Cancer incidence after radiotherapy for skin hemangioma: a retrospective cohort study in Sweden.

The cancer incidence was studied in 18,030 patients (33% males, 67% females) with skin hemangioma who were admitted to Radiumhemmet, Karolinska Hospital, Stockholm, Sweden, 1920-1959. Radium-226 sources were used in 12,821 patients, x-ray therapy was used in 2,515 patients, and no radiotherapy was given to 2,694 patients. Cancer incidence in the cohort was searched by record linkage with the Swedish Cancer Register for the period 1958-1982. The median age was 6 months for the treated patients and 8 months for the patients not receiving radiotherapy. In the group treated with radium-226 or orthovoltage x rays (greater than or equal to 100-kV peak), 224 cancers were observed [relative risk (RR) = 1.18; 95% confidence interval (CI) = 1.03-1.35]. In patients given contact x rays, 10 cancers were observed (RR = 0.71; 95% CI = 0.34-1.30). In patients not treated with ionizing radiation, 34 cancers were observed (RR = 0.93; 95% CI = 0.64-1.29). In patients treated with radium-226 or orthovoltage x rays, an RR of 1.65 was observed for breast cancer (95% CI = 1.26-2.13) and an RR of 2.73 was found for soft tissue tumors (95% CI = 1.18-5.38). Patients with brain tumors, thyroid cancers, and bone tumors had received radiotherapy close to the tumor site more often than expected. For patients with breast cancer, no such difference was found. For cancers of the breast and thyroid, the RR was higher in patients given more than one treatment.

Estradiol receptor analysis in human breast cancer tissue by isoelectric focusing in polyacrylamide gel.

Isoelectric focusing in polyacrylamide gel combined with limited proteolysis is a simple and specific method for quantitation of estradiol receptors in breast cancer tissue. At least eight different samples can be analyzed simultaneously on one gel, and the whole procedure, including sample preparation, takes less than 7 hr. In comparison with sucrose gradient centrifugation, isoelectric focusing is more sensitive, possibly due to the short time (1.5 to 2 hr) needed for the analysis. Furthermore, only one incubation with tritium-labeled estradiol is needed for an analysis, which means that a smaller amount of tumor tissue is needed than for most other methods. This fact allows analysis of the estrogen receptor content in tumor material obtained from fine-needle biopsy.

Prognostic value of amplification of c-erb-B2 in bladder carcinoma.

Amplification of c-erb-B2 is examined in patients with transitional cell bladder carcinoma. In a pilot study we found that the amplification correlated with high tumor grade. Tumor grade is a known prognostic factor. Therefore, we next examined the prognostic value of c-erb-B2 amplification in patients with >16 years of clinical follow-up. The gene copy number was determined, using semiquantitative PCR, in archival formalin-fixed tissues. Twenty-three percent (37/163 patients) showed the amplification. The amplification correlated with grade and stage. Moreover, we found that tumor grade (P < 0.001) and c-erb-B2 amplification (P < 0.001) showed prognostic information for survival. Patients with grade 3 tumors and concomitant c-erb-B2 amplification showed the worst prognosis. Multivariate analysis indicates that grade and c-erb-B2 amplification are independent prognostic factors.

Overestimated risk of second primary malignancies in ovarian cancer patients.

Registry-based cohort studies have established an increased risk of developing second primary malignancies (SPM) in patients with a primary ovarian cancer. In order to examine the accuracy of cancer registration with emphasis on registration of SPM, 344 women with ovarian cancer and 379 subsequent SPM, registered between 1958 and 1992 in the Stockholm-Gotland Cancer Registry (SGCR), a division of the Swedish Cancer Registry (SCR), were investigated. Complete records including pathology reports were examined and an additional histopathological evaluation was conducted for a sample of the group. The results revealed that 28 diagnoses of SPM were incorrectly registered (14 cases were misdiagnosed SPM of the gastrointestinal tract, mainly colon and rectum) and 34 women (with 38 SPM) were incorrectly registered with ovarian cancer. Recalculations of the risk of a subsequent cancer were performed on the basis of these findings and the results suggest an overestimation of the risk of developing SPM. Inferences of these findings to other primary sites of multiple malignancies should be made with caution and further studies are needed.

The impact of tumour angiogenesis, p53 overexpression and proliferative activity (MIB-1) on survival in squamous cervical carcinoma.

Tumour angiogenesis (antifactor VIII-related antigen antibody), p53 overexpression (DO-1) and proliferative activity (MIB-1) were immunohistochemically analysed for the prediction of long-term survival in 113 patients with squamous cervical carcinoma. The median follow-up time was 82 months (range 72-99). In early stages (IB-IIA), neovascularisation was significantly related to tumour size. Significantly more patients in stage IIA had high tumour vascularity compared to stage IB (P < 0.01) but no significant difference was found between early and advanced stages (IIB-IVB) of cervical carcinoma. p53 overexpression was correlated to the stage of disease (P < 0.01). No relationship was found between tumour angiogenesis, p53 overexpression or MIB-1 and pelvic lymph node metastases, histological subtype or differentiation. Tumours with more than 50% p53 overexpression was significantly correlated with survival in the univariate analysis, but no independent predictive value was found. It is concluded that immunohistochemically detectable p53 overexpression as measured by DO-1 and proliferative activity as measured by MIB-1 seems of no clinical value for the prediction of long-term survival in squamous cervical carcinoma. The predictive value of tumour angiogenesis for survival outcome has still to be determined in squamous cervical carcinoma.

Ovarian cancer: the challenge of local tumor control and its impact on survival.

To achieve better understanding of the factors influencing local control of ovarian cancer, an analysis of failure in early stages of ovarian carcinoma has been carried out. The material consisted of 185 patients diagnosed in early stages; 40 of them failed in their disease, 17 with local recurrence, 23 with distant metastases. The material was analyzed with respect to age, histology, grade, size and surface of the tumor, the surgical procedure and treatment modalities, and the time between treatment and recurrence, and recurrence and death. In the analysis, both the behavior of the ovarian cancer tumor and the pattern of failure was shown to be different for each histological group.

Radiation therapy in operable breast cancer: results from the Stockholm trial on adjuvant radiotherapy.

In a randomized trial, 960 women with Stage 1-3 operable breast cancer were treated by a modified radical mastectomy alone, or by the same procedure, preceded or followed by radiotherapy (4500 rad to the breast/chest wall, and internal mammary, axillary and supraclavicular lymph nodes). Up to ten years after treatment, there is an increasing gap between the recurrence-free survival of the irradiated patients and the surgical controls. Between the two types of radiotherapy, there was no difference. There were significantly fewer distant metastases and a tendency for improved survival in node positive patients treated with postoperative radiotherapy, compared to the surgical controls, this difference was, however, statistically not significant.

Mixed müllerian tumours of the uterus--prognostic factors: a clinical and histopathologic study of 147 cases.

One hundred and forty-seven women with uterine mixed Müllerian tumours (UMMT) treated at Radiumhemmet from 1936 through 1981 were reviewed. The prognostic value of clinical and histopathologic data was analysed with bivariate and multivariate techniques. Stage, age and abdominal pain were found to be significant predictors of survival. Surgery and combined radiotherapy (intracavitary + external irradiation) gave in stage I, a lower local failure rate (p = 0.006) and better overall survival (p = 0.001) than surgery in combination with either intracavitary or external irradiation.

High dose rDNA human alpha 2 interferon therapy in patients with advanced colorectal adenocarcinoma: a phase II study.

Eighteen patients with advanced and inoperable colorectal adenocarcinomas were treated with high doses of alpha 2 Interferon (Schering-Plough Corporation). The patients were randomized to receive either subcutaneous injections of 20 X 10(6) I.U./m2 three times weekly for 3 months, or pulsed treatments of 50 X 10(6) I.U./m2 daily, given intravenously, for 5 consecutive days every 4 weeks. No objective tumour regression was seen in any patient. The side effects were considerable.

Immunoreactivity with monoclonal antibody A-80 and nuclear DNA content in benign and malignant human breast disease.

Immunohistochemical analysis with the monoclonal antibody (MoAb) A-80, recognizing a tumor-associated cytoplasmic mucin-type glycoprotein, and cytometric nuclear DNA assessment were performed on 314 surgical specimens of the human mammary gland. The series included 36 benign conditions, 34 epithelial hyperplasias, 40 carcinomas in situ, and 204 primary invasive carcinomas. Normal breast parenchyma, benign tumors, and other nonmalignant lesions were all of DNA diploid (euploid) type and rarely expressed the A-80 glycoprotein. Differences in MoAb A-80 immunoreactivity and nuclear DNA content were noted among subtypes of epithelial hyperplasias. Fifteen of 34 epithelial hyperplasias were of DNA aneuploid type and the majority were A-80 immunoreactive. Of these 15 immunoreactive aneuploid epithelial hyperplasias, atypical intraductal hyperplasia was the most common subgroup. None of the 19 epithelial hyperplasias of DNA euploid type immunoreacted. Most of the intraductal (33 of 40) and invasive (180 of 204) carcinomas immunostained with MoAb A-80. The majority of the A-80 immunoreactive malignant tumors were of DNA aneuploid type (26 of 33 carcinomas in situ and 108 of 180 invasive mammary carcinomas). The results suggest that expression of the A-80 glycoprotein occurs at an early stage of malignant transformation. Genetically stable (euploid) mammary tumors seem to immunoreact with MoAb A-80 less frequently than genetically unstable (aneuploid) tumor variants. Combined analysis with MoAb A-80 and of nuclear DNA content in premalignant and malignant mammary lesions could be a useful tool of differential diagnostic and prognostic value.

Reappraisal of uterine sarcoma diagnosis in the Swedish Cancer Registry.

An investigation of over- and under-registration of uterine sarcomas in the Swedish Cancer Registry during the period 1958-1980 was carried out. A histopathologic review of a 10% sample (159 cases) revealed that 18% of the cases, the majority of which were benign leiomyomas, could not be reclassified as sarcomas. All 186 cases of uterine sarcoma treated at Radiumhemmet during the period 1958-1980 were found in the Cancer Registry, but only 90% as sarcomas. As a consequence of over- and under-registration of the sarcoma tumors, the estimated incidences will be affected. In this study, however, we could not find any time trend in the erroneous registration, which implies that comparisons in incidence over time would still be valid.

Adjuvant interferon treatment in human osteosarcoma.

An update of the adjuvant trial on osteosarcoma in Sweden comparing patients receiving natural interferon (IFN) alpha with a high-dose chemotherapy group and a nonadjuvant group is presented. The overall survival for the IFN group is 49%, for the chemotherapy group 54%, and for the nonadjuvant group 35%. Trial evaluation was complicated by group differences with respect to various clinicopathologic features of prognostic significance. The role of IFN in the treatment of osteosarcoma can still not be established.

Nuclear DNA content and nuclear atypia. Relation to survival in patients with breast adenocarcinoma and serious ovarian tumors.

The grade of nuclear atypia (low, medium, or high) was compared with DNA content in 122 tumors comprising 73 serous ovarian tumors and 49 mammary carcinomas of ductal type. The study was performed on two consecutive histologic sections 4 mu in thickness, one of which was stained with hematoxylin-eosin for estimation of nuclear atypia, and the other with Feulgen for measurements of DNA. In both tumor groups there was a significant correlation between nuclear atypia and nuclear DNA content. The results suggest that DNA analysis is of significant additional prognostic value even when the grade of nuclear atypia is known.

DNA and its synthesis in individual tumor cells from human upper respiratory tract squamous cell carcinomas.

Measurements of cytophotometric Feulgen DNA content and incorporation of 3H-thymidine were made in individual tumor cells from 58 patients with squamous cell carcinomas of the head-neck region. These measurements were correlated with a point ranking system for pathological grading for these types of tumors. Two of the parameters of the grading system, mode of invasion and nuclear polymorphism which had been found to be important factors in prognosis in clinical studies were correlated to the objective cellular DNA measurements. In 40 carcinomas, 10 were found to have a predominantly diploid distribution of DNA values, while the remaining 30 tumor values were either multiples of diploid or were aneuploid. Generally, tumors with low point rankings for individual morphological parameters tended to have diploid DNA values. Those tumors with higher DNA values usually had larger point rankings and more advanced clinical stage. When tumor cells from biopsies of 39 patients were studied by 3H-thymidine incorporation, no relevant connections between the labeling index and cellular DNA amounts, malignancy grading, or clinical stage were found.

Combined preoperative radiotherapy and surgery in the treatment of carcinoma of the anterior two-thirds of the tongue.

Sixty-three patients with squamous cell carcinoma of the anterior two-thirds of the tongue were treated with preoperative external radiotherapy (mean target dose 42.60 Gray or 4260 rad) and surgery. The expected 5-year survival, expressed as life table estimate of percent of survivors, was 77% for patients with Stage I tumors, 69% with Stage II, and 13% for patients with tumors in Stages III-IV (p less than 0.001). Fourteen patients experienced local recurrences, 7 had homolateral neck metastases, 4 had contralateral neck metastases and 3 had distant metastases. In 15 cases no cancer could be detected at review of the surgical specimens, but 2 of these died of their cancers. In 43 cases cancer was present in the specimens, and 26 of these died of their cancer (p less than 0.01).

Origin of the choanal polyp.

To study the origin of the choanal polyp, the maxillary sinus was surgically explored using a preservative technique. An antral cyst or a cystic rudiment, usually attached to the inferolateral aspect of the sinus wall, was disclosed in 15 patients with this condition. As a part of the choanal polyp, the antral cyst exhibited a macroarchitecture and microarchitecture identical to the structure of the common intramural cyst of the maxillary sinus as studied in nine patients. It is concluded that the choanal polyp develops from the expanding intramural cyst protruding through the maxillary ostium and into the nasal cavity.

Paget's disease of the vulva: the Radiumhemmet series 1975-1990.

Twenty-eight patients with a diagnosis of 'extramammary Paget's disease of the vulva' were referred to the Radiumhemmet, Karolinska Sjukhuset, Stockholm, during the period 1975-1990. A clinical and histopathologic retrospective review was undertaken. Six patients had associated malignancies (21.4%). The disease was considered primary invasive in three cases, whereas three patients later developed an invasive cancer. Surgery-local resection, hemivulvectomy or vulvectomy-was performed in 24 cases. Twelve patients, in which surgery was supposed to be radical with respect to free margins, had a significantly longer recurrence-free survival than 12 patients in which the surgical margins were dubious.

Malignant mixed müllerian tumors of the ovary: histopathologic and clinical review of 36 cases.

Among 2,895 malignant ovarian tumor cases referred to Radiumhemmet, Stockholm from 1975 through 1995, 36 were certified to be malignant mixed müllerian tumors. The overall prognosis was poor with only 18% five-year actuarial survival (median survival 16.6 months). Five patients are still surviving after 75, 68, 117, 121, and 168 months, respectively. Fifteen women treated with melphelan, doxorubicin (adriamycin) and cisplatin (MAP) had a five-year actuarial survival of 33.3% and a median survival of 19.8 months. In a multivariate analysis taking into account stage, age, radiation, type of chemotherapy, histopathologic type and completeness of surgery, the most important predictors for survival were stage (stages I-II vs stages III-IV, P < 0.05), histopathologic type (homologous vs heterologous, P < 0.05), and type of chemotherapy (MAP or CAP vs other types, P < 0.05). We concluded that homologous tumor and chemotherapy containing cisplatin, doxorubicin, and melphalan, as well as early stage of the tumor, provided the optimal survival rate.

Carcinoma of the fallopian tube. A clinical and histopathologic review. The Radiumhemmet series.

A histopathologic and clinical review of the Radiumhemmet series of primary fallopian tube carcinoma (PFTC) treated from 1923 to 1991 revealed that 128 cases fulfilled the diagnostic criteria for PFTC. These cases were staged according to the new FIGO staging rules for PFTC. Survival was studied with respect to prognostic factors such as age, stage, histologic subgroups, degree of differentiation and mode of treatment. The mean age at diagnosis was 56 years. Seventy-four per cent were found to be in stage Ia-IIa and 26 % in stage III-IV. Forty-five per cent were nulliparous and 22 % had evidence of previous pelvic inflammatory disease. Treatment modalities changed during the studied period. Thirty-three per cent of patients underwent surgery with total abdominal hysterectomy and bilateral salpingo-oophorectomy while 67 % were incompletely operated. A trend towards improvement in results was noticed-however, it was not statistically significant. Among the 14 prognostic variables tested in the multivariate analysis the first in rank were stage (P = 0.001) and degree of differentiation of the tumors (P = 0.070). Patients receiving chemotherapy had superior survival rates compared with those without chemotherapy (P = 0.0006) and patients with cisplatinum-containing chemotherapy did better than those without cisplatin.

DNA-ploidy and mutant p53 overexpression in primary fallopian tube cancer.

Nuclear DNA content and p53 immunoreactivity were determined in 53 cases of primary fallopian tube cancer (PFTC). All tumors showed a distinctly aneuploid DNA distribution pattern, whereas p53 immunoreactivity was observed in 51% of the cases. If the patients were divided into two groups according to survival time, p53 immunoreactivity was present in 40% of the tumors from patients surviving for more than 8 years and in 65% of tumors from patients who died within 2 years. This difference was not statistically significant (P = 0.438). Patient survival was significantly correlated to the clinical stage (FIGO) (P = 0.0009).