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].

• Weight Loss

  Chest pain A pancreatic NET that makes hormones can cause symptoms like: Dizziness, weakness, and fast heartbeat Headaches, a frequent need to pee, hunger, thirst, and weight loss Heartburn, pain in your belly, and diarrhea Even NETs that don't make [webmd.com]

  loss or gain Vomiting Wheezing Oncology Navigators Every step of neuroendocrine tumor treatment, from a cancer diagnosis and treatment to forming a survivorship plan, comes with different needs and issues that should be addressed. [pennmedicine.org]

  loss Symptomatic spells The symptoms listed above may be constant, or they may occur, or get stronger, occasionally. [mayoclinic.org]

  She denied having a loss of appetite but admitted to a weight loss of approximately 9.0 kg over the previous year. [mayoclinicproceedings.org]

  Other presenting symptoms can be anemia, stomatitis, and weight loss, but these are often absent. VIPomas occur in less than 1% of MEN1 patients. Presenting symptoms can include watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). [emedicine.medscape.com]

• Weakness

  Onset may be gradual or fulminant, and with progression, patients may develop bullae, paresthesias, motor weakness, and compartment syndrome. Forty to 60% of cases have capillary involvement, which may result in irreversible venous gangrene. [ebmedicine.net]

  Fatigue Nausea and vomiting Weight loss When a cancerous NET is in the lung, you might have: A cough Shortness of breath Whistling when you breathe, called wheezing Chest pain A pancreatic NET that makes hormones can cause symptoms like: Dizziness, weakness [webmd.com]

  In extremely rare cases, the acute occurrence of flushing, blood pressure changes, weakness, palpitations, faintness and wheezing constitutes a carcinoid crisis that can be life-threatening. [rarediseases.org]

  […] as cytoplasm showing no staining with positive staining for the internal control; and weak–diffuse pattern as tumours with a cytoplasmic blush lacking definite granularity. [ncbi.nlm.nih.gov]

  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]

• Congestive Heart Failure

  heart failure tachycardia Neuro: cerebral hemorrhage Skin: axillary freckling cafe-au-lait spots sweating Misc: familial pheochromocytoma usually bilateral Clinical features from OMIM: 171420 MalaCards organs/tissues related to Pheochromocytoma--Islet [malacards.org]

  heart failure Cardiac failure Cardiac failures Heart failure [ more ] 0001635 Elevated urinary norepinephrine 0003345 Episodic hypertension Intermittent high blood pressure 0000875 Hypercalcemia High blood calcium levels Increased calcium in blood [ [rarediseases.info.nih.gov]

• Pallor

  Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). [ncbi.nlm.nih.gov]

  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]

  […] sense of doom Epigastric pain Flank pain Constipation Clinical signs associated with pheochromocytomas include the following: Hypertension: Paroxysmal in 50% of cases Postural hypotension: From volume contraction Hypertensive retinopathy Weight loss Pallor [emedicine.medscape.com]

  The clinical presentation of these tumors can overlap with other clinical conditions with non-specific symptoms, such as tachycardia, diaphoresis, pallor, anxiety, headaches, panic attacks, and sensation of sudden death. [frontiersin.org]

• Hodgkin Lymphoma

  Gene ATM Component Cancers/Tumors Breast, pancreatic (heterozygous carriers or one mutation) Non-Hodgkin lymphoma, leukemia, central nervous system (CNS) cancers, gastric cancer, uterine cancer, basal cell carcinoma (BCC), ovarian dysgerminomas (autosomal [utswmed.org]

• Dyspnea

  This tumor may compress the recurrent laryngeal nerve, the esophagus, or trachea, and induce hoarseness, dysphagia, or dyspnea. [symptoma.com]

  During admission, he had acute dyspnea with desaturation but no chest pain at ten days after admission. [ncbi.nlm.nih.gov]

• Diarrhea

  In October 1993, she experienced watery diarrhea. The diarrhea continued for 2 months, at which time she was hospitalized. [mayoclinicproceedings.org]

  Watery diarrhea, hypokalemia and achlorhydria syndrome due to an adrenal pheochromocytoma. [wjgnet.com]

  A rare case of watery diarrhea, hypokalemia and achlorhydria syndrome caused by pheochromocytoma. [bmccancer.biomedcentral.com]

  You might get a lump or have problems like: Diarrhea Heartburn Pain Continued Take Action If you've had symptoms like these, see a doctor who's experienced in treating NETs, Chan says. [webmd.com]

  The diarrhea may be so severe that vital nutrients of the body, such as potassium and water, are depleted creating life-threatening electrolyte imbalance. [rarediseases.org]

• Abdominal Pain

  However, because they originate from hormone-producing tissues, the symptoms they cause can be linked to the release of various hormones into your bloodstream, causing: Abdominal pain A feeling of abdominal fullness Anxiety attacks Clammy skin Diarrhea [pennmedicine.org]

  Case: A 40-year-old patient admitted to our hospital with complaint of abdominal pain. Abdominal MRI performed in the urology department revealed a 7.5x7 cm mass in the left kidney, which showed a close proximity to adrenal gland. [endocrine-abstracts.org]

  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]

  Those caused by the tumour may include abdominal pain, anemia, pneumonia, cough and haemoptysis (cough productive of blood). Carcinoid tumors can also be present without producing any symptoms and may often go undetected for a long period of time. [rarediseases.org]

  Signs and symptoms[edit] Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose.[8]:43–44 Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or [en.wikipedia.org]

• Nausea

  […] feeling of abdominal fullness Anxiety attacks Clammy skin Diarrhea Facial flushing Fever Headaches Heart palpitations Hyperglycemia (high blood sugar levels) Hypertension (high blood pressure) Hypoglycemia (low blood sugar levels) Jaundice Low blood sugar Nausea [pennmedicine.org]

  A carcinoid tumor in the digestive system will cause symptoms like: Diarrhea and cramps Fatigue Nausea and vomiting Weight loss When a cancerous NET is in the lung, you might have: A cough Shortness of breath Whistling when you breathe, called wheezing [webmd.com]

  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]

  Other accompanying features include fever with rigors and chills, malaise, body aches, headache, nausea, and constipation. [ncbi.nlm.nih.gov]

  Other general symptoms include episodic sweating, tremor and rapid heart rate, as well as hunger, nausea, weight gain, and sometimes even central nervous system symptoms (including rarely, seizures). Gastrinomas over-secrete the hormone gastrin. [pancreatica.org]

• Vomiting

  Hyperglycemia (high blood sugar levels) Hypertension (high blood pressure) Hypoglycemia (low blood sugar levels) Jaundice Low blood sugar Nausea Persistent cough/hoarseness Rapid pulse Shortness of breath Skin rash Sweating Unexplained weight loss or gain Vomiting [pennmedicine.org]

  In the cerebellum they are most often associated with increased intracranial pressure, headaches, vomiting, and limb or truncal ataxia. Multiple renal cysts are very common and the lifetime risk of RCC is very high (70%). [orpha.net]

  A carcinoid tumor in the digestive system will cause symptoms like: Diarrhea and cramps Fatigue Nausea and vomiting Weight loss When a cancerous NET is in the lung, you might have: A cough Shortness of breath Whistling when you breathe, called wheezing [webmd.com]

  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]

  He has mild abdominal cramping, lipitor 20 mg indicaciones but no fever or vomiting. Archived from the original on September 11, buy lipitor 20 mg 2014. [vipmums.london]

• Hypertension

  […] positive regitine test Oncology: pheochromocytoma islet cell tumor Eyes: hypertensive retinopathy Endocrine: episodic hypertension Cardiac: congestive heart failure tachycardia Neuro: cerebral hemorrhage Skin: axillary freckling cafe-au-lait spots sweating [malacards.org]

  Hypertensive retinopathy MedGen UID: 101819 •Concept ID: C0152132 • Disease or Syndrome Degenerative changes to the RETINA due to HYPERTENSION. [ncbi.nlm.nih.gov]

  Intracerebral hemorrhage also may occur, because of uncontrolled hypertension. [emedicine.medscape.com]

  […] are generally administered in this context. β-sympatholytics may actually worsen hypertension. [symptoma.com]

• Tachycardia

  Source Accession 1 hyperhidrosis 31 HP:0000975 2 cafe-au-lait spot 31 HP:0000957 3 proteinuria 31 HP:0000093 4 congestive heart failure 31 HP:0001635 5 pheochromocytoma 31 HP:0002666 6 hypercalcemia 31 HP:0003072 7 cerebral hemorrhage 31 HP:0001342 8 tachycardia [malacards.org]

  Profuse sweating Sweating Sweating profusely Sweating, increased [ more ] 0000975 Hypertensive retinopathy 0001095 Pheochromocytoma 0002666 Positive regitine blocking test 0003574 Proteinuria High urine protein levels Protein in urine [ more ] 0000093 Tachycardia [rarediseases.info.nih.gov]

• Chest Pain

  pain A pancreatic NET that makes hormones can cause symptoms like: Dizziness, weakness, and fast heartbeat Headaches, a frequent need to pee, hunger, thirst, and weight loss Heartburn, pain in your belly, and diarrhea Even NETs that don't make hormones [webmd.com]

  During admission, he had acute dyspnea with desaturation but no chest pain at ten days after admission. [ncbi.nlm.nih.gov]

• Axillary Freckling

  […] retinopathy Endocrine: episodic hypertension Cardiac: congestive heart failure tachycardia Neuro: cerebral hemorrhage Skin: axillary freckling cafe-au-lait spots sweating Misc: familial pheochromocytoma usually bilateral Clinical features from OMIM: [malacards.org]

  One of their probands had numerous cafe-au-lait spots up to 4 cm in diameter and axillary freckling. There was, however, no family history of von Recklinghausen disease. [syndromefinder.ncchd.go.jp]

  One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1. [symptoma.com]

  Showing of 14 | Medical Terms Other Names Learn More: HPO ID Percent of people who have these symptoms is not available through HPO Autosomal dominant inheritance 0000006 Axillary freckling 0000997 Cafe-au-lait spot 0000957 Cerebral hemorrhage Bleeding [rarediseases.info.nih.gov]

• Cafe-Au-Lait Spots

  Tumor Syndrome via text searches within MalaCards or GeneCards Suite gene sharing: Human phenotypes related to Pheochromocytoma--Islet Cell Tumor Syndrome: 31 (show all 13) # Description HPO Frequency HPO Source Accession 1 hyperhidrosis 31 HP:0000975 2 cafe-au-lait [malacards.org]

  One of their probands had numerous cafe-au-lait spots up to 4 cm in diameter and axillary freckling. There was, however, no family history of von Recklinghausen disease. [syndromefinder.ncchd.go.jp]

  One of the patients described by Carney and colleagues presented cafe-au-lait spots and axillary freckling characteristic of NF1. [symptoma.com]

  Showing of 14 | Medical Terms Other Names Learn More: HPO ID Percent of people who have these symptoms is not available through HPO Autosomal dominant inheritance 0000006 Axillary freckling 0000997 Cafe-au-lait spot 0000957 Cerebral hemorrhage Bleeding [rarediseases.info.nih.gov]

• Hyperhidrosis

  Pheochromocytoma--Islet Cell Tumor Syndrome via text searches within MalaCards or GeneCards Suite gene sharing: Human phenotypes related to Pheochromocytoma--Islet Cell Tumor Syndrome: 31 (show all 13) # Description HPO Frequency HPO Source Accession 1 hyperhidrosis [malacards.org]

  Cardiac failure Cardiac failures Heart failure [ more ] 0001635 Elevated urinary norepinephrine 0003345 Episodic hypertension Intermittent high blood pressure 0000875 Hypercalcemia High blood calcium levels Increased calcium in blood [ more ] 0003072 Hyperhidrosis [rarediseases.info.nih.gov]

• Increased Sweating

  […] calcium in blood [ more ] 0003072 Hyperhidrosis Excessive sweating Increased sweating Profuse sweating Sweating Sweating profusely Sweating, increased [ more ] 0000975 Hypertensive retinopathy 0001095 Pheochromocytoma 0002666 Positive regitine blocking [rarediseases.info.nih.gov]

• Hypertensive Retinopathy

  […] positive regitine test Oncology: pheochromocytoma islet cell tumor Eyes: hypertensive retinopathy Endocrine: episodic hypertension Cardiac: congestive heart failure tachycardia Neuro: cerebral hemorrhage Skin: axillary freckling cafe-au-lait spots sweating [malacards.org]

  retinopathy 0001095 Pheochromocytoma 0002666 Positive regitine blocking test 0003574 Proteinuria High urine protein levels Protein in urine [ more ] 0000093 Tachycardia Fast heart rate Heart racing Racing heart [ more ] 0001649 Showing of 14 | Last updated [rarediseases.info.nih.gov]

• 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]

• Headache

  If you have a pheochromocytoma, the tumor releases hormones that may cause high blood pressure, headache, sweating and symptoms of a panic attack. [mayoclinic.org]

  When you have neuroendocrine tumors (NETs), you can get a lot of different symptoms, from shortness of breath to headaches to cramps in your belly. Why the variety? It's all about location. [webmd.com]

  Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). [ncbi.nlm.nih.gov]

  […] originate from hormone-producing tissues, the symptoms they cause can be linked to the release of various hormones into your bloodstream, causing: Abdominal pain A feeling of abdominal fullness Anxiety attacks Clammy skin Diarrhea Facial flushing Fever Headaches [pennmedicine.org]

  Fever and chills Severe throat pain that is usually on one side Ear pain on the side of the abscess Difficulty opening the mouth, and pain with opening the mouth Swallowing problems Drooling or inability to swallow saliva Facial or neck swelling Fever Headache [medlineplus.gov]

• Tremor

  Symptoms Signs and symptoms of pheochromocytomas often include: High blood pressure Headache Heavy sweating Rapid heartbeat Tremors Paleness in the face Shortness of breath Panic attack-type symptoms Less common signs or symptoms may include: Anxiety [mayoclinic.org]

  Propranolol is most effective for upper limb tremor and less effective for head and voice tremors. Sponsored ad This sponsor paid to have this advertisement placed in this section. The symptoms of essential tremor usually worsen with age. [centurywest.ca]

  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]

  Epigastric pain Flank pain Constipation Clinical signs associated with pheochromocytomas include the following: Hypertension: Paroxysmal in 50% of cases Postural hypotension: From volume contraction Hypertensive retinopathy Weight loss Pallor Fever Tremor [emedicine.medscape.com]

  Other general symptoms include episodic sweating, tremor and rapid heart rate, as well as hunger, nausea, weight gain, and sometimes even central nervous system symptoms (including rarely, seizures). Gastrinomas over-secrete the hormone gastrin. [pancreatica.org]

• Dizziness

  […] and cramps Fatigue Nausea and vomiting Weight loss When a cancerous NET is in the lung, you might have: A cough Shortness of breath Whistling when you breathe, called wheezing Chest pain A pancreatic NET that makes hormones can cause symptoms like: Dizziness [webmd.com]

  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]

  She had a typical history of acromegaly, with a progressive enlargement of hands, feet, and lips in the previous years, associated with macroglossia, dizziness, weakness, insomnia, and paresthesias. [scielo.br]

• Irritability

  Trismus, "hot potato" voice (speaking as if a hot object was in the mouth), a toxic appearance (eg, poor or absent eye contact, failure to recognize parents, irritability, inability to be consoled or distracted, fever, anxiety), drooling, severe halitosis [merckmanuals.com]

  Do not use large amounts or apply Retino-A 005% more often than directed, shabbily olanzapine borderline as your skin will not clear up faster, instead you may increase the chance for side effects like skin irritation! [windriverdesignandbuild.com]

  Side effects of Butoconazole are generally mild and can include irritation and burning in the vaginal area! [centurywest.ca]

• Personality Change

  Symptoms include confusion, seizure, obtundation, personality change and coma, as well as palpitations, tremulousness, diaphoresis (sweating) and tachycardia (fast heart rate). [pathology.jhu.edu]

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].

• Hepatocellular Carcinoma

  Among primary epithelial tumors, episodes of hypoglycemia were described in patients with hepatocellular carcinoma, gastric cancer, renal cell carcinoma, phyllodes tumor of breast, and ovarian adenocarcinoma [3]. [hindawi.com]

  Front-Horm-Res. 2001; 28: 131-66 Scandurro,-A-B; Weldon,-C-W; Figueroa,-Y-G; Alam,-J; Beckman,-B-S Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. [malattierare.regione.veneto.it]

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].

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

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].

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].

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.

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].

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.

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.

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.
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