[Prophylactic thyroidectomy in carriers of RET oncogene mutation carriers]. / Profylaktisk tyreoidektomi hos baerere av mutasjoner i RET-onkogenet.

BACKGROUND: Medullary thyroid cancer may be inherited dominantly. Germline mutations in the RET oncogene which code for a receptor tyrosine kinase cause MEN2. Thyroidectomy is recommended in family members who carry a mutation. MATERIAL AND METHODS: We have thyroidectomized four children from three families, 12, 10, 7 and 6 years old, because of germline mutations. RESULTS: The 12-year-old had developed a minimal medullary cancer with microscopic lymph node metastases; the others showed variable degrees of C-cell hyperplasia. The mutations were located on exon 10 (C620F) in the two patients from one family, on exon 11 (C634R) in the second family and on exon 14 (V804M) in the third family. In the families with the codon 620 and codon 634 mutations, only medullary thyroid cancer has been diagnosed. In the family with the codon 804 mutation, the index patient has been operated for a pheochromocytoma. The longterm clinical course seems more favorable in the family with the codon 620 mutation than in the two other families. With knowledge of the family mutations, we found that two out of nine family members we previously have thyroidectomized following calcitonin testing did not carry the family mutation. INTERPRETATION: Genetic diagnostic is a safe and reliable predictive test for familial medullary thyroid cancer and should be carried out in any individual with this cancer. Thyroidectomy is recommended in gene carriers at the age of six.

Fine-needle aspiration biopsy diagnosis of a uveal metastasis from a follicular thyroid carcinoma.

PURPOSE: To report a rare tumour of the eye, and to illustrate the importance of performing a fine-needle aspiration biopsy. CASE REPORT: An 80-year-old woman suffering from general malaise, dyspnea and abdominal pain was found to have multiple lung metastases, a large tumour in the upper part of the mediastinum, and a large orange-brown tumour (19 x 15 x 11 mm) situated nasally in the left eye. Fine-needle aspiration biopsy of the uveal tumour and of the goitre was performed. Cytological examination from the two sites disclosed cells compatible with a follicular thyroid carcinoma of oxyfil cell-type. RESULTS: The patient underwent a total thyroidectomy and has so far had 2 series of 131I therapy. Additionally, the eye tumour was treated locally with a 125I plaque, and three months later the tumour thickness had decreased from 11.0 to 6.4 mm. Best-corrected visual acuity is still unchanged. The patient's general state improved as her dyspnea decreased significantly. CONCLUSION: The treatment has improved the patient's quality of life, and probably prolonged her life expectancy. Fine-needle aspiration biopsy was necessary to establish the diagnosis.

Treatment and outcome of patients with extragonadal germ cell tumours--the Norwegian Radium Hospital's experience 1979-94.

This report reviews 48 patients who from 1979 to 1994 were treated at the Norwegian Radium Hospital for newly diagnosed noncerebral extragonadal malignant germ cell tumour (EGGCT). Based on histology and/or serum tumour markers, 12 patients had a seminoma and 36 a non-seminoma. At diagnosis, 33 and 15 patients were classified as having abdominal and mediastinal EGGCT respectively. At the time of diagnosis 13 patients, all with non-seminomatous tumours, had metastases to bone, liver or brain. One patient with abdominal seminoma was cured by radiotherapy alone, whereas cisplatin-based chemotherapy (with or without surgery) was planned in the 47 remaining patients. Twenty-seven out of 42 patients receiving four or more chemotherapy cycles were rendered tumour free by induction chemotherapy, including 5 of the 13 patients with extralymphatic non-pulmonal disease. An additional tumour-free patient died of septicaemia after only two cycles of chemotherapy. Late relapses (after > 2 years) were observed in three patients, and a testicular primary was diagnosed during follow-up in three cases. Seven patients died of treatment-related complications, five of these because of neutropenic septicaemia. The median age of these patients was 52 years compared with 35 years in the remaining 41 patients (P < 0.05). The 5-year overall survival for all 48 patients was 60% (95% CI 46-74%) [cancer-specific 5-year survival 71% (95% CI 50-92%)]. EGGCT is a potentially curable disease, even in patients with very advanced disease. Special attention should, however, be devoted to patients above the age of 40 years because of an increased risk of treatment-related side-effects. Late relapses and the subsequent development of testicular tumours indicate the need for long-term follow-up.

Pattern of expression of intermediate cytokeratin filaments in the thyroid gland: an immunohistochemical study of simple and stratified epithelial-type cytokeratins.

The expression of simple and stratified epithelial-type cytokeratin (CK) intermediate filaments was evaluated by immunohistochemistry in a series of 41 papillary carcinomas, 10 follicular carcinomas, 2 poorly differentiated carcinomas and 34 specimens of normal thyroid parenchyma and lymphocytic thyroiditis. The aim of the study was to establish the CK profile of normal thyroid and thyroid carcinomas in order to clarify the putative application of CK immunostaining in diagnostic surgical pathology, and to evaluate whether the process of neoplastic transformation and tumour progression in the thyroid may be associated with any particular change in CK expression. Normal thyroid strongly expressed simple epithelial-type CKs 7 and 18 and, to a lesser degree, CKs 8 and 19, but did not express stratified epithelial-type CKs. The same pattern was found in lymphocytic thyroiditis, though the CK 19 immunoreactivity was stronger in these lesions than in the normal thyroid. Papillary and follicular thyroid carcinomas shared the expression of simple epithelial-type CKs 7, 8, 18 and 19. Immunoreactivity for CK 19 was frequently stronger and more widely distributed within each particular tumour in papillary than in follicular carcinomas, but it could also be detected, at least focally, in every follicular carcinoma. Strong expression of CK 19 highlighted small foci of papillary carcinoma not easily identifiable by conventional histological examination. Stratified epithelial-type CKs 5/6 and 13 were detected in a high percentage of papillary carcinomas, in contrast to their absence in follicular carcinomas and normal thyroid. The CK pattern was similar in primary and metastatic papillary carcinomas. We conclude that papillary carcinoma of the thyroid presents a distinct CK profile that may be used for diagnostic purposes.

Fibrosarcoma in children--a rare tumour with long-term survival even with advanced disease--a report of 3 cases.

Fibrosarcoma is a rare tumour in children. The potential of malignancy has been questioned. We present three cases of fibrosarcoma in children . The follow-up periods range from 10 to 37 years. The first patient had pulmonary metastases at the time of diagnosis in 1958. The primary tumour in fossa ischio-rectalis was resected in 1960. Lung metastases were resected in 1960 and 1989. Radiotherapy was given in 1992. He is still alive with metastases 37 years after the first manifestation of disease. The second patient had a primary tumour and several local recurrences in the mandible. He is alive without evidence of disease 4 years after resection of pulmonary metastases and 21 years after resection of the primary tumour. The third patient has no signs of recurrence or metastatic spread 10 years after a wide excision of subcutaneous tumours of the left upper arm. The cases demonstrate a special tumour-entity of low-grade malignancy, which show a good prognosis and a wide spectrum of biological behaviour.

Extremity and non-extremity high-grade osteosarcoma -- the Norwegian Radium Hospital experience during the modern chemotherapy era.

Of 103 patients with high-grade osteosarcoma, 27% had tumours localized outside the extremities. Non-extremity patients were significantly older at diagnosis than patients with extremity tumours (median 38 vs. 17 years). More than 90% of patients with extremity tumours received adequate treatment (aggressive chemotherapy plus at least marginal surgery), compared with only 25% of patients with non-extremity tumours. Failure of adequate treatment was due to inoperable tumour, intralesional surgery and age preventing aggressive chemotherapy. There was a highly significant difference in both local tumour control and overall survival, both favouring patients with extremity tumours. Within the extremity tumour group, patients who were treated in prospective multicentre trials had a significantly better outcome than non-trial patients. Our results show that the fraction of patients with high-grade tumours that fall outside trials designed for 'classical osteosarcoma' may be larger than is usually acknowledged, and that the results reported for the classical group are by no means representative of the whole patient population. Improved and new treatment approaches are needed for patients with non-extremity tumours, particularly in the older age groups.

[Pulmonary lymphangioleiomyomatosis]. / Pulmonal lymfangioleiomyomatose.

Pulmonary lymphangioleiomyomatosis is a rare disease with a haphazard proliferation of smooth muscle throughout the lung. Little knowledge about the disease, its clinical presentation and the diagnostic methods used may be a reason for underdiagnosing the disease. In Ostfold county, Norway, with only 250,000 inhabitants, we have seen four patients with this disease in the last few years. The diagnosis was based on histological examination of transbronchial biopsy material in three patients who underwent bronchoscopy the presence of lymphangioleiomyomatosis was not recognized at the initial pathological examination. The disease can be misinterpreted as fibrosis at histological examination. Specific procedures for detecting smooth muscle can be used, eradicating the need for open lung biopsy. Transbronchial biopsy is a valid and useful method for confirming the diagnosis of lymphangioleiomyomatosis. High resolution CT has also shown to be an important diagnostic tool. We emphasize the importance of raising the question of lymphangioleiomyomatosis with the pathologist when this rare, but probably underdiagnosed disease, is suspected by the clinician.

Systemic relapse of patients with osteogenic sarcoma. Prognostic factors for long term survival.

BACKGROUND: A retrospective study of long term outcome after the development of metastases from osteosarcoma was performed, with emphasis on the impact of different treatment strategies and the identification of prognostic factors. METHODS: From 1975 to 1993, a population-based series of 60 patients with distant metastases (relapse) from high grade, extremity-localized osteosarcoma was treated at The Norwegian Radium Hospital. Six patients relapsed after surgery alone, 28 patients relapsed after primary chemotherapy of low potency, and 26 patients after modern, intensive chemotherapy. Lung metastases were present in 88% of the patients, 52% had bilateral lesions, and the median number of lesions was three (range, 1-25 lesions). Forty-seven percent of patients had complete surgical excision of all identifiable metastatic nodules and 54% of these had additional second line chemotherapy defined as adequate. Adequate chemotherapy included further dose escalations of methotrexate in approximately half of the patients, usually from 8 to 12 g. The rest were exposed to novel agents such as cisplatin, etoposide, and ifosfamide. Of the operated patients, 43% had additional thoracotomies after subsequent relapses. RESULTS: The projected 5-year survival rate from the first metastatic event was 24% for all patients and 50% for patients who underwent complete metastasectomy. In a multivariate analysis, the factors with independent predictive value for improved overall survival were the presence of a solitary metastasis, the accomplishment of complete metastasectomy, and the administration of adequate salvage chemotherapy. CONCLUSIONS: Complete metastasectomy is mandatory for long term survival of patients with metastatic osteosarcoma, and repeated lung resections are necessary in nearly half the patients. Second line chemotherapy and following primary treatment with modern intensive chemotherapy protocols may improve survival further.

Immunohistochemical detection of nm23/NDP kinase and cathepsin D in medullary carcinomas of the thyroid gland.

Reduced expression of nm23/NDP kinase and increased expression of cathepsin D seem to be correlated with the high metastatic potential in a variety of malignancies. The expression of nm23/NDP kinase and that of cathepsin D have been evaluated by means of an immunohistochemical technique in paraffin-embedded tissues from 44 primary medullary carcinomas of the thyroid gland (MCT) and from the corresponding lymph node metastases in 32 of these cases. In addition, lymph node metastases from 4 cases were studied. We found that 36 of 44 (82%) primary and 26 of 36 (72%) lymph node metastatic MCT were nm23/NDP kinase positive, whereas 14 of the 44 (32%) primary and 17 of the 36 (47%) lymph node metastatic MCT were cathepsin D positive. We found no indication that the nm23/NDP kinase level has any prognostic significance in MCT. The cathepsin D level is close to being prognostically significant in this study, and we cannot exclude the possibility that it could be of prognostic value. However, it seems to be quite weak, and therefore of little use in a clinical situation.

[Medullary thyroid carcinoma--familial or sporadic disease?]. / Medullaert thyreoideakarsinom--familiaer eller sporadisk sykdom?

Medullary thyroid cancer may be autosomal dominantly inherited. Calcitonin is a very sensitive tumour marker in medullary thyroid cancer. It is essential to measure calcitonin in first grade relatives of these patients, in order to expose familial incidents of subclinical disease. In 55 patients with medullary thyroid cancer and no history of familial disease, nine close relatives with elevated calcitonin were identified in four different families. Eight of these nine have been thyroidectomized. Five were found to have medullary thyroid cancer, one had definite C-cell-hyperplasia, and two had equivocal C-cell hyperplasia. The last two, had elevated basal serum calcitonin-levels were increased, but with no further increase after intravenous pentagastrin bolus injection. Thyroidectomy did not modify these results and DNA-analysis may be necessary to draw a conclusion about the hereditary situation of these patients.

[Treatment of chondrosarcoma. A retrospective study at the Norwegian Radium Hospital]. / Behandling av kondrosarkom. En retrospektiv undersøkelse ved Det Norske Radiumhospital.

The authors present a retrospective analysis of 59 chondrosarcoma patients treated at the Norwegian Radium Hospital during the period 1981 to 1993. 31 patients were admitted with untouched tumour, seven after fine needle cytology and 20 after open biopsy or partial excision. One patient had recurrent local disease. Only 20% of the tumours were of high grade malignancy. 51 patients were treated by surgery. Reconstructions were performed in 16 patients, using allografts or endoprostheses. Amputations were performed in six cases and wide excision in 12 cases. In these 18 patients local recurrence appeared in one case, and two developed lung metastases. Only one of the 18 patients operated by amputation or wide excision has since died from chondrosarcoma. Marginal excisions were performed in 26 cases. Nine of these patients developed a local recurrence, five developed metastases and three have died. Six patients had partial excisions. Postoperative radiotherapy was given to one patient only. Five of the six are alive. In one case, the quality of the margins could not be evaluated. A total of 45 of the 51 patients treated for the primary tumour by surgery are alive. The median observation time is four years. Treatment of nonmetastatic chondrosarcoma should be surgical. Chondrosarcoma patients show wider variations in age, localization of tumour and tumour growth rate than patients with other bone sarcomas. Although wide excisions provide the best local control of any grade of malignancy, the mutilation or risk involved may be so great that some patients may benefit from marginal or even partial excision.

Immunoscintigraphy of bone sarcomas--results in 5 patients.

The feasibility of using the murine monoclonal antibody, TP-1, for clinical immunoscintigraphy was examined in a pilot study involving 5 patients with bone sarcomas. 131I-labelled F(ab')2 antibody fragments were injected in doses of 0.8-1.0 mg (90-130 MBq), and the accumulation of radioactivity was examined by scintigraphy, and assessed by direct measurements on biopsied tumour and normal tissue. One osteosarcoma patient had a primary tumour in the femur, whereas the other 4 had single lung metastases detected by other diagnostic methods. Immunoscintigraphy of the femoral primary was optimally visualised after 22 h. In 2 patients, the method failed to detect lung metastasis, in 1 of the cases possibly related to less than optimal methodological conditions. In 2 other patients, increased accumulation of radioactivity indicated one and three lung tumours, in addition to the single metastasis observed by X-ray and CT scanning, tumours that were later confirmed and removed surgically. The concentration of radioactivity in tumour and normal tissues 44-72 h after antibody injection could be measured in 4 patients. The tumour to blood ratios were in the range of 1.2-4.2, compared to 0.1-0.8 for various normal tissues. The results indicate that immunoscintigraphy with TP-1 antibody fragments have a potential for early detection of lung metastases in patients with bone sarcoma.

Salvage treatment in male patients with germ cell tumours.

The outcome of salvage treatment was reviewed in 55 patients relapsing during or after their primary chemotherapy for advanced malignant germ cell tumours. Fifty-two patients had been given cisplatin-based chemotherapy as their primary treatment, whereas three patients had received carboplatin-based chemotherapy. The median time to relapse was 2 months (range: 0-96 months) from discontinuation of the primary treatment. Two patients underwent radical surgery only, and one patient had radiotherapy to a brain metastasis as his only curatively intended salvage treatment. Six patients did not receive any treatment for their recurrent malignancy (refusal, terminal condition) except for purely palliative measures. The disease-free survival for the total group was 27% at 5 years. Complete response to primary treatment lasting for > or = 6 months was the only parameter which significantly predicted a favourable outcome (45% 5 year disease-free survival in 12 eligible patients).

p53 abnormalities in different subtypes of human sarcomas.

In this report we examined p53 alterations at the DNA, mRNA, and protein levels on tissue from 39 patients with different subtypes of sarcoma. Loss of heterozygosity for the chromosome 17p region was found in 60, 63, and 33% of 10 informative osteosarcomas, 11 malignant fibrous histiocytomas, and 6 leiomyosarcomas, respectively. In addition, 2 of 10 tumors belonging to a heterogeneous group of soft tissue sarcomas showed loss of heterozygosity. Elevated levels of p53 mRNA were found in six tumors, four had a truncated transcript, and in six patients no mRNA was detected. In most cases, elevated transcript levels were accompanied by overexpression of protein as studied by immunohistochemistry, whereas the presence of truncated transcripts was associated with negative immunostaining. Point mutations in exons 5, 7, or 8 of the TP53 gene were detected in seven tumors. Six of these expressed high levels of mRNA and protein, probably reflecting a point mutation in one of the alleles and loss of the other. Three of the mutations have not previously been described. Taken together, p53 abnormalities were found in approximately 65% of the osteosarcomas, malignant fibrous histiocytomas, and leiomyosarcomas examined and in 30% of the other soft tissue tumors. The results indicate that the TP53 gene is involved in the tumorigenesis of several sarcoma subtypes in a higher fraction of cases than was previously recognized.

Long-term survival in patients with follicular thyroid carcinoma. The Oslo experience: variations with encapsulation, growth pattern, time of diagnosis, sex, age, and previous thyroid surgery.

In 98 follicular thyroid carcinoma patients with a follow-up of 10-32 years, 10-year survival varied in subgroups from 15.5-63.4%. Survival with encapsulated primary tumors was 46.7%, compared to 26.9% in widely invasive tumors, and varied from 59.9-35.8% with growth pattern. In patients younger than 60 years of age at diagnosis 10-year survival was 68% of expected survival, compared to 32% in patients older than 60. Patients treated after 1970 had an improved survival of 24.2%. Thirty-one patients had previous thyroid operations for benign lesions. Review of histopathologic slides and medical records demonstrated follicular adenomas in 17 cases, and overlooked carcinomas in 11. Calculating survival from the first surgical intervention improved reported 10-year survival by 14.5%. Papillary carcinoma patients matched for age and sex had significantly better 10-year survival.

Post-chemotherapy tumor residuals in patients with advanced nonseminomatous testicular cancer. Is it necessary to resect all residual masses?

A total of 15 patients with advanced nonseminomatous testicular cancer underwent 2 sequential operations (4 in 1 patient) to remove residual masses after cisplatin-based combination chemotherapy. All patients had normal human chorionic gonadotropin and alpha-fetoprotein levels but persistent radiographic masses after chemotherapy. The operations included retroperitoneal lymph node dissection in 13 patients, thoracotomy in 15, hepatic resection in 3 and craniotomy in 1. Histological comparison of the specimens resected during post-chemotherapy operations 1 and 2 demonstrated different patterns in 7 of 15 patients. Of these 7 patients 4 had less favorable pathological features in the specimen removed during the second procedure. Residual malignant tumor or mature teratoma was found in at least 1 site in 12 of the 15 patients and only 3 had complete necrosis or fibrosis in both specimens examined. These data indicate the favorable impact of excising all post-chemotherapy tumor residuals in patients with advanced nonseminomatous testicular cancer. However, in patients with no teratomatous elements in the testicular tumor and complete necrosis or fibrosis in the initial post-chemotherapy operation specimen the probability of complete necrosis or fibrosis in remaining tumors appears to be high.

[Breast-preserving surgery in breast carcinoma. 10-year experiences]. / Brystbevarende behandling ved carcinoma mammae. Erfaring etter ti år.

From 1979-89, 211 women with cancer mammae were irradiated at the Norwegian Radium Hospital after breast-conserving surgery performed at different hospitals in Norway. 181 of these patients were called in for re-examination to check the procedures for treatment and the cosmetic results. Only 37% of the patients had undergone mammography prior to surgery and 48% of the patients had had two or more operations before the irradiation. The cosmetic results were not very satisfactory in 45% of the patients. Reduced cosmesis was mainly due to less than optimal surgery. We propose better standardisation of the treatment programme for breast preservation. Optimal results require close collaboration between radiologists, surgeons, oncologists and pathologists. The treatment must be organized in a way that facilitates this collaboration.

[Thyroid carcinoma and the recurrent nerve. Recurrence fall-out, incidence and causal circumstances in a large case-load of patients with thyroid carcinoma]. / Thyreoideakarsinomer og nervus recurrens. Recurrensutfall, forekomst og åraksforhold i et stort materiale av pasienter med thyreoideakarsinomer.

Impairment of vocal cord function is a threat to patients with thyroid carcinoma; either due to the tumor having infiltrated the larynx or the recurrent nerve, or to accidental damage to the laryngeal nerves during thyroid surgery. We have reviewed 1,245 patients' records which were filed under the diagnosis of thyroid carcinoma at Det Norske Radiumhospital from 1956 to 1978. Pareses of vocal cords were noted in 465 patients (37.3%) during the course of their illness. In 135 patients (10.8%) the pareses were due to infiltration by the tumor, most commonly seen in anaplastic carcinoma. In 267 patients (21.4%) the pareses followed surgery; planned resections of the recurrent nerves were performed in 48 patients (3.9%). Transient pareses with normal vocal cord movements within months were experienced in 137 cases (11%). Permanent paralysis caused accidentally during surgery was seen in 82 patients, representing 6.6% of all patients and 4.7% of the surgically exposed nerves. We stress the need for pre- and postoperative evaluation of vocal cord movement as an aid to future diagnosis and optimal surgical planning.

Ki67 and 4F2 antigen expression as well as DNA synthesis predict survival at relapse/tumour progression in low-grade B-cell lymphoma.

Previous work has shown that parameters of cell activation studied on lymphoma biopsies can be used to discriminate between low-grade and high-grade non-Hodgkin's lymphomas and to predict prognosis in the low-grade malignancy group alone. We have now examined expression of several activation antigens and indicators of DNA synthesis in 29 patients with low-grade malignant B-cell lymphomas at the time of primary diagnosis and later at relapse and/or tumour progression. At both times, the level of 4F2 antigen expression examined by flow cytometry on cells in suspension as well as the number of Ki67 antigen-positive cells examined by immunohistochemistry were predictive of patient survival. DNA synthesis estimated by (3H-TdR) thymidine incorporation was of prognostic value at the second biopsy only. These parameters were more sensitive than histological demonstration of morphological transformation in secondary high-grade lymphomas in identifying high-risk patients at repeated biopsy. We propose that Ki67 or 4F2 expression or a marker of DNA synthesis (such as 3H-TdR incorporation or labelling index) should be evaluated when repeated biopsies are performed, in order to select patients for whom aggressive chemotherapy may be considered.

Carcinoembryonic antigen in medullary thyroid carcinoma: an immunohistochemical study applying six novel monoclonal antibodies.

Six novel mouse monoclonal antibodies raised against carcinoembryonic antigen (CEA) were used to study 22 medullary, ten papillary, ten follicular, and eight anaplastic thyroid carcinomas. The antibodies CEA 12-140-5, -7, and -10 reacted with the same epitope group (GOLD 4), whereas antibodies CEA 12-140-1, -2, and -4 recognized different epitopes (GOLD 5, 2 and 1, respectively) on the CEA molecule. All medullary carcinomas of the thyroid (MCTs) were stained when the antibodies CEA 12-140-5, -7, and -10 were applied, whereas CEA 12-140-1 stained all but five MCTs; CEA 12-140-2 and CEA-12-140 -4 each stained all but two. The CEA immunoreactivity was predominantly located diffusely in the cytoplasm but occasionally was also concentrated along the cell membrane. CEA immunoreactivity was also observed in normal C-cells and C-cell nodules. The follicular, papillary, and anaplastic carcinomas were all CEA-negative with the monoclonal antibodies applied in this study. The differences in staining pattern of MCTs found with the various antibodies may be explained as a lack of expression of some epitopes in some tumors, or they may be due to a varying degree of masking of the epitopes by the extensive glycosylation of CEA and CEA-like substances.