Pituitary Gangliocytoma Producing TSH and TRH: A Review of "Gangliocytomas of the Sellar Region".

PURPOSE: Pituitary gangliocytomas (GCs) are rare neuronal tumors that present with endocrinological disorders, such as acromegaly, amenorrhea-galactorrhea syndrome, and Cushing's disease. Most pituitary GCs coexist with pituitary adenomas pathologically and are diagnosed as mixed gangliocytoma-adenomas. Herein, we report a case of 45-year-old man who presented with the syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) and discuss the pathogenesis of pituitary GCs. METHODS: Pituitary magnetic resonance imaging showed an 8-mm homogeneous and poorly enhanced mass inside the pituitary gland. Endoscopic transsphenoidal surgery was performed under a preoperative diagnosis of thyrotroph adenoma. However, the tumor was finally diagnosed as gangliocytoma without an adenomatous component. The tumor was further analyzed via immunohistochemistry and electron microscopy. Additionally, we searched MEDLINE and PubMed for previously published cases of isolated pituitary GCs and analyzed the reported clinicopathological findings. RESULTS: The patient showed complete clinical and endocrinological recovery after an operation. The tumor was positive for thyrotropin (TSH), TSH-releasing hormone (TRH), Pit-1, GATA-2, and most neuronal markers. Electron microscopy demonstrated the presence of intracytoplasmic secretory granules and neuronal processes. Co-secreting hypothalamic and pituitary hormone inside the tumor indicated autocrine/paracrine endocrinological stimulation. CONCLUSION: Herein, we report a case of SITSH caused by an isolated pituitary gangliocytoma, expressing both TSH and TRH, which, to our best knowledge, is the first reported case of such a condition. The multidirectional differentiation and multihormonal endocrine characteristics of these tumors indicate that they are a member of neuroendocrine neoplasms, further supporting that they are derived from neural crest cells.

Retroperitoneal paravertebral ganglioneuroma: a multidisciplinary approach facilitates less radical surgery.

BACKGROUND: Ganglioneuroma (GN) of the adult is a rare benign tumour originating from neural crest-derived cells. In most cases, GN is found in the mediastinum or retroperitoneum incidentally and may present with unspecific symptoms caused by space-occupying effects. The correct diagnosis of a retroperitoneal mass is still a challenge. Nevertheless, a preoperatively confirmed diagnosis of GN may support the concept of a less radical approach and may help to prevent unnecessary morbidity or loss of function. CASE PRESENTATION: We report a case of a symptomatic retroperitoneal paravertebral GN in a 33-year-old woman. She has been referred with abdominal discomfort, lancinating pain in the right leg, headache and nausea. Magnetic resonance imaging revealed a solid paravertebral tumour adjacent to the psoas muscle. Computed tomography-guided core needle biopsy yielded the diagnosis of GN. The tumour was resected completely via a laparotomy. Immunohistopathological examinations confirmed a benign GN. CONCLUSIONS: Diagnostic studies and therapeutic interventions of retroperitoneal GN are discussed. In our case, a core needle biopsy preceding complete resection was helpful to prevent too extensive surgical approach.

Infrasellar pituitary gangliocytoma causing Cushing's syndrome.

INTRODUCTION: Pituitary gangliocytomas are uncommon neuronal tumours that may present with endocrine disorders, the most frequent being acromegaly caused by growth hormone hypersecretion. Cushing's syndrome is very rarely seen with gangliocytomas. MATERIAL AND METHODS: We report the unique case of a 62 year-old woman whose clinical picture and endocrine testing clearly demonstrated adrenocorticotropin (ACTH)-dependent Cushing's syndrome. Pituitary magnetic resonance imaging showed a 12-mm homogeneous, infra- and retrosellar mass first diagnosed as pituitary macroadenoma. Transsphenoidal surgery was performed and allowed complete resection of the tumour with sparing of normal anterior pituitary. Very low postoperative serum cortisol and ACTH levels were observed in the early postoperative period and the patient is still in remission 18 months after surgery, thus demonstrating that the resected lesion was entirely responsible for the clinical picture. RESULTS: Histological and immunocytochemical analyses demonstrated a benign tumour composed of mature neuronal cells suggestive of a gangliocytoma, expressing both ACTH and corticotropin-releasing hormone (CRH). The tumour was surrounded by a rim of pituitary tissue containing ACTH-producing endocrine cells. Careful analysis of the resected lesion did not reveal any pituitary microadenoma. We search literature for similar cases and retraced only nine cases of gangliocytomas associated with Cushing's syndrome. In most of them, the tumour was combined with either pituitary corticotroph adenoma or hyperplasia. CONCLUSIONS: Our case represents a unique case of an infrasellar pituitary gangliocytoma which was able to cause Cushing's syndrome by both direct ACTH production and CRH-induced stimulation of neighbour normal corticotroph cells.

Pheochromocytoma with histologic transformation to composite type, complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome.

OBJECTIVE: To describe the rare occurrence of histologic transformation of a pheochromocytoma to a composite type of tumor during a long-term follow-up, which was complicated by watery diarrhea, hypokalemia, and achlorhydria syndrome. METHODS: We report the case of a 12-year-old girl who presented with headache, hypertension, and elevated catecholamine levels in the blood and urine. A tumor was found in the right adrenal gland and resected. When she was 15 years of age, multiple metastatic nodules were found in the lung and liver. Intensive chemotherapy was ineffective, and she underwent follow-up with conservative therapy. At 25 years of age, she complained of diarrhea. Laboratory studies revealed hypokalemia and an increase in the level of serum vasoactive intestinal polypeptide (VIP). A year later, she died of extensive metastatic disease. The primary and recurrent tumors at autopsy were histologically examined. RESULTS: The primary tumor was pure pheochromocytoma, and the tumors at autopsy were a composite type of pheochromocytoma and ganglioneuroma. Only a few VIP-positive cells were found in the primary tumor, whereas both pheochromocytoma and ganglioneuroma cells of composite tumors were frequently positive for VIP. CONCLUSION: Our case showed histologic transformation from pheochromocytoma to a composite type of tumor during a 14-year clinical course, which was associated with additional hormone production and a change in symptoms. Careful attention should be paid to the alteration of endocrine symptoms and hormone levels during prolonged follow-up of pheochromocytoma in young patients.

Comparison of plasma metanephrines measured by a commercial immunoassay and urinary catecholamines in the diagnosis of pheochromocytoma.

BACKGROUND: The diagnosis of pheochromocytomas requires consideration among patients suffering from hypertension, unexplained spells, incidental adrenal masses, or a family history of pheochromocytoma. Accordingly, the diagnosis requires a biochemical test with high sensitivity and specificity. AIM: To compare plasma free metanephrines as measured by a commercial immunoassay and the 24-hour urinary excretion of catecholamines. METHOD: Plasma free metanephrines were measured in 185 patients suspected of pheochromocytoma. Concomitant measurements of urinary catecholamines were performed in 115 patients. Based on clinical findings, imaging and biochemistry 11 cases were found; 9 were diagnosed with pheochromocytoma, one patient with paraganglioma and one patient with ganglioneuroma. RESULTS: All patients with pheochromocytoma/paraganglioma had abnormally elevated concentrations of either plasma metanephrine or normetanephrine. The patient with ganglioneuroma had normal plasma metanephrine levels, corresponding to a sensitivity of 91%. In two patients where pheochromocytoma was excluded, plasma metanephrin or normetanephrine was above the reference level, corresponding to a specificity of 99%. Urinary catecholamines were determined in 10 of 11 patients with a positive diagnosis, and all 10 showed elevated levels of either urinary epinephrine or norepinephrine, including the patient with ganglioneuroma (equivalent to a sensitivity of 100%). Seven patients, in whom pheochromocytoma was excluded, had elevated urinary catecholamines (equivalent to a specificity of 94%). CONCLUSION: Measurement of plasma free metanephrines by immunoassay appears to be a useful diagnostic test in patients suspected of pheochromocytoma, with a high specificity as compared with urinary catecholamines. The latter may result in fewer false-positive findings, an outcome which may be particularly troublesome.

Virilizing adrenal ganglioneuroma in a woman with subclinical Cushing syndrome.

OBJECTIVE: To describe a patient with a virilizing adrenal ganglioneuroma and subclinical Cushing syndrome. METHODS: Detailed clinical, laboratory, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed. RESULTS: A 56-year-old postmenopausal woman was referred for evaluation of a 3.6- by 3.0-cm right adrenal mass, which had been diagnosed during a work-up for hirsutism. A bilateral oophorectomy done 2 months before the presentation failed to correct the elevated testosterone levels. On examination, she had severe hirsutism on her face, chest, back, and extremities, as well as male pattern baldness and clitoromegaly. Biochemical evaluation showed elevated total and free serum testosterone levels of 319 ng/dL (reference range, 20 to 70) and 78 pg/mL (reference range, 1 to 9), respectively, values in the adult male range. The serum dehydroepiandrosterone sulfate level was 117 microg/dL (reference range, 10 to 152), and the urine free cortisol was 10.4 microg/24 h (reference range, <45). A laparoscopic adrenalectomy revealed a 5.0-cm adrenal ganglioneuroma containing nests of adrenocortical cells. On the first day postoperatively, the serum cortisol level was <1.0 microg/dL. At 1 month after adrenalectomy, the total and free testosterone levels had declined to 16 ng/dL and 3.1 pg/mL, respectively. At 2 months postoperatively, normal results of a cosyntropin stimulation test (basal and peak cortisol levels of 13.6 and 20.0 microg/dL, respectively) indicated recovery of the hypothalamic-pituitary-adrenal axis. CONCLUSION: To our knowledge, this is the first case report of a virilizing adrenal ganglioneuroma with this unique pathologic finding and concomitant subclinical Cushing syndrome.

Association of pheochromocytoma and ganglioneuroma: unusual finding in neurofibromatosis type 1.

OBJECTIVE: To report a rare case of association of pheochromocytoma and ganglioneuroma in an asymptomatic patient with neurofibromatosis type 1 (NF1) and to discuss the importance of annual biochemical and imaging studies. METHODS: We present the clinical, laboratory, and pathology findings in a 41-year-old woman with NF1 and review the pertinent literature. RESULTS: A 41-year-old woman with NF1 presented for a routine gynecologic examination, at which time a right adrenal mass (4 by 3 cm) was discovered by abdominal ultrasonography and confirmed by abdominal computed tomographic scans and magnetic resonance imaging. The patient was normotensive and complained only of discrete essential tremors. Biochemical studies showed a serum epinephrine level of 195 pg/mL (normal, <100) and a 24-hour urine epinephrine excretion of 55 microg (normal, <20), findings consistent with pheochromocytoma. Metaiodobenzylguanidine scintigraphy revealed uptake in the right adrenal gland, with no evidence of metastatic lesions. Before surgical treatment, the patient received an alpha-adrenergic antagonist for 30 days. Laparoscopic excision of the right adrenal gland yielded excellent postoperative results. Surgical pathology revealed a multinodular mass composed of pheochromocytoma and ganglioneuroma. In patients with NF1 (von Recklinghausen's disease), a tumor consisting of pheochromocytoma and ganglioneuroma is rare and may be more aggressive than pheochromocytoma alone. An asymptomatic catecholamine-producing tumor may cause substantial morbidity and mortality, especially in patients who are undergoing surgical intervention or are under other stressors. CONCLUSION: The current guidelines for managing patients with NF1 are an annual history and physical examination. Because of the increased prevalence of pheochromocytoma and ganglioneuroma in patients with NF1, and the potential associated adverse effects, we emphasize the importance of periodic clinical evaluation with biochemical testing and imaging studies.

Laparoscopic resection of large adrenal ganglioneuroma.

We report on a 23-year-old woman with a right adrenal tumor 13 cm in diameter who was treated by laparoscopy. The patient was asymptomatic, and the tumor was incidentally diagnosed on abdominal ultrasonography. A subsequent computed tomography (CT) of the abdomen confirmed a 12 x 7 x 8-cm homogenous mass of the right adrenal. Magnetic resonance imaging (MRI) showed a solid mass measuring 13 x 7 x 7.5 cm arising from the right adrenal. Laparoscopic complete excision of the mass was accomplished through a transabdominal lateral approach. The postoperative period was uneventful, and the patient was discharged on the second postoperative day. Histology was consistent with an adrenal ganglioneuroma. Two years later, there is no evidence of recurrence on abdominal CT scan.

Polysialylated neural cell adhesion molecule in childhood ganglioneuroma and neuroblastoma of different histological grade and clinical stage.

BACKGROUND AND AIMS: Neuroblastoma cells express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which normally becomes restricted to a few neural regions after embryogenesis. The aim of the present study was to evaluate PSA-NCAM as a marker in childhood neuroblastoma. PATIENTS/METHODS: We studied the expression of PSA-NCAM on tumor specimens and in sera of 27 children, altogether, with ganglioneuroma and neuroblastoma of different histological grades and clinical stages. For both methods, immunohistochemistry on 5-microm frozen sections and immunoluminescence serum assay, the polysialic-acid-specific monoclonal antibody 735 was used. RESULTS: PSA-NCAM expression was highest in patients with undifferentiated neuroblastoma and advanced stages of disease, whereas children with differentiated tumor types and low clinical stages had distinctly reduced or no reactivity in immunohistochemistry and, simultaneously, normal serum levels. PSA-NCAM expression correlated with other prognostic and diagnostic markers, such as MYCN gene amplification, and serum concentrations decreased during successful treatment. CONCLUSIONS: We conclude that PSA-NCAM, both immunohistochemically and in the serum, is a promising candidate for another useful diagnostic and prognostic tumor marker in childhood neuroblastoma.

Pancreastatin immunoreactivity in favourable childhood neuroblastoma and ganglioneuroma.

Neuroblastoma and its benign counterpart, ganglioneuroma, are tumours of the sympathetic nervous system, and known to produce and release various regulatory peptides. In this study, pancreastatin, a 52 amino acid regulatory peptide derived from chromogranin A, was analysed in plasma and tumour tissue from 15 children with neuroblastoma and one with ganglioneuroma. Detectable pancreastatin immunoreactivity (> 1.9 pmol/l) was found in plasma in 13 of 15 children with highest concentrations in samples from children with favourable outcome (P < 0.05). In tumour tissue, non-metastatic tumours showed higher concentrations of pancreastatin immunoreactivity (P < 0.05). However, the highest concentrations were detected in tumours from children with favourable prognosis, regardless of clinical stage at presentation (P < 0.01). Serial plasma samples from one child with neuroblastoma and one with ganglioneuroma were investigated and showed significant systemic release of pancreastatin immunoreactivity during surgical manipulation of tumours with high pancreastatin concentrations. It is concluded that pancreastatin immunoreactivity may be detected in plasma samples and tumour extracts from children with neuroblastoma and ganglioneuroma. Systemic release during surgery implied tumour origin of elevated plasma pancreastatin. Furthermore, higher pancreastatin concentrations correlate with tumour differentiation, localised clinical stage and a favourable outcome for children with these tumours. It is suggested that pancreastatin in plasma and tumour tissue may be utilised as a marker indicating favourable tumour behaviour.

[A case of endocrinologically active retroperitoneal ganglioneuroma].

A 27-year-old female complained of right upper abdominal pain. Computed tomography revealed a retroperitoneal tumor located between the right kidney and the vena cava. The preoperative value of noradrenaline in urine was high, 221.1 micrograms/day. She underwent surgery and the resected tumor was 330 g in weight and 8 x 6 x 4 cm in size. Histopathological diagnosis was ganglioneuroma. Retroperitoneal ganglioneuroma is rare and only 82 cases including our case have been reported in Japan, in recent years, adult cases are increasing in number. Endocrinological abnormalities were observed in 9 cases. Although six of the 9 patients were younger than 5 years old, the others were adults. These adult patients had no endocrinological symptoms.

Virilizing adrenal ganglioneuroma containing Leydig cells.

An adrenal medullary ganglioneuroma containing Leydig cells and revealed by a virilizing syndrome in a 56-year old woman is presented. The syndrome, associating with masculinization an elevated serum testosterone level and a normal urinary 17 ketosteroids, is uncommon in adrenal tumours. The tumour was located by computed tomographic (CT) scan and treated by right adrenalectomy. Microscopic examination showed typical features of an adrenal medullary ganglioneuroma containing Leydig cells with Reinke crystalloids. Positive immunohistochemical study confirmed the testosterone secreting nature of the cells. The presence of Leydig cells in the adrenal gland is discussed according embryogenic studies: 1. the common origin of the gonad and the adrenal cortex from the coelomic epithelium, 2. the vicinity of adrenocortical gland and gonad during embryogenesis, 3. the thecal metaplasia of mesenchymal cells, 4. the development of Leydig cells from Schwann cells. Fourth case published in the world literature.

Neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma.

1. We investigated the usefulness of neuropeptide Y as a plasma marker for phaeochromocytoma, ganglioneuroblastoma and neuroblastoma using a simple and highly sensitive r.i.a. for human neuropeptide Y. 2. Plasma immunoreactive neuropeptide Y concentrations were measured without extraction in plasma samples (100 microliters) from patients with various diseases. 3. The plasma immunoreactive neuropeptide Y concentration in patients with phaeochromocytoma (172.3 +/- 132.4 pmol/l, mean +/- SD, n = 23) was significantly higher than that in healthy adult subjects (40.1 +/- 10.1 pmol/l, n = 40, P < 0.0001). The plasma immunoreactive neuropeptide Y concentrations in patients with ganglioneuroblastoma (590.7 +/- 563.6 pmol/l, n = 6) and patients with neuroblastoma (566.9 +/- 524.4 pmol/l, n = 15) were significantly higher than those in control children (1-9 years old, 82.2 +/- 39.9 pmol/l, n = 72, P < 0.0001). 4. The plasma immunoreactive neuropeptide Y concentration in patients with essential hypertension (34.0 +/- 3.7 pmol/l, n = 18) was within the normal range, but in patients with chronic renal failure undergoing maintenance haemodialysis (192.1 +/- 68.0 pmol/l, n = 25) and in non-dialysed patients with chronic renal failure (85.1 +/- 23.1 pmol/l, n = 7) it was significantly higher than that in healthy adult subjects (P < 0.0001). 5. Eighty-seven per cent of the patients with phaeochromocytoma, 67% of the patients with ganglioneuroblastoma and 80% of the patients with neuroblastoma showed plasma immunoreactive neuropeptide Y concentrations higher than the upper limits in the control subjects [62 pmol/l (adult) and 160 pmol/l (children)].(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y as a marker in pediatric neuroblastoma.

Neuropeptide Y (NPY) was investigated as a possible tumor marker in pediatric patients with tumors of the sympathetic nervous system. Seven patients with neuroblastoma, 3 patients with ganglioneuroblastoma, and 2 with ganglioneuroma, were compared with 12 matched healthy controls and 34 tumor controls. NPY-like immunoreactivity (NPYLI) was analyzed in extracted plasma using a competitive radioimmunoassay. At diagnosis, plasma NPYLI was significantly increased (p less than .001) in the neuroblastoma patients (352 +/- 99 pM; mean +/- SEM) when compared with healthy controls (36 +/- 4 pM) and tumor controls (30 +/- 2 pM). Ganglioneuroblastoma and ganglioneuroma patients had lower levels (57 +/- 8 pM) than neuroblastoma patients but still significantly higher than the controls. In all patients with sympathetic tumors, the NPYLI level was decreased after treatment. Five neuroblastoma patients relapsed; all had increasing NPYLI levels. In 3 of these patients, incresing NPYLI was the first sign of relapse. Plasma NPYLI correlated well to urinary levels of homovanillic acid. NPY in plasma (NPYLI) may be a clinically useful marker of pediatric neuroblastoma for diagnosis and differential diagnosis. NPYLI correlates well with the clinical course and can be the first sign of relapse. Plasma determinations of NPYLI make it possible to monitor rapid alterations of disease.

Occult ganglioneuroma with diarrhea: localization by venous catecholamines.

Neural crest tumors can be complicated by secretory diarrhea mediated by vasoactive intestinal peptide (VIP). An eight-month-old male with a several-month history of secretory diarrhea is described. Elevated urine vanillylmandelic acid (VMA), total urine catecholamines, and plasma VIP indicated that a neural crest tumor was responsible for his protracted diarrhea. An extensive search for the tumor including CT scans of his head, neck, thorax, abdomen, and pelvis was unrevealing. A selective vena caval catheterization showed elevated catecholamines in a sample obtained above the renal veins. Subsequent laparotomy disclosed a benign ganglioneuroma arising from the left adrenal; the diarrhea resolved after its removal. Selective venous sampling proved useful in establishing the tumor's location where other techniques had been unsuccessful.

Vasoactive intestinal polypeptide (VIP) in children with neural crest tumours.

The concentration of vasoactive intestinal polypeptide (VIP) in plasma was measured in 22 children with neural crest tumours (NCT) during a 5-year period; the mean concentration of VIP in plasma was 22.5 pmol/l (interval 2.0-95.0 pmol/l). To establish a reference interval the plasma concentration of VIP was measured in 41 children without tumours; the mean concentration of VIP in plasma was 6.2 pmol/l (interval 0.5-19.0 pmol/l). Of the 22 children with NCT 16 had a plasma concentration of VIP within the normal range while 6 children (27%) had elevated plasma concentration of VIP between 28 and 95 pmol/l. Only one child, whose plasma concentration of VIP was 95 pmol/l had diarrhoea. Elevated plasma concentration of VIP in children with NCT but no diarrhoea has not previously been described. The urinary excretion of vanillylmandelic acid (VMA) was increased in 18 of the children with NCT (82%). In 2 of the children with normal excretion of VMA the concentration of VIP in plasma was elevated. Thus, the plasma concentration of VIP may be a supplement to VMA as a tumour marker in some cases of NCT.