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Pheochromocytoma-Islet Cell Tumor Syndrome

Pheochromocytoma and islet cell tumor are endocrine neoplasms that may occur in families harboring mutations leading to von Hippel-Lindau disease (VHL), multiple endocrine neoplasia (MEN), or neurofibromatosis type 1 (NF1), among others. These are genetic disorders, so familial anamnesis usually reveals additional members of the family to be affected, too. Notwithstanding, rare cases of familial pheochromocytoma and islet cell tumor could not be related to mutations known to cause either of the aforementioned conditions. Pheochromocytoma-islet cell tumor syndrome (PICT) has thus been proposed as a distinct entity, but its causes have not been elucidated, and its existence remains to be proven.


Presentation

PICT patients may present with an islet cell tumor of the pancreas, with pheochromocytoma, or both. The concomitant occurrence of adrenal and pancreatic neoplasms has been reported in 27% of all patients [1]. In any case, signs and symptoms correspond to the local and systemic effects of the endocrine neoplasms. Thus, in the absence of a positive family history, sporadic tumors cannot be distinguished from hereditary variants.

Pheochromocytoma was detected in the vast majority of PICT patients and proved to be bilateral in more than half of them. Symptom onset may occur in childhood but is usually delayed until the second decade of life. Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients [1] [2]. Beyond that, easy fatigability and weakness, flushing, blurred vision, paresthesias, tremor, dyspnea, and fainting have been described [1].

About one-third of PICT patients is diagnosed with island cell tumors, but multifocal neoplasms are rare. PICT-related island cell tumors have been found to be non-functional, and in the absence of pheochromocytoma, the clinical picture is dominated by local mass effects. This condition has been described in a single patient only, in a man who presented with abdominal pain and jaundice. He suffered from chronic pancreatitis causing stenosis of the sphincter of Oddi, cholecystitis, and cholelithiasis. During advanced stages of the disease, he developed gastrointestinal hemorrhages, hematemesis, and melena [1].

One of Carney's patients showed cafe-au-lait spots, measuring up to 4 cm in diameter, and axillary freckling. Additional lesions suggestive of NF1 have neither been detected in the index case nor been observed in the affected family [1].

Weakness
  • Beyond that, easy fatigability and weakness, flushing, blurred vision, paresthesias, tremor, dyspnea, and fainting have been described. About one-third of PICT patients is diagnosed with island cell tumors, but multifocal neoplasms are rare.[symptoma.com]
Pallor
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Dyspnea
  • This tumor may compress the recurrent laryngeal nerve, the esophagus, or trachea, and induce hoarseness, dysphagia, or dyspnea.[symptoma.com]
Aspiration
  • Tissue samples may be obtained by means of endoscopic ultrasound-guided fine-needle aspiration. Both pancreatic adenomas and carcinomas have been found in PICT patients.[symptoma.com]
Diarrhea
  • Facial flushing and diarrhea have been related to this type of endocrine neoplasia, as have been ganglioneuromas of the gastrointestinal tract. MEN type 2 is related to mutations of the RET gene.[symptoma.com]
Abdominal Pain
  • This condition has been described in a single patient only, in a man who presented with abdominal pain and jaundice. He suffered from chronic pancreatitis causing stenosis of the sphincter of Oddi, cholecystitis, and cholelithiasis.[symptoma.com]
Nausea
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Vomiting
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Hypertension
  • […] are generally administered in this context. β-sympatholytics may actually worsen hypertension.[symptoma.com]
Tachycardia
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Blurred Vision
  • Beyond that, easy fatigability and weakness, flushing, blurred vision, paresthesias, tremor, dyspnea, and fainting have been described. About one-third of PICT patients is diagnosed with island cell tumors, but multifocal neoplasms are rare.[symptoma.com]
Axillary Freckling
  • One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1.[symptoma.com]
Cafe-Au-Lait Spots
  • One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1.[symptoma.com]
Freckles
  • One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1.[symptoma.com]
Flushing
  • Facial flushing and diarrhea have been related to this type of endocrine neoplasia, as have been ganglioneuromas of the gastrointestinal tract. MEN type 2 is related to mutations of the RET gene.[symptoma.com]
Axillary Freckling
  • One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1.[symptoma.com]
Suggestibility
  • Additional lesions suggestive of NF1 have neither been detected in the index case nor been observed in the affected family.[symptoma.com]
Headache
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Dizziness
  • Pheochromocytoma frequently induces paroxysmal hypertension with headaches, dizziness, nausea and vomiting, sweating, pallor, tachycardia, and palpitations, and these are the most common presenting symptoms of PICT patients.[symptoma.com]
Tremor
  • Beyond that, easy fatigability and weakness, flushing, blurred vision, paresthesias, tremor, dyspnea, and fainting have been described. About one-third of PICT patients is diagnosed with island cell tumors, but multifocal neoplasms are rare.[symptoma.com]
Paresthesia
  • Beyond that, easy fatigability and weakness, flushing, blurred vision, paresthesias, tremor, dyspnea, and fainting have been described. About one-third of PICT patients is diagnosed with island cell tumors, but multifocal neoplasms are rare.[symptoma.com]

Workup

To date, the causes of PICT remain unknown, so its diagnosis relies on anamnestic data, clinical findings and the exclusion of other diseases predisposing to endocrine tumors.

The families described by Carney and colleagues seemed to harbor a gene for autosomal dominant PICT, so the patient should be asked whether endocrine anomalies had been diagnosed or suspected in previous generations. It should be noted, though, that familial pheochromocytoma and islet cell tumor due to VHL, MEN, and NF1, which are the main differential diagnoses, are all inherited in an autosomal dominant manner. The clinical presentation may tip the scale in either direction: The phenotypic spectra of VHL, MEN, and NF1 are broader than that of PICT:

  • VHL typically manifests with renal involvement, with hematuria being a common presenting symptom indicating multiple renal cysts or renal cell carcinoma. Hemangioblastomas developing in the retina or central nervous system interfere with vision or trigger neurological symptoms, while VHL patients with phaeochromocytoma present as described above. Pancreatic neoplasms are less frequently diagnosed but may develop in these same individuals [3]. VHL is caused by mutations of the VHL gene [4].
  • Functional neoplasms of the parathyroid glands are very common in those suffering from MEN type 1, and they are seen in a significant share of MEN type 2 patients [5]. Excess secretion of parathyroid hormones results in hyperparathyroidism, the mobilization of osseous calcium, pathological fractures, hypercalcemia, nephrolithiasis, and nephrocalcinosis. In the course of hypercalcemia, peptic ulcers and mental disorders may be developed. Furthermore, MEN type 1 may manifest in pituitary adenoma and non-endocrine tumors like angiofibroma, collagenoma, and lipoma [6]. The disease is caused by mutations of the MEN1 gene [7].
  • Medullary thyroid cancer is the clinical hallmark of MEN type 2. This tumor may compress the recurrent laryngeal nerve, the esophagus, or trachea, and induce hoarseness, dysphagia, or dyspnea. Facial flushing and diarrhea have been related to this type of endocrine neoplasia, as have been ganglioneuromas of the gastrointestinal tract. MEN type 2 is related to mutations of the RET gene.
  • Islet cell tumors are almost exclusively seen in patients suffering from MEN type 1, while adrenal pheochromocytoma is more typical of MEN type 2 [8]. Accordingly, both endocrine neoplasms had long since been considered components of separate and mutually exclusive entities. After the exclusion of VHL, their concomitant occurrence may thus be interpreted as a strong indicator of PICT [2].
  • One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1. Such dermatological findings may warrant the sequencing of the NF1 gene, even in the absence of neurofibromas and Lisch nodules. PICT-like tumors are rare complications of NF1.

Regardless of the underlying disease, pheochromocytoma is suspected in patients with elevated levels of plasma and urinary catecholamines, total and fractionated metanephrines, and vanillylmandelic acid. Inconclusive findings can be clarified by means of a clonidine suppression test. Furthermore, adrenal masses and metastases, if present, should be visualized employing diagnostic imaging techniques like computed tomography or magnetic resonance imaging. Clinically manifest pheochromocytoma usually measures several centimeters in diameter and can be detected sonographically, but this approach is not recommended for the early detection of neoplasms in predisposed patients [9].

Laboratory analyses of blood samples are rarely helpful to detect non-functional island cell tumors, but may reveal the development of neuroendocrine active neoplasms. With regard to the former, endoscopic ultrasound and computed tomography may be used to depict pancreatic masses. When traditional imaging fails to confirm the tentative diagnosis or metastases are suspected, magnetic resonance imaging or somatostatin-receptor scintigraphy may be employed [10]. Contrary to pheochromocytoma, histopathological studies should be carried out to assess the tumor's malignancy. Tissue samples may be obtained by means of endoscopic ultrasound-guided fine-needle aspiration. Both pancreatic adenomas and carcinomas have been found in PICT patients [1].

Multiple Renal Cysts
Pneumoperitoneum
  • Regardless of adequate premedication, utmost attention to the patient's blood pressure is required during intubation, the creation of pneumoperitoneum, and the manipulation of the adrenal gland.[symptoma.com]

Treatment

Causal therapy is not available, but patients may become asymptomatic after the removal of adrenal and/or pancreatic masses.

Surgical excision is the most effective therapy of PICT-associated pheochromocytoma:

  • To reduce the risk of a hypertensive crisis, the preoperative management of blood pressure is crucial in patients with pheochromocytoma. α-sympatholytics like phenoxybenzamine are generally administered in this context. β-sympatholytics may actually worsen hypertension. Regardless of adequate premedication, utmost attention to the patient's blood pressure is required during intubation, the creation of pneumoperitoneum, and the manipulation of the adrenal gland [9].
  • The possible need for corticosteroid replacement therapy and the likelihood of recurrence should be considered before choosing a more or less radical approach, but no such data are available for PICT patients. In those suffering from VHL or MEN type 2, tissue-sparing, partial adrenalectomy is usually preferred to preserve adrenocortical function [11] [12].
  • After surgery, hypotension may become an issue. Volume expansion has been recommended to avoid this phenomenon [9].

Similarly, surgery is the main treatment of islet cell tumors. Depending on the size and location of the pancreatic tumor, enucleation, pancreaticoduodenectomy, central pancreatectomy, or distal pancreatectomy may be carried out [10].

In case of metastatic disease and curative intent, a multidisciplinary approach is required. Surgery remains the cornerstone of management, but should possibly be complemented by high-dose 131I-MIBG scintigraphy, radiofrequency ablation, and the embolization of metastases [9] [10]. Data regarding the efficacy of these therapies in PICT cannot be provided, though.

Otherwise, palliative treatment for symptomatic relief should be offered [9].

Prognosis

PICT follows a progressive, possibly fatal course. Adrenal and pancreatic tumors may metastasize to lymph nodes, to the liver, kidneys, and peritoneal cavity [1].

Etiology

PICT is a hereditary disorder whose triggers remain elusive. Genealogical analyses were performed in the three families described by Carney et al., and autosomal dominant inheritance was suspected in all of them. Presumably, PICT skipped a generation in at least one of these families, so the penetrance of the underlying mutation is assumed to be incomplete [1].

Epidemiology

A total of eleven PICT patients have been described in the early 1980s; no further cases have been reported since then [1] [2]. All patients were attended in the United States and belonged to three unrelated families with Franco-Irish, Slavic, and Swedish background. Both males and females were diagnosed with PICT, and their age at symptom onset ranged from 5 to 53 years. Pheochromocytoma was diagnosed at a mean age of 22 years [1].

Sex distribution
Age distribution

Pathophysiology

Due to knowledge gaps regarding the causes of PICT, it can only be speculated about the pathogenesis of the disease. Related disorders, namely VHL, MEN, and NF1, have all been related to heterozygous mutations of tumor suppressor genes (VHL, MEN1, and NF1) or proto-oncogenes (RET). They are unlikely to trigger cancerogenesis in the absence of a so-called "second hit". According to Knudson's theory, tumors only develop upon the acquisition of a second mutation affecting the wild-type allele of the tumor suppressor [13] [14] or proto-oncogene [15]. It may be assumed that PICT follows a similar path, but this hypothesis cannot be proven until the underlying gene defect is identified.

Prevention

Since the molecular biological causes of PICT remain unknown, prenatal diagnosis is not currently feasible. Nevertheless, genealogical analyses may be realized to estimate the risk of individual family members to be carriers of the pathogenic mutation. Those who might have inherited the causal mutation should be included in screening programmes for the early detection of adrenal and pancreatic tumors. Additionally, symptoms consistent with PICT should raise suspicion as to the development of such neoplasms, even if they couldn't be detected during the most recent examination. Annual screenings should be offered from childhood [1].

Summary

In 1980, Carney et al. described an increased incidence of pheochromocytoma and islet cell tumor in three families. The results of genealogical analyses suggested the autosomal dominant inheritance of a predisposition to the respective endocrine neoplasms. Nevertheless, clinical data argued against VHL, MEN, and NF1, which had previously been related to these adrenal and pancreatic tumors: Neither did any of the patients show additional features characteristic of the aforementioned disorders, nor did they mention such features in familial anamnesis. Thus, the authors postulated they were describing a new syndrome, which has subsequently been named PICT [1].

No further cases have been reported to date, and the existence of PICT as a separate entity is doubted by part of the scientific community.

Patient Information

While pheochromocytoma is a tumor of the adrenal gland, an islet cell tumor develops in the pancreas. Thus, both types of neoplasms derive from neuroendocrine tissues. Several hereditary disorders have been described that predispose for the development of neuroendocrine tumors, namely von Hippel-Lindau disease (VHL), multiple endocrine neoplasia (MEN), and neurofibromatosis type 1 (NF1). Patients suffering from VHL, MEN, or NF1 usually present additional symptoms, though. The diagnosis of these diseases relies on anamnestic data, clinical findings, laboratory results, and genetic studies.

In 1980, three families have been reported where several family members were diagnosed with pheochromocytoma and/or islet cell tumor. Surprisingly, neither patient presented further symptoms that would have been suggestive of VHL, MEN, or NF1, and no such symptoms have been mentioned in familial anamnesis. The authors postulated they were describing a new syndrome, which has subsequently been named pheochromocytoma-islet cell tumor syndrome (PICT). It was inherited in an autosomal dominant manner but could not be related to a pathogenic mutation. Also, no additional cases have been reported to date, so the existence of PICT as a separate entity is doubted by part of the scientific community.

References

Article

  1. Carney JA, Go VL, Gordon H, Northcutt RC, Pearse AG, Sheps SG. Familial pheochromocytoma and islet cell tumor of the pancreas. Am J Med. 1980; 68(4):515-521.
  2. Zeller JR, Kauffman HM, Komorowski RA, Itskovitz HD. Bilateral pheochromocytoma and islet cell adenoma of the pancreas. Arch Surg. 1982; 117(6):827-830.
  3. FJ O'Brien, Danapal M, Jairam S, et al. Manifestations of Von Hippel Lindau syndrome: a retrospective national review. Qjm. 2014; 107(4):291-296.
  4. Nielsen SM, Rhodes L, Blanco I, et al. Von Hippel-Lindau Disease: Genetics and Role of Genetic Counseling in a Multiple Neoplasia Syndrome. J Clin Oncol. 2016; 34(18):2172-2181.
  5. Marx SJ, Lourenco DM. Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory Tissue. Horm Metab Res. 2017; 49(11):805-815.
  6. Gaztambide S, Vazquez F, Castaño L. Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1). Minerva Endocrinol. 2013; 38(1):17-28.
  7. Falchetti A. Genetics of multiple endocrine neoplasia type 1 syndrome: what's new and what's old. F1000Res. 2017; 6.
  8. Tsang VH, Tacon LJ, Learoyd DL, Robinson BG. Pheochromocytomas in Multiple Endocrine Neoplasia Type 2. Recent Results Cancer Res. 2015; 204:157-178.
  9. Farrugia FA, Martikos G, Tzanetis P, et al. Pheochromocytoma, diagnosis and treatment: Review of the literature. Endocr Regul. 2017; 51(3):168-181.
  10. Amin S, Kim MK. Islet Cell Tumors of the Pancreas. Gastroenterol Clin North Am. 2016; 45(1):83-100.
  11. Schmid S, Gillessen S, Binet I, et al. Management of von Hippel-Lindau Disease: An Interdisciplinary Review. Oncol Res Treat. 2014; 37(12):761-771.
  12. Scholten A, Valk GD, Ulfman D, Borel Rinkes IH, Vriens MR. Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg. 2011; 254(6):1022-1027.
  13. Ganeshan D, Menias CO, Pickhardt PJ, et al. Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review. Radiographics. 2018; 38(3):849-866.
  14. Pannett AA, Thakker RV. Somatic mutations in MEN type 1 tumors, consistent with the Knudson "two-hit" hypothesis. J Clin Endocrinol Metab. 2001; 86(9):4371-4374.
  15. Iwashita T, Murakami H, Kurokawa K, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000; 268(3):804-808.

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Last updated: 2019-07-11 19:56