Terry C. Lairmore

Lethality of Multiple Endocrine Neoplasia Type I

Abstract. The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years,p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years,p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n= 12), ulcer disease (n= 6), hypercalcemia/uremia (n= 3), carcinoid tumor (n= 6), and nonendocrine malignancies (n= 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes

ObjectiveThe authors sought to determine the optimal surgical management of pheochromocytomas that develop in patients with multiple endocrine neoplasia (MEN) type 2 syndromes. Summary Background dataThe performance of empirical bilateral adrenalectomy in patients with MEN 2A or MEN 2B, whether or not they have bilateral pheochromocytomas, is controversial. MethodsThe results of unilateral or bilateral adrenalectomy were studied in 58 patients (49 with MEN 2A and 9 with MEN 2B). Recurrence of disease was evaluated by measuring 24-hour urinary excretion rates of catecholamines and metabolites and by computed tomography (CT) scanning. ResultsThe mean postoperative follow-up was 9.40 years. There was no operative mortality and malignant or extra-adrenal pheochromocytomas were not present. Twenty-three patients with a unilateral pheochromocytoma and a macroscopically normal contralateral gland underwent unilateral adrenalectomy. A pheochromocytoma developed in the remaining gland a mean of 11.87 years after the primary adrenalectomy in 12 (52%) patients. Conversely, 11 (48%) patients did not develop a pheochromocytoma during a mean interval of 5.18 years. In the interval after unlateral adrenalectomy, no patient experienced hypertensive crises or other complications related to an undiagnosed pheochromocytoma. Ten (23%) of 43 patients having both adrenal glands removed (either at a single operation or sequentially) experienced at least one episode of acute adrenal insufficiency or Addisonian crisis, including one patient who died during a bout of influenza. ConclusionsBased on these data, the treatment of choice for patients with MEN 2A or MEN 2B and a unilateral pheochromocytoma is resection of only the involved gland. Substantial morbidity and significant mortality are associated with the Addisonian state after bilateral adrenalectomy.

Progress in the operative management of sporadic primary hyperparathyroidism over 34 years.

Background:Progress in the diagnosis, localization of abnormal parathyroids, and intraoperative management of primary hyperparathyroidism has been observed over the past 34 years. The goal of this study is to report the outcome of patients undergoing 2 different operative approaches in a single institution, showing the evolution of surgical management of sporadic primary hyperparathyroidism (SPHPT). Methods:Parathyroidectomy was performed in 890 (827 initial, 63 reoperative) patients with SPHPT using 2 different approaches: traditional bilateral neck exploration (BNE, n = 396) or limited parathyroidectomy guided by parathormone dynamics (LPX, n = 494). Seven hundred eighteen patients (335 BNE, 383 LPX) followed ≥ 6 months or identified as operative failures were studied. Operative failure is defined as hypercalcemia and high intact (1–84) parathyroid hormone molecule (iPTH) within 6 months after operation. Successful parathyroidectomy is normocalcemia for 6 months; hypercalcemia and elevated iPTH after this time is recurrent hyperparathyroidism. Results:There were 20 (6%) of 335 operative failures in the BNE group and 11 (3%) of 383 failures in the LPX group (P = 0.04). The incidence of multiglandular disease (MGD) determined by gland size (10%) versus hormone hypersecretion (3%) was statistically different (P < 0.001). Since most of the recurrences occurred later than 30 months, the incidence of recurrent hyperparathyroidism in patients followed for longer than 2.5 years was 4% (11/287) in the BNE group (average, 11.5 years) and 3% (5/183) in the LPX group (average, 4.2 years). Conclusion:LPX, with its reported advantages of minimal dissection, shorter operative time, and use in ambulatory settings, compares favorably with the traditional BNE. Parathyroidectomy guided by parathormone dynamics has an improved success rate and should be considered as a standard operative approach in SPHPT.

Routine bilateral central lymph node clearance for papillary thyroid cancer

BACKGROUND Controversy exists regarding the extent of surgical treatment for paratracheal (level VI) lymph nodes in patients with papillary thyroid cancer (PTC). Local recurrence within lymph nodes in the central neck compartment after total thyroidectomy can be difficult to detect and more hazardous to treat surgically. An initial bilateral central lymph node dissection (CLND) can best minimize this risk of local recurrence, if CLND is established as reasonably safe and oncologically justified. METHODS This study is based on a retrospective review of the institutional tumor registry of all patients treated for PTC between January 2000 and May 2008 at a 636-bed tertiary referral center and university-affiliated hospital. The following data were analyzed: the operative procedures, tumor characteristics (size, lymph node metastasis), injury to the recurrent laryngeal nerve (RLN), tumor recurrence, and need for further operative procedures. RESULTS Of 310 patients identified as treated surgically for PTC, 281 received total thyroidectomy and 29 received a lesser operation. Bilateral CLND was performed in 169 patients, unilateral CLND in 11, and no CLND in 130. The central lymph nodes were positive in 84 (46.7%) of 180 patients with CLND. Excluding isthmus tumors and those with bilateral same-size PTC, 41 (25.5%) of 161 patients with bilateral CLND had positive contralateral lymph nodes. Of the 603 RLNs at risk, 13 temporary injuries occurred, and 8 (1.3%) permanent injuries resulted. The risk of RLN injury was not greater with bilateral CLND compared to unilateral or no CLND (P = .18), and those patients with bilateral CLND had statistically larger tumors (1.60 cm vs 0.84 cm; P < .0001). Of the 10 documented cancer recurrences requiring reoperation, 4 were in the central neck, and all of these occurred in patients who did not have CLND. CONCLUSION Lymph node metastases are present in both the ipsilateral and contralateral central lymph node basins in a significant percentage of patients with PTC. Routine bilateral CLND in patients with PTC has the potential to clear metastatic disease without significantly increasing the risk of RLN injury.

Preservation of the recurrent laryngeal nerves in thyroid and parathyroid reoperations

BACKGROUND The recurrent laryngeal nerve (RLN) is vulnerable to injury in thyroid and parathyroid reoperations because of the presence of scar tissue and displacement of the nerve from its normal position. METHODS Since 1993, we have performed 132 reoperations for recurrence of thyroid or parathyroid carcinoma (102 cases), persistent hyperparathyroidism (21 cases), and recurrent goiter (9 cases). One or both RLNs were identified in all cases (208 nerves). Exposure of the nerve was accomplished by a lateral approach (159 nerves), a low anterior approach (41 nerves), or the identification of the nerve between the larynx and the upper pole of the thyroid, in parathyroid reoperations (8 nerves). Dissection was then done while the nerve was kept in view at all times. RESULTS Preoperatively, unilateral vocal cord paralysis was noted in 6 patients. Resection of a functioning RLN encased with a tumor was intentionally carried out in 5 patients. The RLNs were identified and preserved in all other cases. Among these 121 patients, transient hoarseness lasting up to a month occurred in 12 patients. CONCLUSIONS Careful identification and exposure of the RLN through a previously undissected area can be done safely in thyroid and parathyroid reoperations and resulted in no permanent recurrent nerve injuries in our experience.

Clinical Genetic Testing and Early Surgical Intervention in Patients With Multiple Endocrine Neoplasia Type 1 (MEN 1)

Objective:We sought to develop a comprehensive program for clinical genetic testing in a large group of extended families with multiple endocrine neoplasia type 1 (MEN 1), with the ultimate aim of early tumor detection and surgical intervention. Summary Background Data:Germline mutations in the MEN1 tumor suppressor gene are responsible for the MEN 1 syndrome. Direct genetic testing for a disease-associated MEN1 mutation is now possible in selected families. The neuroendocrine tumors of the pancreas/duodenum and the intrathoracic neuroendocrine tumors that occur in MEN 1 carry a malignant potential. Importantly, these tumors arise in otherwise young healthy patients and are complicated by the potential for multifocality and involvement of multiple target tissues. The optimal screening methods and indications for early surgical intervention in genetically positive patients have yet to be defined. Methods:Nine MEN 1 kindreds were included in the study. The mutations for each kindred were initially identified in the research laboratory. Subsequently, mutation detection was independently validated in the clinical Molecular Diagnostic Laboratory. Each patient in the study underwent formal genetic counseling before testing. Results:Genetic testing was performed in 56 at-risk patients. Patients were stratified according to risk: Group I (n = 25), 50% risk, younger than 30 years old; Group II (n = 20), 50% risk, 30 years old or older; Group III (n = 11) 25% risk. Seven patients (age, 12 to 42 years; mean, 20.6 ± 3.8 years) had a positive genetic test. Patients with a novel positive genetic test were in either Group I (n = 6) or Group II (n = 1) and have been followed for 35.8 ± 2.0 months. Of the 7 genetically positive patients, hypercalcemia was either present at the time of diagnosis or developed during the period of follow-up in 6 patients. Four patients have undergone parathyroidectomy as early as age 16 years. One genetically positive patient has not yet developed hyperparathyroidism. Intensive biochemical screening in this select group of patients identified an elevated pancreatic polypeptide level and pancreatic tail mass lesion in a 15-year-old male who is asymptomatic and currently normocalcemic. Conclusions:Genetic testing identifies patients harboring an MEN1 mutation before the development of clinical signs or symptoms of endocrine disease. When genetically positive patients are carefully studied prospectively, biochemical evidence of neoplasia can be detected an average of 10 years before clinically evident disease, allowing for early surgical intervention. Genetically positive individuals should undergo focused cancer surveillance for early detection of the potentially malignant neuroendocrine tumors that account for most of the disease-related morbidity and mortality.

Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome characterized by parathyroid hyperplasia, pituitary adenomas, and neuroendocrine tumors of the pancreas and duodenum. In 1997, the MEN1 tumor suppressor gene was identified, and numerous germline mutations have been reported to be distributed throughout the gene. We used single strand conformational variant (SSCV) analysis to search for germline mutations in the members of 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 25 conformational variants representing germline mutations that are predicted to result in loss of normal menin function. Twenty different disease‐associated mutations were identified: five resulting in potential abnormal RNA splicing, two missense mutations, seven nonsense mutations, and six frameshift mutations. The aberrant splice products were identified and confirmed by RT‐PCR and direct sequence analysis for two of the five splice mutations. Sixteen of the 20 (80%) mutations identified have not been previously reported. Mutations were not identified in eight kindreds with signs and symptoms consistent with MEN 1. The SSCV analysis revealed mutations in 76% (25 of 33) of the kindreds investigated, thus showing SSCV analysis to be a reliable mutation detection strategy. One‐fifth of the mutations identified in this study involve intron sequences, therefore, highlighting the importance of including intron sequences in the search for germline mutations in the MEN1 gene. The need to investigate the entire gene when characterizing new MEN 1 families presents challenges in the translation of genetic studies to efficient clinical diagnostic tests. Hum Mutat 13:175–185, 1999.

Adrenalectomy for Familial Pheochromocytoma in the Laparoscopic Era

ObjectiveTo report the results of treatment of patients with familial pheochromocytomas in the laparoscopic era. Summary Background DataThe optimal surgical management of pheochromocytomas that arise in familial neoplasia syndromes may be complicated by bilateral involvement and associated endocrinopathies. MethodsTwenty-one patients with familial pheochromocytomas (15 with multiple endocrine neoplasia [MEN] 2A, 4 with MEN 2B, 1 each with von Hippel-Lindau and neurofibromatosis type 1) underwent adrenalectomy between December 1993 and July 2001. Clinical, biochemical, and pathologic data were obtained by retrospective review of perioperative medical records, postoperative biochemical testing, and patient questionnaire. ResultsMean age at diagnosis was 37 ± 11 years. Twenty of the 21 patients had elevated urine catecholamines, and all had radiographic evidence of an adrenal tumor or tumors. Pheochromocytoma-related symptoms were present in 11 patients (52%). One patient with MEN 2B underwent open adrenalectomy due to previous adrenal surgery and megacolon. Laparoscopic adrenalectomy was attempted in the remaining 20 patients (9 right, 11 left, 2 bilateral). Two patients (9.1%) were converted to open adrenalectomy. Intraoperative hypertensive episodes occurred in 15 patients (71%) and were easily controlled medically. Mean operative time was 216 ± 57 minutes, mean postoperative length of stay was 3.1 ± 1.3 days, and mean tumor size was 3.1 ± 1.0 cm. Minor complications occurred in three patients (14.3%) and major complications in two patients (9.5%). During a mean follow-up of 57 months, a contralateral pheochromocytoma developed in four patients with MEN 2 (33%); three of them underwent adrenalectomy. There have been no long-term complications related to hypertension or adrenalectomy. ConclusionsThis study is the largest series of patients with familial pheochromocytoma undergoing adrenalectomy during the laparoscopic era. The results suggest that the laparoscopic approach is safe and effective for managing unilateral or bilateral adrenal medullary disease in this population.

Gastrointestinal Manifestations of Multiple Endocrine Neoplasia Type 2

ObjectiveTo determine the clinical features, natural history, and role of surgery for gastrointestinal manifestations of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. Summary Background DataThe MEN 2 syndromes are characterized by medullary thyroid carcinoma and other endocrinopathies. In addition, some patients with MEN 2A develop Hirschsprung’s disease (HD), and all patients with MEN 2B have intestinal neuromas and megacolon that can cause significant gastrointestinal problems. MethodsFrom 83 families with MEN 2A, eight patients with HD were identified (MEN 2A-HD). These and all patients with MEN 2B followed at the authors’ institution (n = 53) were sent questionnaires to describe the onset and type of gastrointestinal symptoms and treatment they had before the diagnosis of MEN 2. Records of all patients responding were reviewed, including radiographic imaging, histology, surgical records, and genetic testing. ResultsThirty-six of the 61 patients (59%) responded (MEN 2A = 8, MEN 2B = 28) to the questionnaires. All patients with MEN 2A-HD were operated on for HD 2 to 63 years before being diagnosed with MEN 2. All patients responding were underweight as infants and had symptoms of abdominal pain, distention, and constipation. Eighty-eight percent had hematochezia, 63% had emesis, and 33% had intermittent diarrhea before surgery. All patients with MEN 2A-HD had rectal biopsies with a diverting colostomy as the initial surgical procedure. This was followed by a colostomy takedown and pull-through procedure at a later interval. Ninety-three percent of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), and vomiting (14%). Seventy-one percent of patients with MEN-2B with gastrointestinal symptoms had radiographic imaging, 32% were admitted to the hospital, and 29% underwent surgery. ConclusionsPatients with MEN 2A-HD had a typical HD presentation and always required surgery. Patients with MEN 2B have significant gastrointestinal symptoms, but less than a third had surgical intervention. Understanding the clinical course and differences in these patients will improve clinical management.

Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome

BackgroundMultiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100) is an autosomal dominant disorder characterized by endocrine tumors of the parathyroids, pancreatic islets and pituitary. The disease is caused by the functional loss of the tumor suppressor protein menin, coded by the MEN1 gene. The protein sequence has no significant homology to known consensus motifs. In vitro studies have shown menin binding to JunD, Pem, Smad3, NF-kappaB, nm23H1, and RPA2 proteins. However, none of these binding studies have led to a convincing theory of how loss-of-menin leads to neoplasia.ResultsGlobal gene expression studies on eight neuroendocrine tumors from MEN1 patients and 4 normal islet controls was performed utilizing Affymetrix U95Av2 chips. Overall hierarchical clustering placed all tumors in one group separate from the group of normal islets. Within the group of tumors, those of the same type were mostly clustered together. The clustering analysis also revealed 19 apoptosis-related genes that were under-expressed in the group of tumors. There were 193 genes that were increased/decreased by at least 2-fold in the tumors relative to the normal islets and that had a t-test significance value of p < = 0.005. Forty-five of these genes were increased and 148 were decreased in the tumors relative to the controls. One hundred and four of the genes could be classified as being involved in cell growth, cell death, or signal transduction. The results from 11 genes were selected for validation by quantitative RT-PCR. The average correlation coefficient was 0.655 (range 0.235–0.964).ConclusionThis is the first analysis of global gene expression in MEN1-associated neuroendocrine tumors. Many genes were identified which were differentially expressed in neuroendocrine tumors arising in patients with the MEN1 syndrome, as compared with normal human islet cells. The expression of a group of apoptosis-related genes was significantly suppressed, suggesting that these genes may play crucial roles in tumorigenesis in this syndrome. We identified a number of genes which are attractive candidates for further investigation into the mechanisms by which menin loss causes tumors in pancreatic islets. Of particular interest are: FGF9 which may stimulate the growth of prostate cancer, brain cancer and endometrium; and IER3 (IEX-1), PHLDA2 (TSS3), IAPP (amylin), and SST, all of which may play roles in apoptosis.