Primary Medullary Thyroid Carcinoma Research Articles

Role of FNA cytology and immunochemistry in the diagnosis and management of medullary thyroid carcinoma: Report of six cases and review of the literature

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine thyroid malignancy. This study retrospectively reviewed 10 fine-needle aspiration samples from six MTC patients. Aspirated specimens were from thyroid (3), cervical lymph nodes (5), left lung (1), and anterior chest wall (1). Cytomorphology consisted predominantly of plasmacytoid cells (3 cases), spindle cells (2 cases), and epithelioid cells (1 case). However, all specimens had a mixture of other cell types and "salt and pepper" chromatin. Only one specimen showed Congo-red-positive amyloid. Calcitonin was expressed in 7/7 specimens. Four patients underwent surgical excision and MTC was confirmed in all four. Follow-up studies included serum calcitonin (3/6 cases) and imaging (2/6 cases). One patient had MTC associated with multiple endocrine neoplasia IIA syndrome and one had familial MTC with a history of MTC in mother. In conclusion, the cytomorphology of MTC is typical and calcitonin immunostain is a reliable method for confirming primary or metastatic MTC. Early cytological diagnosis of MTC positively impacted patient management. Follow-up with serum calcitonin and imaging is helpful in the early detection of recurrences.

Calcitonin Measurement in Wash-Out Fluid from Fine Needle Aspiration of Neck Masses in Patients with Primary and Metastatic Medullary Thyroid Carcinoma

The aim of the study was to evaluate the usefulness of calcitonin (CT) assay in fine-needle aspiration biopsy (FNAB) wash-out fluid alone or combined with cytology in the presurgical study of medullary thyroid carcinoma (MTC) patients with thyroid nodules (TNs) and of suspicious neck MTC recurrences/metastases. A total of 36 ultrasound-guided FNABs were performed in neck masses from 23 patients with borderline or high basal and pentagastrin-stimulated serum CT. Cytology and CT-FNAB were performed on a total of 18 TNs and three neck lymph nodes (LNs) from 12 patients examined before thyroidectomy, and on six suspicious local recurrences (LRs) and nine LNs from nine totally thyroidectomized MTC patients. On the basis of CT-FNAB values found in 15 non-MTC lesions, CT-FNAB more than 36 pg/ml was considered as indicative of MTC. All 21 positive CT-FNAB lesions (10 TNs, six LNs, and five LRs), 13 with positive cytology, were confirmed as MTC at histology. Of the 15 negative CT-FNAB suspicious masses (eight TNs, six LNs, and one LR), five displayed a benign lesion at histology. The remaining 10 cases, all with benign cytology, were not operated on, and no evidence of MTC was detected at follow-up. CT-FNAB reached 100% sensitivity and specificity for MTC, while cytology displayed 61.9% sensitivity and 80% specificity. Ultrasound-guided CT-FNAB was the best tool to identify primary MTC and LRs/node metastases in MTC operated subjects. This may have important implications in the management of MTC.

Novel SRESPHP Peptide Mediates Specific Binding to Primary Medullary Thyroid Carcinoma After Systemic Injection

Novel SRESPHP Peptide Mediates Specific Binding to Primary Medullary Thyroid Carcinoma After Systemic Injection

Novel SRESPHP Peptide Mediates Specific Binding to Primary Medullary Thyroid Carcinoma After Systemic Injection

The efficient and specific introduction of genes into cancer cells in vivo remains a major challenge for current gene therapy modalities. Peptides possess appropriate properties to serve as tumor-targeting agents. Thus, finding new cancer-selective peptides directing gene transfer to neoplastic cells by reducing transduction of normal cells is a central goal for molecular targeting. We have previously reported identification of a peptide (HTFEPGV) that selectively binds to human medullary thyroid carcinoma (MTC)-derived TT cells in vitro and transplanted tumor xenografts in vivo, using phage display. In the present study, we have performed this approach in primary orthotopically growing murine MTCs of RET-C634R transgenic mice as a clinically relevant model for thyroid cancer by intravenous injection of a complex peptide library. Two rounds of screening on primary tumors yielded multiple copies of a phage that displays a cyclic 7-amino acid peptide, SRESPHP, with a 3000-fold increase in titer between rounds 1 and 2. The selected phage showed highly specific binding to the tumor after systemic administration, whereas binding to other organs such as lung, liver, kidney, and heart was reduced up to 90%. After tail vein injection, homing to the tumor was substantially reduced in the presence of synthetic SRESPHP peptide, indicating that tumor phage interaction strictly depends on the displayed peptide. Immunohistochemical analysis of paraffin sections from mouse tissues revealed direct binding of the SRESPHP peptide to MTC tissue. Moreover, this peptide also mediates binding to human MTC cells in vitro and in vivo, suggesting abundant expression of its cognate receptor in murine and human medullary thyroid carcinoma. Because the SRESPHP peptide is also efficiently internalized into MTC cells, it likely provides the basis for a new selective therapy of medullary thyroid carcinoma.

Human Medullary Thyroid Carcinoma: A Source and Potential Target for Relaxin‐Like Hormones

We investigated the expression of H1, H2 relaxin and INSL-3, mRNA and protein, and LGR7 and LGR8 transcripts in human C-cell hyperplasia, primary medullary thyroid carcinoma (MTC) tissues, MTC metastases, and the human MTC-TT and mouse MTC-M cell lines. Relaxin-like peptide hormones were detected in C-cell hyperplasia and in MTC tissues, but were absent in human normal parafollicular C-cells of benign goiter tissues. In contrast to calcitonin, mRNA, and immunoreactive protein, no differences in the expression of relaxin and INSL3 were observed in MTC tissues of different pTNM classification or between primary and metastatic MTC tissues studied. All MTC tissues constitutively expressed LGR7 and LGR8 transcripts. Thus, relaxin-like hormones appear to be present early during C-cell hyperplasia and potentially functional relaxin/INSL3 ligand-receptor systems are present in human MTC tissues and in MTC cell lines.

310. Discovered Peptide Mediates Specific Binding to Primary Medullary Thyroid Carcinoma after Systemic Injection

The efficient and specific introduction of genes to cancer cells in vivo remains a major challenge for current gene therapy modalities. Peptides possess appropriate properties to serve as tumor targeting agents. Thus, finding new cancer selective peptides directing gene transfer to neoplastic cells by reducing transduction of normal cells is a central goal for molecular targeting. To identify medullary thyroid carcinoma (MTC) specific peptides, a complex phage display peptide library was intraveniously injected into RET(C634R)-transgenic mice carrying orthotopic MTCs as a clinical relevant model for thyroid cancer. Two rounds of screening on primary tumors yielded multiple copies of a phage that displays a cyclic 7-amio-acid peptide, SRESPHP, with a 3000-fold increase in titer between round one and two. The selected phage showed a highly specific binding to the tumor after systemic administration, whereas binding to other organs such as lung, liver, kidney, and heart was reduced up to 90%. After tail vein injection, homing to the tumor was substantially reduced (to approximately 70%) in the presence of synthetic SRESPHP peptide, indicating that tumor phage interaction strictly depends on the displayed peptide. Immunohistochemical analysis of paraffin sections from mice tissues revealed the strongest staining within MTC cells and at the tumor invasion front, suggesting that the SRESPHP-peptide promotes phage internalization in vivo. Thus, the identified peptide is potentially useful to mediate selective gene and/or vector transfer to medullary thyroid tumors.

943. Loss of Neoplastic Phenotype by Specific Inhibition of RET Oncogene Signalling in a Transgenic Model of Primary Medullary Thyroid Carcinoma

Background: Dominant activating mutations in the RET proto-oncogene trigger the development of medullary thyroid carcinoma (MTC). These mutations render the RET receptor independent of ligand-induced stimulation and turn it into a dominant acting oncoprotein by inducing constitutive trans-autophosphorylation. Methods: To study effects related to endogenous RET autophosphorylation in MTC cells and orthotopic MTCs in RET transgenic mice, we constructed adenoviral vectors expressing a dominant-negative truncated form of the receptor (RETDTK). Results: Expression of RETDTK in MTC cells impaired the autophosphorylation activity leading to decreased cell survival. This effect was specific to oncogenic RET expressing cells as RET-negative cells did not exhibit any treatment related cytoxicity. To delineate mechanisms responsible for the observed effect, we analyzed downstream targets potentially implicated in RET mediated transformation. We show that phosphorylation of Akt and ERK, as the major contributors to RET triggered transformation, is abolished after RETDTK expression. RETDTK mediated inactivation of Akt and ERK signaling is further accompanied by reduced cell cycle progression (through downregulation of cyclin D1 and upregulation of p21CIP1/WAF1 and p27KIP1) and stimulation of apoptosis (through downregulation of Bcl-2) in MTC derived cells. Furthermore, we demonstrate that tumor growth and maintenance of orthotopic MTCs in transgenic mice expressing oncogenic RET in their germline is significantly affected after inhibition of oncogenic RET through RETDTK expression (p<0,0001; two-sided unpaired Student's t test). Conclusion: Our results indicate that targeted therapy by selective disruption of oncogenic RET signaling responsible for cellular transformation can be an effective new treatment for primary MTC in vivo

Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients

Background The surgical management and follow-up strategy in patients with medullary thyroid carcinoma (MTC) remain controversial because of the lack of data on the natural history of these tumors and their patterns of progression. Methods We reviewed the records of all patients who underwent a cervical operation for MTC between 1991 and 2002. Compartment-oriented surgery (COS) was performed to minimize the risk of cervical recurrence. Results We identified 92 consecutive patients who underwent a cervical operation for MTC: 80 had invasive MTC, and 12 had C-cell hyperplasia after prophylactic thyroidectomy for familial MTC. Ten (13%) of the 80 patients with invasive MTC presented with distant metastases and underwent COS to achieve local-regional control; cervical recurrence developed in none, but three have died of MTC. The remaining 70 patients underwent COS for primary (n = 23) or recurrent (n = 47) MTC. Disease recurred in 18 (26%) of these 70 patients at a median follow-up of 35 months, with 10 (14%) of the recurrences being cervical. Recurrent disease was associated with a basal calcitonin level of >250 pg/mL in all but four patients, two of whom showed tumor dedifferentiation. In contrast, only 5 (11%) patients without evidence of recurrence had basal calcitonin levels of >250 pg/mL at last follow-up. Conclusions Complete COS minimizes cervical recurrence. Radiographic evidence of recurrent disease is unlikely when the calcitonin level is ≤250 pg/mL. These data could be used to develop a logical, cost-effective treatment and follow-up strategy for patients with MTC.

Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.

Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1.

Cancer/testis antigens (CTA) are tumor-associated antigens expressed during ontogenesis, in a number of solid tumors but not in normal tissues except testis. Most of these CTA are highly immunogenic, eliciting a humoral and cellular response in the patients with advanced cancer, and are useful for tumor-specific immunotherapy. Medullary thyroid carcinoma (MTC) is a neoplasm derived from the parafollicular cells of the thyroid and occurs in either a sporadic or a familial form. In the present study, we examined by RT-PCR the expression of a number of genes encoding CTA in 23 surgical samples of sporadic MTC. Among the 11 cDNA antigens examined, RAGE, MAGE-4, and GAGE 1-2, were not expressed in any of the tissues. SSX 2 was present only in one tissue, whereas BAGE, GAGE 1-6, MAGE-1, MAGE-2, MAGE-3, and SSX 1-5 were detected in two to five samples. NY-ESO-1 cDNA was the most frequent, being detected in 15 of 23 examined samples (65.2%). Six (26.1%) tissues did not express any CTA-specific mRNA, whereas 10 tumors expressed only one gene (43.5%), 3 (21.4%) expressed 2 genes, and 4 displayed a broad CTA gene expression. NY-ESO-1 expression in primary MTC tissues significantly correlated with tumor recurrence. The presence of specific anti-NY-ESO-1 antibodies was searched in the sera of MTC-affected patients examined by ELISA using recombinant NY-ESO-1 protein. A humoral response against this CTA was detected in 6 of 11 NY-ESO-1 expressing patients (54.5%), and in 1 of 6 patients with NY-ESO-1-negative tumor. No anti-NY-ESO-1 antibodies were detected in healthy subjects (n = 17). The presence of anti-NY-ESO-1 antibodies was searched also in the sera of MTC affected patients whose tissues were not available for CTA analysis. Anti-NY-ESO-1 antibodies were present in 15 of 42 sera (35.7%), demonstrating that MTC is a neoplasm frequently associated with humoral immune response to NY-ESO-1. Serological survey may be useful as a way to identify patients with humoral immune response to NY-ESO-1 that provide a new attractive target for vaccine-based immunotherapy of MTC.

Is there any consensus in diagnostic and operative strategy with respect to medullary thyroid cancer? A questionnaire answered by 73 endocrine surgical units.

The purpose of this investigation was to analyze the individual diagnostic and operative strategy in the treatment of medullary thyroid carcinoma (MTC) in international specialized centers and to assess whether standard procedures are carried out in practice everywhere. A questionnaire concerning diagnosis and treatment of patients with primary, persistent, or recurrent sporadic or familial MTC was sent to 263 members of the International Association of Endocrine Surgeons. Primary treatment of MTC does not show significant differences for patients with sporadic or familial disease (Chi-square, n.s.), and standard procedures are performed in only 25-40% of patients. Computed tomography scan is the most common localization procedure in persistent or recurrent disease (52-72%), followed by scintigraphy (43-71%), ultrasonography (41-56%), and magnetic resonance imaging (31-49%). In case of negative localization studies, 68-86% of colleagues do not recommend reoperation. In symptomatic patients with stage-IV tumors, however, 84% of colleagues advocate reoperation to provide relief from the tumor burden. Even with experienced endocrine surgeons, a consensus to uni- and/or bilateral neck dissection in primary MTC is lacking. The majority of authors supports at least total thyroidectomy with central lymph-node dissection. In recurrent disease, there is a general tendency to reoperate in case of positive localization studies and in case of symptomatic disease.

Prognostic value of codon 918 (ATG-->ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.

We have determined the frequency of 918 RET proto-oncogene mutations (ATG-->ACG) in primary MTC tumors and metastases and correlated the presence or absence of this mutation with the clinical outcome of patients suffering from sporadic medullary thyroid carcinoma (MTC). A total of 197 samples, consisting of both primary tumors and lymph node metastases from 34 patients with sporadic MTC, were collected for PCR analysis of the RET 918 mutation. In 75 of the samples (38%), codon 918 (ATG-->ACG) mutations could be detected. The mutations showed a heterogeneous distribution: 21/34 patients (62%) had mutations in at least 1 tumor sample, and in 13 patients (38%) the mutation was present in all examined samples. Patients were considered 918mt when at least 1 tumor sample showed the RET 918 mutation. These 918mt and 918 wild-type (918wt) patients did not differ significantly concerning sex, age at diagnosis, TNM stage at diagnosis, number of examined tumor samples or follow-up time. However, 918mt patients showed more aggressive development of distant metastases during follow-up (p = 0.032, Fisher's exact test) with decreased metastases-free survival (p < 0.005, log-rank test). Furthermore, 918mt patients had a significantly lower survival rate than 918wt patients (p = 0.048, log-rank test). These data show that the RET codon 918 mutation has a prognostic impact on patients with sporadic MTC which may influence follow-up treatment.

Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation.

This study assessed the suitability of pentagastrin stimulation in hypercalcitoninaemia for differential diagnosis of neuroendocrine carcinoma of the foregut. A prospective institutional study (March 1997-September 1999) was conducted involving all patients admitted to the pneumological and general surgical wards for small cell lung cancer (SCLC) or primary medullary thyroid carcinoma (MTC). Basal and stimulated serum calcitonin levels were measured using an improved immunoradiometrical assay for the monomeric form of calcitonin. Increased basal calcitonin levels were noted in six non-MTC patients (one mediastinal and one laryngeal neuroendocrine carcinoma, and four SCLCs). Because of chronic renal failure, one SCLC patient had to be excluded. The remaining five non-MTC patients with normal renal function were compared to eight primary MTC patients. In terms of pentagastrin stimulation, an increase in serum calcitonin levels of less than twofold the baseline significantly correlated with both non-MTC (r=0.85; P=0.005) and SCLC (r=0.81; P=0.024). Immunostaining of tissue specimens for calcitonin was positive in the patients with mediastinal and laryngeal neuroendocrine carcinoma and in all eight patients with primary MTC, but was negative in the two SCLC patients with adequate tissue samples. Irrespective of the pathophysiological background, pentagastrin stimulation affords a differential diagnosis in neuroendocrine carcinoma of the foregut when chronic renal failure is excluded.

Demonstration and Diagnostic Significance of Pro-Gastrin-Releasing Peptide in Medullary Thyroid Carcinoma

The expression of pro-gastrin-releasing peptide (proGRP) in medullary thyroid carcinoma (MTC) and other histological types of thyroid carcinoma was studied by an immunohistochemical technique, using polyclonal anti-proGRP antiserum. Immunoreactivity for proGRP was detected exclusively in MTC (n = 7); other histological types (n = 12) were all negative for proGRP. In addition, serum proGRP levels were elevated in patients with primary or recurrent MTC (n = 3), and they changed in parallel with serum calcitonin (CT), and carcinoembryonic antigen (CEA). These results show that proGRP, which is considered to be a specific marker for small-cell lung carcinoma, may be also a potential tumor marker for MTC, in addition to CT and CEA.

Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma.

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.

Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma.

Normalization of calcitonin levels after surgery has been regarded as the most powerful prognostic factor for medullary thyroid carcinoma (MTC). Although the prognosis of patients with persistent hypercalcitoninemia may be acceptable, the biochemical cure rate can be improved by new microdissection techniques. This raises certain questions: Can extension of locoregional lymphadenectomy (LA) further improve biochemical cure and survival after primary or reoperative MTC surgery? Which factors concerning TNM categories are associated with the possibility of postoperative normalization of calcitonin levels? This study included 64 patients with sporadic MTC operated on from 1986 to 1997. Altogether 27 patients underwent primary surgery, and 37 patients were reoperated, performing a microdissection of all four locoregional compartments (four-compartment lymphadenectomy, or 4CLA). For primary MTC the biochemical cure rate was 100% in node-negative patients and 33% in node-positive patients; the latter could be improved to 45% after 4CLA. In contrast to reoperative MTC, the rate of lymph node metastases (LNMs) with primary MTC correlated with the pT category (pT1 33%, pT2 53%, pT3 100%, pT4 100%) but not with age or sex. Again in contrast to reoperative MTC, mediastinal LNMs in primary MTC were present only in patients with a pT4 tumor. At reoperation, 4CLA was able to cure 22% of node-positive patients, 28% without proved distant metastases. No patient with extrathyroidal tumor involvement or distant metastases was biochemically cured after either primary or reoperative surgery. For all node-positive MTC patients, in addition to cervicocentral LA at least a bilateral cervicolateral LA is recommended. Transsternal mediastinal lymph node dissection is indicated in patients with LNMs in the cervicomediastinal transition, facilitating biochemical cure in up to 45% after the first operation and 22% after reoperative surgery of sporadic MTC.

Fine‐needle aspiration cytology of amyloid associated with nonneoplastic and malignant lesions

To assess the value of fine-needle aspiration (FNA) cytology for the diagnosis of amyloid, we retrospectively studied all FNA cases diagnosed as having amyloid during a 6-yr period (1990–1996). FNA was performed on both superficial and deep locations. A total of 6 cases containing amyloid was studied, including primary medullary thyroid carcinoma, metastatic medullary thyroid carcinoma to a vertebrae, multiple myeloma, squamous-cell carcinoma of the lung metastatic to a hilar lymph node, primary pulmonary amyloid, and amyloid tumor in a vertebral body in a patient with primary systemic amyloidosis. Despite the location or disease association, the cytologic appearance of amyloid in all cases was similar. On Diff-Quik stain, amyloid appeared as amorphous, irregular, waxy, basophilic to metachromatic clumps of material. Papanicolaou stain revealed cyanophilic to organophilic clumps of material with occasional prominent fissures. In all 6 cases, amyloid was confirmed by Congo red stain and in 3 cases by a thioflavin T stain. In 4 of the 6 cases (67%), amyloid was associated with an underlying malignancy. In 3 cases malignant cells were admixed with the amyloid, and in another case malignancy was present at a distant site. We conclude that FNA biopsy is a helpful initial procedure for the evaluation of patients with amyloid deposits. The clinical implications of amyloid found in any particular body site include both benign and malignant conditions. The presence of an associated neoplasm must be especially considered in the differential diagnosis of amyloid deposits. Diagn. Cytopathol. 1998;18:270–275. © 1998 Wiley-Liss, Inc.

Fine-needle aspiration cytology of amyloid associated with nonneoplastic and malignant lesions.

To assess the value of fine-needle aspiration (FNA) cytology for the diagnosis of amyloid, we retrospectively studied all FNA cases diagnosed as having amyloid during a 6-yr period (1990-1996). FNA was performed on both superficial and deep locations. A total of 6 cases containing amyloid was studied, including primary medullary thyroid carcinoma, metastatic medullary thyroid carcinoma to a vertebrae, multiple myeloma, squamous-cell carcinoma of the lung metastatic to a hilar lymph node, primary pulmonary amyloid, and amyloid tumor in a vertebral body in a patient with primary systemic amyloidosis. Despite the location or disease association, the cytologic appearance of amyloid in all cases was similar. On Diff-Quik stain, amyloid appeared as amorphous, irregular, waxy basophilic to metachromatic clumps of material. Papanicolaou stain revealed cyanophilic to organophilic clumps of material with occasional prominent fissures. In all 6 cases, amyloid was confirmed by Congo red stain and in 3 cases by a thioflavin T stain. In 4 of the 6 cases (67%), amyloid was associated with an underlying malignancy. In 3 cases malignant cells were admixed with the amyloid, and in another case malignancy was present at a distant site. We conclude that FNA biopsy is a helpful initial procedure for the evaluation of patients with amyloid deposits. The clinical implications of amyloid found in any particular body site include both benign and malignant conditions. The presence of an associated neoplasm must be especially considered in the differential diagnosis of amyloid deposits.

Combined use of 111in-DTPA-D-Phe-1-octreotide (OCT) and 123I-vasoactive intestinal peptide (VIP) in the localization diagnosis of medullary thyroid carcinoma (MTC)

Although serum calcitonin and CEA are sensitive indicators for the presence of medullary thyroid carcinoma (MTC), the localization of tumor sites may be very difficult. In an approach to localize MTC lesions we performed comparative in vivo studies in 12 patients with primary MTC and in 4 patients with suspected recurrent MTC using 123I-VIP (150 MBq/1 μg) and 111In-DTPA-D-Phe-1-octreotide ( 111In-OCT; 150 MBq/1 μg). Despite elevated calcitonin values in all patients with suspected recurrent or metastatic lesions, both ultrasound and computed tomography (CT) were unable to localize a tumor site. 111In-OCT localized the primary tumor in the thyroid gland in 7 of 11 patients (63.5%). In 2 of 4 patients (50%) with suspected recurrent MTC, pathological uptake of 111In-OCT in the mediastinum or liver was demonstrable. In none of the 11 patients did 123I-VIP-receptor scanning indicate primary, recurrent, or metastatic tumor lesions. In vitro binding studies showed an absence of high-affinity VIP receptors in MTC tissue, whereas high-affinity 111In-OCT receptors were present in 4 of 6, and low-affinity 123I-VIP as well as 111In-OCT receptors were present in 6 of 6 MTC tissue samples. We conclude that somatostatin receptor scanning using 111In-OCT may visualize primary MTC, but it has only a low sensitivity in the detection of recurrent disease. The 123I-VIP-receptor scan is not helpful in the localization diagnosis of primary or recurrent MTC.

A primary, lateral-cervical medullary thyroid carcinoma: a case report.

Medullary thyroid carcinoma (MTC) arises from the parafollicular cells of the thyroid and occurs in a sporadic or in an inherited form. We present a case of an aberrant MTC in a patient with a functioning thyroid gland. At surgical dissection, the thyroid was present in its anatomical site with a nodule in the upper one third of the right lobe. A mass was also found in a lateral-cervical position distinct from the thyroid gland. Histological examination showed the mass to be the primary MTC, whereas the thyroid nodule was a follicular adenoma. Analysis of DNA extracted from the MTC, from the adenoma, and from peripheral blood revealed a mutation within exon 16 of the RET proto-oncogene only in the DNA from the tumor. The reported case represents a sporadic MTC in an aberrant localization, probably originating from a developmental abnormality of the primordial C cells. This event might have occurred during the migration and/or differentiation of the C cells and might be related to, or caused by, the mutated RET proto-oncogene.