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Tumors of the endocrine system


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Tumors of the endocrine system

  1. 1. By Ihab Samy Fayek Lecturer of Surgical Oncology National Cancer Institute – Cairo University Egypt 2014
  2. 2. 1. Thyroid Tumors 2. Parathyroid Tumors 3. Adrenal Tumors 4. Pancreatic Neuroendocrine Tumors 5. Neuroendocrine (Carcinoid) Tumors and the Carcinoid Syndrome 6. Multiple Endocrine Neoplasias
  3. 3. Studies of hereditary endocrine tumors have been especially fruitful, not only in defining the molecular genetic basis of these complex diseases, but in understanding the pathogenesis of the individual component tumor of the syndromes as well as their sporadic counterparts.
  4. 4.  Most endocrine tumors involve a single endocrine gland, are usually benign, and occur sporadically.  Rarely, endocrine tumors occur in a familial pattern where they are multiple, involving more than one endocrine gland.  Over the past 50 years at least six multiple endocrine neoplasia (MEN) syndromes have been described.  The genetic mutation causing each of these six MEN syndromes has been identified, in many cases leading to improved diagnosis and treatment of patients with a specific syndrome.
  5. 5.  MEN-1  MEN-2  Von Hippel-Lindau (VHL) disease  Neurofibromatosis type 1  Carney complex (CNC)  McCune-Albright syndrome (MAS)
  6. 6.  In 1954 Wermer described a family with hyperparathyroidism and tumors of the pancreatic islet cells and the pituitary gland.  2 to 3 per 100,000.  Males and females are equally affected.  All patients develop parathyroid hyperplasia by age 40.  50% develop malignant pancreatic islet cell tumors (usually gastrinomas, less often insulinomas, and rarely glucagonomas, or vasoactive intestinal polypeptide secreting tumors [VIPomas]).  25% develop pituitary tumors (usually prolactinomas).
  7. 7. While familial hyperparathyroidism is most commonly a component of MEN-1, it can occur in other settings, the most notable being:  Familial (benign) hypocalciuric hypercalcemia (FHH)  The hyperparathyroidism jaw-tumor (HPT-JT) syndrome.  Familial isolated hyperparathyroidism (FIHP).  MEN-2A.
  8. 8.  An autosomal dominant disease characterized by hypocalciuria, hypercalcemia, and parathyroid hyperplasia.  The calcium-sensing receptor (CASR), a critical regulator of extracellular calcium homeostasis.  Expressed in cells of the parathyroid gland and the kidney tubule.  Sensitive to changes in the ambient calcium concentration and when activated it inhibits parathyroid hormone (PTH) secretion and the renal reabsorption of calcium.
  9. 9.  With heterogenous inactivating mutations of the CASR gene the parathyroid cell fails to sense properly an increased serum calcium concentration, and the resulting increase in PTH secretion causes FHH.  Conversely, activating mutations of the CASR gene cause the parathyroid cells to sense that serum calcium is “elevated” when it is actually normal and a resulting decrease in the blood calcium level expressed as the syndrome of autosomal dominant hypoparathyroidism [ADH].  To date approximately 115 mutations (60% inactivating and 40% activating) have been described in the CASR gene.
  10. 10.  HPT-JT is characterized by the autosomal dominant occurrence of hyperparathyroidism, ossifying fibromas of the mandible or maxilla, renal cysts or solid tumors, and uterine fibromas.  Approximately 50 families with HPT-JT have been reported and 80% of patients have hyperparathyroidism, and in 15% of cases the parathyroid tumors are malignant.
  11. 11.  The syndrome of FIHP is a heterogenous condition.  Have germline mutations of MEN1, CASR, or HRP-JT.  Suggesting that the disease represents incompletely expressed forms of MEN1, FHH, or HPT-JT.  Over 100 families with FIHP have been reported and in most cases the causative genetic mutation is unknown, although there are convincing data that it resides on chromosome 2p13.
  12. 12.  There is no relationship between genotype and phenotype in patients with MEN-1, thus there is no way to predict the presence or behavior of pancreatic islet cell tumors or pituitary tumors.  There are important genetic mutations associated with other hereditary and sporadic pituitary tumors.  Carney Complex (CNC)  Familial Isolated Pituitary Adenomas (FIPA)
  13. 13.  Pituitary adenomas can occur as a component of CNC.  A familial disease characterized by: 1. Hypersomatotropenemia. 2. Cardiac or cutaneous myxomas. 3. Spotty skin pigmentation. 4. Primary pigmented nodular adrenal disease. 5. Testicular tumors. 6. About 75% of patients exhibit subclinical increases in growth hormone (GH), insulinlike growth factor-1 (IGF- 1), and prolactin. 7. Acromegaly occurs in about 10% of patients.
  14. 14.  Pituitary adenomas can also occur as FIPA.  Of the 138 affected family members, 55 had prolactinomas, 47 had somatotropinomas, 28 had nonsecreting adenomas, and 8 had adrenocorticotropic hormone–secreting tumors.  The incidences of a homogenous (single tumor) phenotype and a heterogeneous tumors phenotype were approximately equal.  Affected patients were found to have no mutations in either the MEN1 or PRKRA1A genes.
  15. 15.  In 1968 Steiner et al. described a large family with medullary thyroid carcinoma (MTC), pheochromocytomas, hyperparathyroidism, and Cushing's syndrome.  All patients with MEN-2A develop MTC, approximately half develop pheochromocytomas, and 30% develop hyperparathyroidism.  Less often MEN-2A is associated with cutaneous lichen amyloidosis (CLA), which develops on the upper back and serves as a precocious marker of the disorder, or Hirschsprung's disease (HD), which is characterized by loss of ganglion cells in variable segments of the large bowel.
  16. 16.  Patients with MEN-2B develop MTC and pheochromocytomas with the same frequency as patients with MEN-2A, but rather than hyperparathyroidism, they express a generalized gastrointestinal neuromatosis and a characteristic physical appearance.  Patients with FMTC develop only MTC. Of patients with hereditary MTC, 80% have MEN-2A, 15% have FMTC, and 5% have MEN-2B.
  17. 17.  Medullary thyroid carcinoma originates from C cells, which are derived from the neural crest.  The C cells have great biosynthetic capability and secrete the polypeptide hormone calcitonin (CTN) and the glycoprotein carcinoembryonic antigen (CEA).  Plasma CTN serves as an excellent marker for MTC, and presently its main use is in detecting persistent or residual MTC following thyroidectomy.  The MTC is the most common cause of death in patients with MEN-2A, MEN-2B, and FMTC, and the only effective therapy is timely thyroidectomy as standard chemotherapy and external beam radiotherapy are not useful.
  18. 18.  The discovery that mutations in the RET protooncogene cause MEN-2A, MEN-2B, and FMTC changed the management of patients with both sporadic and hereditary MTC and represents a paradigm for personalized genomic medicine.  DNA analysis for RET germline mutations is indicated in patients with presumably sporadic MTC, as approximately 5% of them will be found to have hereditary disease.  It is imperative to screen the family members of patients with newly found germline RET mutations, since they are at risk for MTC and approximately half of them will be affected.
  19. 19. Considering patients with familial cancer syndromes, hereditary MTC fulfills each of the criteria necessary for prophylactic removal of the organ at risk: 1. Near complete penetrance, such that virtually all patients who have inherited a mutated allele will develop the malignancy. 2. A highly reliable genetic test to detect family members who have inherited a mutated allele. 3. The organ at risk is expendable or its function can be easily replaced. 4. Resection of the organ at risk can be performed with minimal risk. 5. There is a sensitive tumor marker, to determine whether the malignancy has been prevented or cured following organ removal.
  20. 20.  The MEN Consortium Meeting in 2000 evaluated the relationship between specific RET codon mutations and the biological aggressiveness of hereditary MTC.  Based on combined clinical data the panel defined three levels of thyroid cancer severity, on which to base the timing of thyroidectomy
  21. 21.  Patients with mutations in RET codons 609, 768, 790, 791, 804, or 891 (level 1) are at risk for developing MTC; however, their tumors are generally more indolent and develop at a later age than is the case in patients with other RET codon mutations. Recommendation for thyroidectomy in this group is controversial, and many clinicians base their advice for thyroidectomy on plasma calcitonin levels.  In patients with mutations in RET codons 611, 618, 620, or 634 (level 2) thyroidectomy is recommended at or before 5 years of age.  Patients with MEN-2B and mutations in RET codons 883 or 918 (level 3) have the most severe form of MTC, and thyroidectomy is recommended within the first 6 months of life.
  22. 22.  Realizing the criticalness of removing the thyroid gland while the MTC is curable, and understanding that it is impractical to establish strict guidelines for the timing of thyroidectomy based on the various RET codon mutations, clinicians should err on the side of advising thyroidectomy too early rather than too late.  This approach is strengthened by the fact that once the MTC has spread beyond the thyroid gland it is virtually incurable, as no chemotherapy or radiotherapy regimen has proven effective.
  23. 23.  Insulinomas, glucagonomas, gastrinomas, and nonfunctioning endocrine tumors can all present as cystic lesions.  Isolated or associated with the multiple endocrine neoplasia syndrome type 1 (MEN 1), which is characterized by the triad of parathyroid, pituitary, and pancreatic lesions (3P’s).  Solitary, multiple, or diffuse; different histologic types may occur in the same patient.  Gastrinomas, however, are an uncommon pancreatic neoplasm in MEN 1 because most gastrinomas are located in the duodenum rather than in the pancreas.
  24. 24.  Insulinoma is the most common functioning islet cell tumor.  The clinical triad leading to the diagnosis is fasting hypoglycemia, symptoms of hypoglycemia, and immediate relief of symptoms after the administration of IV glucose.  Symptoms and signs are caused by both hypoglycemia and the secondary release of catecholamines and include palpitations, headache, confusion, pallor, sweating, slurred speech, and coma.  Despite this striking list of symptoms, the clinical presentation is often insidious.  Fasting hypoglycemia with no decrease in insulin level is confirmatory.  Approximately 10% of insulinomas are multiple, 10% are malignant, and 10% of patients have hyperplasia rather than neoplasia.  Most insulinomas are small and hypervascular. Some contain calcification.  Malignant tumors tend to be large. Cystic lesions are rare.
  25. 25. Cystic insulinomas in 36-year-old woman with multiple endocrine neoplasia type 1. CT scan shows small cystic masses (arrows) in body and tail of pancreas. Patient presented with primary hyperparathyroidism.
  26. 26.  Gastrinoma is the second most common functioning islet cell tumor.  Most are sporadic and associated with the Zollinger-Ellison syndrome.  The initial manifestations are most often in young adults who have peptic ulcer disease that suggests the diagnosis when ulcers are recurrent, intractable, multiple, or in unusual locations.  Diarrhea due to the large volume of hydrochloric acid and a direct effect of gastrin on the small bowel is common.  The diagnosis is confirmed by increased serum gastrin concentrations.  Gastinomas are frequently multiple, extrapancreatic, difficult to locate, and malignant.  Hepatic metastases are associated with a poor prognosis, whereas patients with metastases isolated to lymph nodes often have long-term survival.  The tumor size is variable, but pancreatic lesions average 3-4 cm. The lesions are often hypervascular, so they may be visible on arterial phase CT and angiography.  Rare cystic lesions have been reported.
  27. 27.  Most lesions are malignant and present with equal incidence in middle-aged men and women.  Most patients present with a necrolytic migratory rash and various other elements of the “glucagonoma syndrome” including diabetes mellitus, stomatitis, diarrhea, anemia, and weight loss.  The characteristic rash involves the lower extremities and the perineum, begins with erythema and progresses to coalescent blisters and pustules, and is pruritic.  An elevated plasma glucagon level establishes the diagnosis, but there are often increased blood levels of other hormones, including insulin, serotonin, and gastrin.  Approximately 50% of patients survive at least 5 years after diagnosis.  Tumor size is variable, but most are large and have metastasized at the time of diagnosis.  Most are located in the distal pancreas and are vascular.  Tumors may be solid or contain central low-attenuation areas on CT. Cystic lesions are rare.
  28. 28. Cystic glucagonoma in 34-year-old woman. CT scan shows large cystic mass in tail of pancreas. Patient had diabetes and presented with characteristic eczematous dermatitis termed “necrolytic migratory erythema.”