Sipple's syndrome. A urologist's viewpoint.

A case of Sipple's syndrome, a triad of medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid hyperplasia is presented. The cause, laboratory diagnosis, and operative management of the syndrome are discussed. The need for thorough endocrine screening of patients with pheochromocytoma and family screening of patients with the full syndrome is stressed.     

Dilemmas in the early diagnosis and treatment of multiple endocrine adenomatosis, type II.

Fifteen patients with the diagnosis of multiple endocrine adenomatosis, type II, syndrome (MEA II) were reported from a single center to discuss the dilemmas of early detection and treatment of the adrenal medullary, thyroid, and parathyroid gland diseases. Ten patients came from three families. Three of the patients died, none in hypertensive crisis. Bilateral adrenal medullary disease was present in six patients. Five patients with proved pheochromocytoma had hypertension. All had diagnostic urinary catecholamine values. Nine normotensive patients without proved pheochromocytoma but in a high-risk category for adrenal medullary disease, have multiple suspicious urinary cathecholamines suggestive of adrenal medullary hyperplasia. Bilateral adrenalectomy is recommended for proved adrenal medullary disease in the MEA II syndrome. Medullary carcinoma of the thyroid gland was found in 13 patients and is believed to be present in two others. Five of the proved cases were occult, being discovered by elevation of pentagastrin-stimulated serum calcitonin levels, justifying total thyroidectomy. Parathyroid hyperplasia was found in three patients with preoperative hypercalcemia and in four others with preoperative normocalcemia. Conservative treatment of parathyroid gland hyperplasia in the MEA II syndrome is substantiated. Metachronous phenotypic expression of the syndrome components was significant.     

A case of Sipple syndrome whose bilateral pheochromocytomas were resected separately after a 3-year interval

A 23-year-old woman who had undergone total thyroidectomy and parabronchial lymphadenectomy at the Department of Otolaryngology in our hospital was suspected to have a thyroid carcinoma. Histological examination revealed a medullary carcinoma of the thyroid and normal parathyroid glands. Because a computed tomographic scan after surgery revealed a tumor of the left adrenal gland, the patient was examined at our department two months after the thyroidectomy, 1994. Endocrinic examinations and 123I-MIBG scintigraphy revealed a left adrenal pheochromocytoma of Sipple syndrome. She then underwent left adrenalectomy. Histological diagnosis was pheochromocytoma of the left adrenal gland. Three years after the surgery, a right adrenal tumor was detected by computed tomography. Although results of endocrine examinations were normal, 131I-MIBG scintigraphy showed a hot spot in the right adrenal gland. Right adrenal pheochromocytoma was diagnosed 3 years after surgery for a contralateral adrenal pheochromocytoma. Although surgery was recommended, the patient consented to right adrenalectomy, 1 year later after marriage and before becoming pregnant. Histological examination of the resected specimen revealed pheochromocytoma of the right adrenal gland.     

A case of composite pheochromocytoma-ganglioneuroblastoma in the adrenal gland with primary hyperparathyroidism

We report a case of composite pheochromocytoma-ganglioneuroblastoma in the adrenal gland with primary hyperparathyrodisim. A 55-year-old woman consulted our hospital for an examination of a right adrenal tumor, incidentally found by screening abdominal ultrasound sonography. On the clinical diagnosis of pheochromocytoma in the right adrenal gland from the findings of enhanced abdominal computed tomography, endocrinal examinations and 123I-metaiodobenzyl-guanidine scintigram, right adrenalectomy was performed transperitoneally. Histopathological diagnosis was an adrenal composite pheochromocytoma-ganglioneuroblastoma. This combination of compound adrenal tumor is extremely rare, and to date this case may be the seventh reported in Japan. Moreover, since her serum calcium level and intact parathyroid hormone level were high, so we considered the existence of multiple endocrine neoplasia type 2A. 99mTc-methoxyisobutylisonitrile scintigram and ultrasound of the neck revealed hyperparathyroidism, but medullary thyroid carcinoma was not detected. One year later, she was readmitted for parathyroid tumor excision, and histopathological finding was parathyroid adenoma. We concluded that she had both adrenal composite pheochromocytoma and hyperparathyroidism incidentally.     

Sipple's syndrome: A case diagnosed preoperatively

A case of familial Sipple's syndrome diagnosed preoperatively is presented. Clinically, thyroid carcinoma and its metastasis to the cervical and upper mediastinal lymph nodes were first noticed. The diagnosis of medullary carcinoma was strongly suspected on the physical and roentgenologic evidences unique to this variety of thyroid cancer. Clinically pheochromocytomas were asymptomatic, but urinary catecholamine study revealed an increased epinephrine excretion. Furthermore this case had a parathyroid adenoma and preoperative serum parathormone (PTH) was high, though the serum calcium level remained normal. The patient was successfully treated by total adrenalectomy followed by thyroidectomy.     

2型多发内分泌腺瘤病的诊断及外科治疗

目的探讨2型多发内分泌腺瘤病的临床特点、治疗方法及疗效。方法回顾分析我院1980～2002年诊治的8例2型多发内分泌腺瘤病患者的临床特点、诊断及治疗方法与疗效。结果7例有阵发性高血压,5例最高血压超过200mmHg(1mmHg=0．133kPa),3例查体发现肿瘤。经B超、CT及24h尿儿茶酚胺检查确定诊断,2A型6例,2B型2例;表现为甲状腺髓样癌合并嗜铬细胞瘤伴或不伴甲状旁腺腺瘤或增生(6例),1例伴多发黏膜神经瘤,1例为嗜铬细胞瘤伴有马凡综合征;双侧肾上腺肿瘤7例;分期行肾上腺与甲状腺、甲状旁腺结节切除或次全切除术。术后平均随访9年,效果良好。结论2型多发内分泌腺瘤病的诊断主要依赖相应的内分泌检查及B超和CT检查,手术是主要的治疗手段,当嗜铬细胞瘤与其他肿瘤同时存在时,宜首先切除嗜铬细胞瘤。     

Pheochromocytoma in multiple endocrine neoplasia type II: an example of the two-hit theory of neoplasia

Six kindreds in which pheochromocytomas were present as manifestations of the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type II were studied. The patients underwent bilateral total adrenalectomy with the finding that the pheochromocytomas were bilateral, multifocal, and associated with distinct medullary hyperplasia and reduction in the normal corticomedullary ratio-- features not usually seen in patients with sporadic pheochromocytoma. These findings were exemplified in recent cases of a 34-year-old woman and a 40-year-old man who both had undergone total thyroidectomy for medullary carcinoma of the thyroid. Diagnoses of pheochromocytoma were made by catecholamine studies, computerized tomography, and 131I meta-iodobenzylguanidine (MIBG) scan. Bilateral adrenalectomy was performed with the finding of multiple bilateral pheochromocytomas and adrenal medullary hyperplasia. As in hereditary medullary carcinoma of the thyroid, the histologic findings in pheochromocytomas of the MEN II syndrome are consistent with Knudson's two-mutational-event theory for the initiation of neoplasia, with adrenal medullary hyperplasia representing the manifestation of the first or genetic mutational event and being present invariably in the hereditary cases.     

Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers

Sixteen multiple endocrine neoplasia type II (MEN II) gene carriers--12 who had undergone thyroidectomy because of medullary carcinoma of the thyroid and 4 whose thyroid glands had been removed because of C cell hyperplasia--were examined for the presence of pheochromocytomas. No patient had sought medical advice for pheochromocytoma symptoms. Fourteen patients had MEN IIa syndromes, one patient had a MEN IIb and another patient had a mixed syndrome of von Recklinghausen's neurofibromatosis and MEN II. Eight patients had undergone unilateral adrenalectomy for pheochromocytoma 11 +/- 4 years before. The patients underwent clinical examination, determination of the urinary excretion of catecholamines and metabolites, and 131I-metaiodobenzylguanidine (131I-MIBG) and CAT scans. 131I-MIBG scanning was performed with images 1, 4, and 7 days after the radionuclide injection. In seven of eight patients who had undergone unilateral adrenalectomies, the 131I-MIBG scans showed accumulation of the radionuclide in the remaining adrenal gland. Bilateral adrenal accumulation of the radionuclide was demonstrated in seven of eight MEN IIa gene carriers who had not undergone adrenalectomy. Five patients, two of whom had undergone adrenalectomy, were found to have unilateral pheochromocytomas less than 2 cm in diameter. Only one of these five patients had an elevated excretion of urinary catecholamines. Between day 4 and day 7 after 131I-MIBG injection, adrenal glands with pheochromocytomas increased their relative accumulation of the radionuclide significantly more (p less than 0.02) than did adrenal glands without any demonstrable pheochromocytomas. All the pheochromocytomas were viewed by means of CAT scans. Only one MEN IIa patient had bilateral pheochromocytomas, but our findings indicate that there is a tendency to bilateral adrenal medullary hyperfunction in most MEN II gene carriers. As 131I-MIBG and CAT scans can facilitate the early diagnosis of pheochromocytomas, unilateral adrenalectomy can safely be performed in most MEN IIa patients. Bilateral pheochromocytomas develop in a majority of patients with MEN IIb syndromes. Bilateral adrenalectomy should therefore be performed in these patients.     

Spontaneous adrenal pheochromocytoma rupture complicated by intraperitoneal hemorrhage and shock

MEN2A is a hereditary syndrome characterized by medullary thyroid carcinoma, hyperparathyroidism, and pheochromocytoma. Classically patients with a pheochromocytoma initially present with the triad of paroxysmal headaches, palpitations, and diaphoresis accompanied by marked hypertension. However, although reported as a rare presentation, spontaneous hemorrhage within a pheochromocytoma can present as an abdominal catastrophe. Unrecognized, this transformation can rapidly result in death. We report the only documented case of a thirty eight year old gentleman with MEN2A who presented to a community hospital with hemorrhagic shock and peritonitis secondary to an unrecognized hemorrhagic pheochromocytoma. The clinical course is notable for an inability to localize the source of hemorrhage during an initial damage control laparotomy that stabilized the patient sufficiently to allow emergent transfer to our facility, re-exploration for continued hemorrhage and abdominal compartment syndrome, and ultimately angiographic embolization of the left adrenal artery for control of the bleeding. Following recovery from his critical illness and appropriate medical management for pheochromocytoma, he returned for interval bilateral adrenal gland resection, from which his recovery was unremarkable. Our review of the literature highlights the high mortality associated with the undertaking of an operative intervention in the face of an unrecognized functional pheochromocytoma. This reinforces the need for maintaining a high index of suspicion for pheochromocytoma in similar cases. Our case also demonstrates the need for a mutimodal treatment approach that will often be required in these cases.     

Tumeurs des deux surrénales. A propos d’un cas

Bilateral adrenal tumors are rare. We report a case of adrenal pheochromocytoma associated with a contralateral adrenocortical carcinoma in a 65-year-old woman. Her presenting symptoms, consisting of hypertension associated with headache, sweating and palpitations, suggested the diagnosis of pheochromocytoma, which was confirmed by measurement of catecholamine metabolites in her urine. Ultrasonography and computed tomography revealed bilateral solid adrenal masses with tissue enhancement after the injection of contrast medium. Based on these clinical, biological and morphological findings, the diagnosis of bilateral adrenal pheochromocytoma was made and bilateral adrenalectomy was performed. Histopathological examination revealed a pheochromocytoma in the right adrenal and an unsuspected adrenocortical carcinoma in the left adrenal gland. The postoperative course was uneventful, without recurrence at 4 years follow-up. Based on the present case and a literature review, we discuss the various characteristics of this unusual entity.     

A case of adrenal pheochromocytoma with contralateral adrenocortical adenoma

A case of a pheochromocytoma in the right adrenal gland and adrenocortical adenoma in the left adrenal gland of a 58-year-old male is reported. The patient was incidentally found to have a right adrenal tumor by ultrasonographic study. A computerized tomographic (CT) study and magnetic resonance image (MRI) study revealed bilateral adrenal tumors. The sizes of the right tumor and left tumor were 2.5 x 3.5 cm and 1.2 x 1.0 cm, respectively. The intensity of each tumor was different on T2-weighted MRI. 131I-MIBG scintigram showed the uptake of right adrenal gland. The existence of pheochromocytoma was confirmed by the elevated levels of catecholamines. We performed venous sampling to be certain whether the patient had unilateral or bilateral pheochromocytoma. As a result, bilateral adrenal pheochromocytoma was diagnosed. Therefore, we performed bilateral adrenalectomy. However, histopathological examination revealed right pheochromocytoma and left non-functioning adrenocortical adenoma.     

An operated case of multiple endocrine neoplasia type IIb and review of the Japanese literature

Multiple endocrine neoplasia, type IIb (MEN IIb) is a rare syndrome characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma and mucosal neuroma. A 35-year-old male patient with MEM IIb having megacolon, marfanoid habitus and no family history of the disease underwent surgery. Because MTC was present in both lobes, total thyroidectomy and modified neck dissection were performed. Pheochromocytoma was found bilaterally and bilateral adrenalectomy with adrenal autotransplantation in the rectus abdominis muscle was carried out. Postoperative course was satisfactory except for transient hypocalcemia and mild ileus. After the slow corticosteroid weaning process, his adrenocortical function was at the lower level within a normal range. In August 1986 (24 postoperative months), he was maintained by the administration of 10mg of hydrocortisone every three days, and calcitonin and CEA levels in sera were normal. We collected 15 cases reported in Japanese literatures. MTC and mucosal neuroma were found in all cases, whereas pheochromocytoma was present in 9 cases. Bilateral and multicentric occurrences were usual, and total thyroidectomy and bilateral adrenalectomy were, warranted. We believe that autotransplantation following bilateral adrenalectomy is a worthy alternative.     

Thyroidectomy for non-familial medullary carcinoma.

Two cases of non-familial medullary carcinoma of the thyroid which had thyroid tissue remaining after initial thyroidectomy were shown to contain residual, intra-glandular carcinoma at reoperation. This observation, the distribution of C cells in the normal thyroid gland and the lymph node spread of this carcinoma have led to the proposal of a bilateral 90 per cent upper pole thyroidectomy including the superior parathyroids for cases of non-familial medullary carcinoma. This operation removes all the C-cell-bearing area and leaves a small thyroid remnant at the lower pole for preservation of the inferior parathyroid glands. The operation is discussed with reference to these factors.     

Multiple endocrine neoplasia II A syndrome: relationship between age of the patient, levels of basal calcitonin and size of the thyroid tumor]

This paper presents our experience in four families having the multiple endocrine neoplasia (MEN) II-A syndrome, with a total of 19 affected patients. All had medullary thyroid carcinoma (MTC), 6 also had pheochromocytoma (PH) and 3 had hyperparathyroidism. The screening of the members of the families to measure basal and pentagastrin response calcitonin (CT) serum levels allowed an early diagnosis of medullary thyroid carcinoma, when lesions were only 1 mm in diameter. Measurement of vanillymandelic acid, catecholamines and metanephrines in 24-hour urine collections allowed the diagnosis of pheochromocytoma in patients, some of whom were asymptomatic. A clear relationship was found between the age of the patients, the basal serum calcitonin level and size of the MTC.     

Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2

We studied the gross and microscopic pathology of the adrenal gland in 69 cases of sporadic phenochromocytoma in order to develop a profile of the neoplasm to compare with that of pheochromocytoma observed in the syndrome of multiple endocrine neoplasia, type 2 (MEN 2). The results showed that sporadic pheochromocytoma was a unicentric (93%), unilateral (100%) neoplasm, which was associated with normal extratumoral adrenal medulla (100%). The findings contrast with those encountered in the adrenal gland in MEN 2, in which the tumor involvement is frequently multicentric, usually bilateral, and associated with extratumoral medullary hyperplasia in cases of early involvement. Therefore, the interpretation of the results of pathologic examination of a pheochromocytoma should be immediately communicated to the surgeon.     

Diagnosis of adrenal medullary diseases in patients with sporadic or hereditary medullary thyroid carcinoma. A report of 37 cases with 8-year follow-up study

Thirty-seven patients with medullary thyroid carcinoma were investigated to determine the status of adrenal medulla by computed tomography and 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy as well as measurements of urinary catecholamine excretion. Patients were followed up for 8 years in maximum. Fifteen patients belonged to multiple endocrine neoplasia type 2 including patients with incomplete phenotype. Computed tomography demonstrated adrenal tumors or enlargement in all 6 patients with urinary epinephrine (E) more than 30 micrograms/day, 4 of them were confirmed to have pheochromocytoma or adrenal medullary hyperplasia by surgery. In 2 patients with E less than 30 micrograms/day and epinephrine to norepinephrine (E/N) ratio more than 0.3 suggesting adrenal medullary hyperfunction, computed tomography revealed small adrenal tumors. Three of the remaining 7 patients with E less than 30 micrograms/day and E/N ratio less than 0.3 had equivocal enlargement of unilateral gland on computed tomography. 131I-MIBG scintigraphy demonstrated tracer uptake in adrenal glands with tumor more than 1cm in diameter. One of 2 adrenal glands with medullary hyperplasia showed a faint adrenal image on the scintiscan, but the other showed no tracer uptake. Pheochromocytoma became manifest in 4 patients during the follow-up period, 4, 13, 14 and 34 years after thyroid surgery. None of 22 patients with sporadic medullary thyroid carcinoma showed adrenal abnormalities on the examinations mentioned above.     

Medullary carcinoma of the thyroid gland

Nine cases of medullary carcinoma of the thyroid gland (MTC) are reported. Four of the carcinomas were of the familial type. Five of the patients were men and four were women. Patient age ranged from 23 to 66 years, with a mean age of 40 years. The median age of the four patients with the familial MTC was 32 years. A total or a subtotal thyroidectomy was performed in four and five patients, respectively, associated with a modified neck dissection in six patients with involved cervical lymph nodules. An underlying pheochromocytoma of the left adrenal was excised in one patient prior to thyroidectomy. In all cases the parathyroid glands were identified, and in two cases of familial MTC, in which they were grossly enlarged, the parathyroid glands were removed. Four patients died as a result of their disease within 3 years, whereas patients are well 4 to 12 years after surgery. The best chance of cure lies in early diagnosis and an aggressive surgical removal of the primary tumor and any cervical metastases.     

Diagnostic and operative problems in multiple pheochromocytomas.

Two children, aged 14 yr, with multiple pheochromocytomas are presented. Both patients had a positive family history. In the preoperative aortographies the intra-adrenal pheochromocytomas of both patients were well visualized, but not the extra-adrenal tumors of the first case. Chlorpromazine as an adrenergic blocking agent was successfully used in the preoperative treatment. Postoperative catecholamine excretion in the first case was repeatedly slightly increased indicating residual pheochromocytoma. In addition to the bilateral adrenal pheochromocytomas, multiple islet cell adrenomas and cholecystolithiasis were revealed at the operation of the second case. After bilateral adrenalectomy and total pancreaticoduodenectomy, regular follow-up examinations were carried out for 28 months. Hyperparathyroidism and signs of possible medullary thryoid carcinoma were discovered. Thus the patient had an unique pattern of MEA syndrome.     

Bilateral subtotal adrenal resection for bilateral pheochromocytomas in multiple endocrine neoplasia, type IIa: a case report

Our treatment philosophy for the management of the adrenal glands in patients with multiple endocrine neoplasia, type IIa has been bilateral total adrenalectomy. In the patient described, exceptional and pressing reasons necessitated preservation of adrenocortical function. Bilateral pheochromocytomas were resected with preservation of the adrenal cortices. Adrenocortical function was normal 36 months after resection. Although the patient remained symptom free, elevated basal immunoreactive plasma calcitonin levels suggested the presence of residual or metastatic medullary thyroid carcinoma. There was no evidence of recurrent pheochromocytoma.     

Medullary thyroid carcinoma and pheochromocytoma accompanied with nodular hyperplasia in multiple endocrine neoplasia type 2

Three patients with familial multiple endocrine neoplasia type 2 underwent total adrenalectomy and subsequently near-total or total thyroidectomy. The overt pheochromocytomas were present bilaterally in two patients and unilaterally in another patient. In addition, multiple nodules measuring a few mm in diameter were demonstrated in all adrenal medullas examined. All patients exhibited bilateral medullary thyroid carcinomas which varied in size from a few minute nodules accompanied by the microscopic C-cell hyperplasia to distinct large tumors. The thyroid C-cell hyperplasia appeared to be confined to the upper and middle thirds of the lateral lobe, and micronodules of the C-cell hyperplasia enlarged to coalesce, forming one large carcinoma mass. On the other hand, nodular hyperplasia of the chromaffin cells was distributed diffusely throughout the adrenal medulla and each nodule appeared to develop individually into a large pheochromocytoma. These findings suggested that, at least in the family members at a high risk for multiple endocrine neoplasia type 2, the development of both medullary thyroid carcinoma and pheochromocytoma was always preceded by a multicentric nodular hyperplasia. On the basis of the pathogenesis of these tumors, the most rational surgical approach was presented.