Rao R. Paladugu

Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids.

Typical and atypical carcinoids constitute less than 5% of lung tumors. They and small cell undifferentiated lung cancers (SCLC) belong to the same family of apudomas arising from bronchopul‐monary Kulchitzky cells. To reflect the overlap among these cancers, the authors suggest calling them Kulchitzky cell carcinomas (KCC); to indicate their spectrum of aggressiveness, the authors suggest calling typical carcinoids KCC‐I, atypical carcinoids KCC‐II, and small cell cancers KCC‐III. One hundred fifty‐six KCCs were reviewed: 115 were KCC‐I and 41 were KCC‐II. The ratio of women to men equals 2:1. At time of initial diagnosis, all patients with KCC‐I, except one patient, were in Stage I. Among patients with KCC‐II, 16 (39%) were in Stages II or III at time of presentation. The incidence of carcinoid syndrome was 1.9%. Treatment was lobectomy in 112 (72%) of patients, the remainder having lesser resections or pneumonectomy in approximately equal distribution. Our data cannot support the use of radical resection in the treatment of KCC because none of the patients died of local recurrence. The mean diameters of KCC‐I and ‐II tumors were 1.5 and 2.8 cm, respectively. Increased mitotic activity and tumor necrosis were reliable criteria for diagnosing KCC‐II. Electron microscopic examination did not help in differentiating KCC‐I and KCC‐II. Thorough sampling of the entire tumor was found to be mandatory for precise diagnosis and for differentiation from KCC‐III (SCLC). Measurement of nuclear DNA was done using integrated optical density (IOD) by image analysis. The IODs of KCC‐I, ‐II and ‐III were 1.36, 1.55 and 1.94, respectively. These significant differences (P < 0.001) correlated with the aggressiveness of the cancers. Of patients with KCC‐I, 1.7% succumbed to KCC; this included one patient reported to have died of KCC‐III (SCLC). Of 41 patients with KCC‐II, 11 (27%) died of KCC; this includes at least 3 deaths from KCC‐III. Cancer 55:1303‐1311, 1985.

Malignant lymphoma with primary manifestation in the gonad a clinicopathologic study of 38 patients

This study is based on 38 patients, each of whom had a malignant lymphoma in which the gonad was the site of the main tumor mass at the time of diagnosis. Histiocytic lymphoma was the predominant type in the 27 male patients; in the 11 female patients, poorly differentiated lymphocytic lymphoma was the most frequent type (36%). All of the neoplasms in the males were diffuse, whereas two of the females had neoplasms that were nodular and diffuse. A striking feature was the high frequency of vascular invasion (41%) in the testicular lymphomas, which was reflected in a high incidence (86%) of noncontiguous lung involvement at autopsy, suggesting hematogenous spread. Clinically occult disease is probably responsible for the short interval between the discovery of a gonadal mass and the appearance of generalized disease. A poor prognosis may be expected if there is evidence of generalized disease within one year after diagnosis. Only 2 patients had disseminated disease after a year, whereas all those who died of disseminated disease manifested it within six months after diagnosis. Disease‐free survival times in excess of 60 months in 3 patients who were treated only by orchiectomy or oophorectomy indicate that the gonads may be the primary site of a malignant lymphoma.

Acral lentiginous melanoma A clinicopathologic study of 36 patients

Acral lentiginous melanoma (ALM) is a distinct variant of malignant melanoma with a predilection for the soles, palms, and nail beds. This melanoma has characteristic histologic features, and its biologic behavior is similar to that of nodular melanoma. It occurs predominantly in the sixth, seventh, and eighth decades of life, with a peak incidence in the seventh decade for males and in the sixth decade for females. Diagnosis of ALM during the radial growth phase is often difficult, and it may not be recognized initially, but treatment in this phase offers an excellent prognosis. There is a high incidence of regressive changes and desmoplasia in ALM; these changes, together with the anatomic peculiarities of nail beds, palms, and soles as compared with other skin areas, make it difficult to determine the Clarks level and to measure the depth of invasion. Wide local excision with lymph node dissection is recommended for subungual melanomas measuring more than 1.00 mm and for lesions showing severe regression. Volar melanomas less than 1.00 mm deep and those in the radial growth phase with minimal invasion require only wide local excision. Amputation of digits and lymph node dissection are recommended for subungual melanomas, if the melanomas exhibit the vertical growth phase. If there is only radial growth without regressive changes, wide local excision is adequate. Patients with metastasis to lymph nodes at the time of diagnosis usually have shorter survival times than do those without lymph node involvement (P = 0.027). Cancer 52:161‐168, 1983.

Glassy cell carcinoma of the cervix cytologic and clinicopathologic analysis

A clinicopathologic analysis of 15 patients with glassy cell carcinoma confirmed that this is a rare disease, having an incidence of 1.2%. It is a rapidly progressive and biologically aggressive disease with early extrapelvic metastasis. The five‐year survival and the median survival in our series were 28% and 14 months, respectively. The majority of patients (87%) were understaged, which may have played a role in the poor prognosis. Four of 12 patients (33%) were initially diagnosed as having a benign disease (false‐negatives). Defining of cytologic characteristics and differential features of this tumor may facilitate an early and more accurate diagnosis to improve prognosis. Cancer 52:307‐312, 1983.

Effects of 5-azacytidine in syrian golden hamsters: Toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis

5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F1D) hamsters wherein benzol[a]pyrene (BP) from sustained release implants (SRI) induces preneoplastic mucosal changes which progress to bronchogenic cancer. In pilot studies to evaluate AZC toxicity, a dose schedule of 5 mg/kg biweekly was found suitable and was then used for long-term administration in all subsequent studies. Three groups of outbred hamsters were studied: BP SRi alone (n = 60), BP SRI + AZC (n = 60), and AZC alone (n = 54). AZC treatment was begun 3-5 days after SRI placement. Sixty-one days after the start of the experiment, seven or eight hamsters were sacrificed from each group. Later sacrifices were at 3-week intervals in groups receiving BP SRI and at 6-week intervals in the AZC only group. Four groups of F1D syngeneic hamsters were studied: BP SRI alone (n = 50); BP + AZC starting 3-5 days after SRI placement and continuing until death (n = 52); BP + AZC from 3 to 5 days until 75 days after SRI placement (n = 49); BP + AZC starting 80 days after SRI placement and continuing until death (n = 52). Hamsters (n = 9-14) from each group were sacrificed at 120, 150, 180, and 220 days after SRI implantation. AZC alone was not carcinogenic under these conditions. Both outbred and F1D hamsters treated with early or continuous AZC had slower rates of neoplastic change from BP SRI than did animals receiving BP SRIs alone or BP + late AZC. The incidence of epidermoid cancer were the same for all regimens, but the tumors in those receiving AZC early in carcinogenesis were smaller than in those receiving late or no AZC. The incidences of nonepidermoid cancer were lower in those receiving AZC during early carcinogenesis, and larger tumors were noted in the absence of AZC. Thus, within the study period in this unique hamster lung cancer model, AZC given early in carcinogenesis inhibited only the later (promotional) phase of BP epidermoid carcinogenesis, but inhibited all phases of nonsquamous cancer development induced by BP. This differential modulation of bronchial carcinogenesis, which occurs from AZC given during preneoplastic stages, may prove useful for delineating molecular mechanisms underlying specific phenotypic types of bronchogenic cancers.

A Clinically Relevant Canine Lung Cancer Model

Research on early human lung cancer is difficult; we have sought a canine correlate. Regimens included endobronchial submucosal injections and topical focal applications of benzo[a]pyrene, nitrosomethylurea, dimethylbenzanthracene, and methylcholanthrene, singly or in combinations. Sustained-release discs were placed into lung parenchyma or sutured into major bronchi. Tracheal segments were isolated as cervical pedicle grafts. Gross and histological evolution was reproducible. Columnar and basal hyperplasia and squamous metaplasia were early changes. Atypia occurred within 6 weeks and was found in all dogs within 16 to 18 weeks. Invasive cancers occurred within 8 to 65 months. No tracheal graft developed cancer. Of 15 dogs with parenchymal sustained-release implants, 1 to date has developed cancer in 8 months. Four endobronchial regimens have produced 16 cancers in 56 lungs at risk for 18 to 65 months. No cancers developed in 23 lungs at risk from eight other regimens. Of 10 dogs at risk for unilateral endobronchial cancer, 5 have had cancer. Of 23 dogs with both lungs at risk, 9 developed cancer. We have shown focal carcinogenesis with well-defined pathogenesis and an extended preneoplastic period at predictable sites in a lung cancer model.

A Family of Epidermoid Lung Cancer Models

A method of sustained release implantation has been developed whereby Silastic cylinders, impregnated with benzo[alpha]pyrene (BP) or methylcholanthrene (MCA) each at 2% (low dose) and 10% (high dose) concentrations, were inserted into the bronchus intermedius of hamsters. High-dose BP and MCA, and low-dose MCA had first-order exponential release rates: the half-time of release was 40 days for high-dose BP, 30 days for high-dose MCA, and 165 days for low-dose MCA. Release rate of low-dose BP was a second-order function: half-time of release was 40 days. Atypical squamous metaplasia was noted by 4 weeks in more than 65% of hamsters after insertion of each high-dose carcinogen but in less than 30% with the low-dose carcinogens. Carcinoma in situ was noted approximately 8 weeks after high-dose BP and 19 weeks after low-dose BP. At about 15 to 17 weeks after a high-dose carcinogen, 64% of animals had invasive epidermoid cancer, whereas after a low-dose carcinogen, only 21% did. After 25 weeks of exposure to a high-dose carcinogen, more than 85% of hamsters had invasive epidermoid cancer; up to 52 weeks were required for invasive epidermoid cancer to develop in 30% after a low-dose carcinogen. Measured by image analysis, nuclear deoxyribonucleic acid content of cells with severe atypical squamous metaplasia was greater than tetraploid (mean +/- standard deviation [SD], 3.77 +/- 1.4), whereas cells with invasive epidermoid cancer were suprahexaploid (mean +/- SD, 6.48 +/- 3.6). These differences are significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinogenesis in Canine Bistomal Heterotopic Tracheal Grafts

Successful canine lung cancer models have required repeated focal bronchial carcinogen exposure under general anesthesia. To simplify serial studies of the respiratory mucosa during carcinogenesis, bistomal autologous heterotopic tracheal pedicle grafts have been made. These grafts can readily be returned to the original orthotopic site, and this has been shown to be a method with which to study reversibility of mucosal changes. Polycyclic aromatic hydrocarbons were applied topically to the mucosa three times a week for 21 to 22 months in 21 grafts. Implants of Silastic polymer from which carcinogen was released in sustained-release fashion were then left in the grafts for 4 to 6 weeks. Serial cytological and histological examinations showed development of atypical squamous metaplasia in the graft mucosa. Mucosal papillomatosis was noted in 4 of 7 grafts surgically excised 17 to 18 months after completion of carcinogen exposure. The heterotopic bistomal tracheal graft provides a useful method for studying respiratory epithelial carcinogenesis without repeated general anesthesia.