Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome

BACKGROUND/PURPOSE: Although medullary thyroid carcinoma (MTC) can occur sporadically, in the pediatric population it is most often associated with the multiple endocrine neoplasia syndrome (MEN type 2). Traditional screening was based on evaluation of basal and stimulated serum calcitonin levels. The recent cloning of the MEN2 gene on the RET proto-oncogene of chromosome 10 now allows for testing of gene carrier status in individuals at risk who could benefit from prophylactic treatment. The current study was undertaken to determine the appropriate age for safe total prophylactic thyroidectomy. METHODS: Over a 16-year period, 12 patients with a family history of MEN2A and one with a MEN2B underwent total thyroidectomy and central neck dissection without parathyroid autotransplantation. Four patients (31%) were treated previously for Hirschsprung's disease. RESULTS: In seven patients (mean age, 11.8 years) undergoing biochemical screening for diagnosis, multifocal MTC and C cell hyperplasia (CCH) were found in all the resected specimens. Of six patients identified with genetic screening (mean age, 9.1 years), two had elevated stimulated calcitonin levels, one (age 14) had evidence of MTC, and one (age 6) had CCH. Four patients with normal calcitonin levels had no evidence of MTC (ages 6, 8, 10) but there was one occurrence of CCH (age 11). No permanent postoperative hypoparathyroidism or recurrent laryngeal nerve damage occurred in this series. With a mean follow-up of 4 years (range, 1 to 14 years), the overall disease-free survival is 100%. CONCLUSIONS: From this study the authors conclude that total thyroidectomy can be performed safely in children and should be the treatment of choice in patients with a family history of MEN2A carrying a germinal RET mutation even if the serum basal or stimulated serum calcitonin level is normal. Total thyroidectomy should be performed as early as 5 years of age before the occurrence of CCH or MTC.     

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC.     

Metastatic carcinoma of the prostate presenting as a superior vena cava syndrome

A 75-year-old patient presented with a superior vena cava syndrome (SVCS) lasting 3 years. A prostatic carcinoma was found and a supraclavicular lymph node biopsy specimen disclosed metastasis of the prostatic carcinoma. Antiandrogen and luteinizing hormone-releasing hormone analogue therapy produced a marked improvement. Prostatic carcinoma, although a very rare cause, must be considered in the diagnosis of cases of SVCS with a protracted course, since it is a treatable disease.     

Metastatic basal-cell carcinoma

Three cases of metastatic basal-cell carcinoma are reported. All of the cases were relatively small when compared with other lesions reported in the literature. With early chemosurgical treatment of small recurrent carcinomas, metastasizing basal-cell carcinoma will be a condition of the past.     

Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation

Germline mutations of RET gene, encoding a receptor tyrosine kinase, have been associated with the MEN2A and MEN2B inherited cancer syndromes. In MEN2A mutations affecting cysteine residues in the extracellular domain of the receptor cause constitutive activation of the tyrosine kinase by the formation of disulfide-bonded homodimers. In MEN2B a single mutation in the tyrosine kinase domain (Met918Thr) has been identified. This mutation does not lead to dimer formation, but has been shown (both biologically and biochemically) to cause ligand-independent activation of the Ret protein, but to a lesser extent than MEN2A mutations. Intramolecular activation by cis-autophosphorylation of RetMEN2B monomers has been proposed as a model for activation, although alternative mechanisms can be envisaged. Here we show that the activity of RetMEN2B can be increased by stable dimerization of the receptor. Dimerization was achieved experimentally by constructing a double mutant receptor with a MEN2A mutation (Cys634Arg) in addition to the MEN2B mutation, and by chronic exposure of RetMEN2B-expressing cells to the Ret ligand GDNF. In both cases full activation of RetMEN2B, measured by 'in vitro' transfection assays and biochemical parameters, was seen. These results indicate that the MEN2B phenotype could be influenced by the tissue distribution or concentration of Ret ligand(s).     

Primary hyperparathyroidism due to parathyroid carcinoma

OBJECTIVES: Our aim was to determine whether tissue factor pathway inhibitor (TFPI), a physiologically important natural anticoagulant that acts by inhibiting the extrinsic pathway, concentrations decrease as liver disease progresses, and, second, whether TFPI has an etiologic role in portal vein thrombosis in cirrhotics. METHODS: After taking their informed consent, we determined TFPI concentrations in the plasma of healthy subjects (group I) (n = 15) (average age, 45.1 = 11.8 yr), cirrhotics (group II) (n = 16) (average age, 43.6 +/- 9.8 yr), and cirrhotics with portal vein thrombosis (group III) (n = 12) (average age, 42.6 +/- 10.7 yr). Mean and median TFPI values and interquartile ratios were determined for groups I, II, and III. Then group II and III were further divided according to the Child classes A, B, or C, and mean and median TFPI values and interquartile ratios were determined for these classes as well. Using the Man-Whitney U test, we compared the results. RESULTS: Statistically important differences were documented (p = 0.005) between the median TFPI levels of healthy adults and Child C cirrhotics (concentration lower in Child C) and between normal subjects and cirrhotics with portal vein thrombosis (p = 0.02) (TFPI concentration being lower in the latter group again). CONCLUSIONS: TFPI concentration decreases in advanced liver disease, and this may be a contributory factor for portal vein thrombosis in at least some cases of cirrhotics.     

Results of the calcitonin stimulation test in normal volunteers compared with genetically unaffected members of MEN 2A and familial medullary thyroid carcinoma families

SETTING: Sample survey based on pulmonary tuberculosis (TB) patients registered in 264 health centres in Korea, compared with data obtained from nationwide TB prevalence surveys conducted since 1965. OBJECTIVE: To determine the level of antituberculosis drug resistance (DR) and to assess its impact on treatment outcome and its relationship with cure rates in the National TB Programme (NTP). DESIGN: Mycobacterium tuberculosis isolates from 2,486 new patients and 189 previously treated patients were subjected to susceptibility testing against 10 antituberculosis drugs. Treatment outcome was assessed. The DR levels were compared with those observed in the national TB prevalence surveys, and the trend was correlated with the cure rate of patients treated in the NTP. RESULTS: Resistance to any drug was 11.3% in new cases and 54.0% in previously treated cases. Initial resistance to isoniazid (INH) or rifampicin (RMP) was 7.7% or 2.2%, and to INH and RMP (+/- other drugs) 1.6%. Compared with previous data, initial drug resistance (IDR) has decreased significantly and is inversely related to improvement of cure rates in the NTP. The treatment outcome of patients with single drug resistance was satisfactory. CONCLUSION: Drug-resistant TB has decreased remarkably during the last decades in Korea as a result of improved efficiency in the treatment programme of the NTP.     

Metastatic carcinoma to skeletal muscle. A report of 15 patients

The records of 15 patients with metastatic carcinoma to skeletal muscle treated between 1979 and the present were reviewed. Fourteen patients were referred with a diagnosis of soft tissue sarcoma and one with suspected infection. There was a previous diagnosis of carcinoma in eight patients but seven patients had no prior diagnosis of a known malignancy. Primary tumors were lung (eight), melanoma (two), gastrointestinal (one), kidney (one), and bladder (one). No primary tumor could be identified in two patients. Local control of metastatic lesions was achieved by radiotherapy in 11 patients as an initial measure. Two patients underwent wide excision and one declined treatment for local tumor control. Eight patients died within 12 months of presentation and survival analysis indicated a 25% overall survival at 60 months. Two patients remained free of disease at 132 months and 72 months. From this study and a review of 52 cases reported in the literature, the authors are unable to find any clinical or radiographic characteristics that distinguish metastatic carcinoma to muscle from soft tissue sarcomas. Surgical resection can be reserved for cases in which radiation does not provide local control.     

Metastatic carcinoma to the mandible. Report of two cases

Two cases of rare metastases from malignant neoplasms to the posterior mandible in young adults are reported. Multiple imaging modalities were necessary to identify the many metastases and, in one case, the suspected primary site. Many of the radiographic images are presented for that case.     

Control of hypercalcaemia of parathyroid carcinoma by immunisation

BACKGROUND: Patients with parathyroid tumours can develop extreme hypercalcaemia and osteitis fibrosa cystica. Clinical features result from the action of parathyroid hormone (PTH) on bone receptors. Because this hormone is produced in microgram quantities, inhibition of its metabolic effects with potent PTH antibodies should be possible. We tested whether an immunisation with synthetic human and bovine PTH peptides could stimulate autoantibodies against PTH. METHODS: A patient with metastatic parathyroid carcinoma in the lungs and pleura developed severe bone disease and extreme hypercalcaemia that proved resistant to conventional therapy. She was immunised with 200 microg human and bovine PTH peptides and 50 microg human PTH. Booster doses were also given at 4 weeks and 11 weeks. The patient was then seen every week. FINDINGS: Antibodies against PTH were produced within 4 weeks of initial immunisation and titres increased with repeated doses of immunogens. Total serum calcium concentrations, which had ranged from 3.5 mmol/L to 4.2 mmol/L over the previous 18 months, fell to between 2.5 mmol/L and 3.0 mmol/L over 6 months of therapy. This fall was accompanied by striking clinical improvement. INTERPRETATION: We believe this is the first use of immunotherapy to control remote, non-metastatic complications of malignant disease. B-cell tolerance to human PTH was broken by immunisation with PTH peptides in adjuvant. This therapeutic approach could be used to control excess hormone production in several types of endocrine tumour and may have applications in other diseases.     

Metastatic squamous carcinoma manifesting as a periapical lesion

Periapical pathoses which often appear as vague radiolucent areas on routine roentgenographs, are treated by endodontic therapy alone or followed by apicoectomy. Clinicians as well as histopathologists should be aware that a metastatic carcinoma to the jaws can mimic apical lesions. A case of metastatic carcinoma from the larynx, which manifested as a periapical lesion with the clinical signs and symptoms of pulpal pathology, is described.     

Metastatic basal cell carcinoma presenting as unilateral lymphedema

BACKGROUND: Metastatic basal cell carcinoma (MBCC) is rare, occurring in only 0.0028-0.55% of all basal cell carcinomas (BCCs). Patients with MBCC may present with a variety of findings, related to the site of metastasis. OBJECTIVE: Clinical presentation of a MBCC that became symptomatic due to unilateral lymphedema and a review of the relevant literature. METHODS: Case report with literature review. RESULTS: Patients may present with lymphadenopathy, ulcerations, anemia, bone pain, or muscle weakness related to the site of metastasis. In this reported case, MBCC presented as unilateral lymphedema. Risk factors for MBCC include radiation, large and invasive tumors, and a history of recurrence. The average survival time for localized lymph node metastasis in BCC is 3.6 years. This patient is currently 2 years since MBCC presentation and is currently without evidence of recurrence. CONCLUSION: To our knowledge, we report the first case of MBCC that presented as unilateral lymphedema.     

MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are potent tachykinin NK-2 receptor antagonists

The activity and selectivity of MEN 10,573 and MEN 10,612, novel cyclic pseudopeptides which are selective tachykinin NK-2 receptor antagonists is described, as compared to that of previously characterized linear and cyclic compounds. For the NK-2 receptor, the activity of test compounds was investigated in the hamster isolated trachea (HT) and the endothelium-deprived rabbit isolated pulmonary artery (RPA), two preparations which are endowed with pharmacologically distinct forms of the NK-2 receptor. The novel cyclic pseudopeptides, MEN 10,573 and MEN 10,612 displayed very high affinity for the NK-2 receptor in the HT (pA2 8.66 and 9.06, respectively) which is higher than that observed in the RPA (pA2 7.31 and 7.41 for MEN 10,573 and MEN 10,612, respectively). The antagonism exerted by MEN 10,573 and MEN 10,612 was of competitive nature in both preparations. MEN 10,573 and MEN 10,612 also displayed competitive antagonism for NK-2 receptor-mediated responses in the rabbit bronchus (RB), rat vas deferens (RVD), circular muscle of the human colon (HUC) and ileum (HUI). In the RB, HUC and HUI, the potency of the novel cyclic pseudopeptides was comparable to that of MDL 29,913 and about 10-fold greater than that of L659,877. In the RVD however, the potency of MEN 10,573 MEN 10,612 or MDL 29,913 was similar to that of L659,877. In anaesthetized rats, i.v. injection of MEN 10,612 produced a selective and long-lasting blockade of the urinary bladder contraction produced by the i.v. injection of the NK-2 receptor selective agonist [beta Ala8]neurokinin A(4-10), without affecting the response to the NK-1 receptor selective agonist [Sar9]substance P sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metastatic cutaneous squamous cell carcinoma derived from actinic keratosis

BACKGROUND: Squamous cell carcinoma (SCC) with histologically contiguous actinic keratosis has long been thought of as a tumor with minimal risk for metastasis. The objective of this study was to determine if contiguous actinic keratosis is present in the original tumors of metastatic cutaneous SCC and to describe the histologic features of these tumors. METHODS: The primary lesions of 22 patients with metastatic cutaneous SCC were examined using light microscopy. RESULTS: Contiguous actinic keratosis was present histologically in 44% of the original lesions of cutaneous SCC that metastasized. The average tumor thickness was 6.6 mm. Greater than 66% of the tumors were well or moderately differentiated. The skin adjacent to the tumors showed solar degeneration in almost all instances. CONCLUSIONS: The histologic presence of contiguous actinic keratosis is not a useful predictor of the metastatic behavior of cutaneous SCC. Increased tumor thickness and depth of invasion are the most consistent histopathologic features of cutaneous SCC that metastasize.