, 75% did so within two years (average, 1.8 years); however, later recurrence and death may occur. An argument for resection of localized disease is presented. Mitotic index and nuclear diameter were of diagnostic importance, and associated lesions such as pseudolymphomas are discussed in relation to pathogenesis. Histologic variation within tumors suggested visualization of clonal development in non-Hodgkin's lymphomas.

Gardner's syndrome with duodenal adenomas, gastric adenomyoma and thyroid papillary--follicular adenocarcinoma.

A case of a woman with Gardner's syndrome, originally manifested by multiple adenomatous polyps of the colon, is presented. She underwent subtotal colectomy at 14 years of age. Over the next 15 years she had a composite odontoma, an impacted supernumerary tooth, two epidermal inclusion cysts, multicentric paillary-follicular adenocarcinoma of the thyroid, two tubulovillous adenomas of the duodenum in which argyrophilic cells were a prominent feature, and an adenomyoma of the gastric antrum. The presence of all of these lesions in one patient expands the spectrum of lesions seen with Gardner's syndrome and supports the concept of a generalized abnormality of growth regulation as the cause of the syndrome.

Lobular carcinoma of the breast in situ and infiltrating.

Lobular carcinoma in situ, while histologically delineated almost 35 years ago, is still being diagnosed and reported with differing qualitative and quantitative criteria. It is important to recognize this lesion because of its frequent bilaterality and risk of developing infiltrating carcinoma in the affected breast. Because of the apparent morphologic identity of the cell of ALH and the cell of LCIS, because both are associated with some increased risk of developing carcinoma, and because both have an increased propensity to be found simultaneously with carcinoma--especially lobular carcinoma--we believe these lesions should be looked upon as basically identical. Beginning with Ewing's astute intuition nearly 60 years ago18 and culminating with the 1967 report of McDivitt and others,50 pathologists and surgeons have gradually become aware of the long-term risk associated with this nonobligatorily, premalignant lesion (LCIS). As further studies have become available, it is clear that a large majority of women with lobular carcinoma in situ or atypical lobular hyperplasia retaining the involved breast will not develop infiltrating carcinoma. However, there is an increased risk of roughly 1 percent per year. Because of the increased risk, we believe that a meticulous long-term followup is mandatory, and suggest a physical examination every two to three months for the first few years supplemented with yearly mammography (as is now being done at Memorial Hospital for patients with atypical breast lesions6). With such a followup, we believe the mortality should fall well below 5 percent in a 20-year followup, and believe this is a risk that may be acceptable to the patient and her surgeon. The boundaries of the morphologic changes acceptable as ILC have been difficult for many pathologists (including ourselves) to delineate. This is borne out by widely varying incidence figures and is due, at least in part, to the frequent admixture of ILC with poorly differentiated duct carcinoma as well as problems in deciding how large and pleomorphic the cell nuclei may be, and still be designated as lobular in origin. We believe that about 4 to 6 percent of all breast carcinomas are infiltrating lobular, and incidence rates widely divergent from this should be scrutinized carefully. Prognostically, ILC behaves similarly to poorly differentiated duct carcinomas except for some increased risk of subsequent contralateral carcinoma. Future study of lobular disease should be directed toward its histogenesis, long-term risk, and the relative success of different treatment modalities. Hormonal studies and cell culture with chromosomal analysis might shed some light on the mechanism of what may be postmenopausal regression of LCIS.

The macroscopic appearance of colorectal polyps.

The macroscopic (10 to 30 times magnification) surface features of 187 colonic lesions are described. The lesions were studied using a dissecting microscope and a 1% trypan blue solution as a contrast agent. Using five criteria, lesions were evaluated for the presence or absence of adenoma, the type of adenoma present, the presence of dysplasia or carcinoma-in-situ, and the presence of invasive carcinoma. The technique has proven to be a rapid, sensitive, and relatively specific means of separating tumors in the adenoma--carcinoma sequence from nonadenomatous lesions (sensitivity, 99%, specificity 90%). The technique is accurate in differentiating tubular, tubulovillous, and villous lesions. It is suggested that areas of dysplasia (sensitivity 100%, specificity 93%), carcinoma-in-situ, and microinvasive carcinoma may also be differentiated, but need further investigation. The present study suggests that the macroscopic architecture of the various lesions in the adenoma--carcinoma sequence is unique and may be used diagnostically. These preliminary findings need to be confirmed in a prospective double-blind study, and to be adapted to use in colonoscopic and radiologic diagnosis.