ELSEVIER
Rare syndromes
Serge A. Jabbour, MDª,*, Batya B. Davidovici, MDb, Ronni Wolf, MDb
ªDivision of Endocrinology, Diabetes and Metabolic Diseases, Thomas Jefferson University, Philadelphia, PA 19107, USA bDermatology Unit, Kaplan Medical Center, Rechovot, Israel
Abstract Dermatologists may also encounter patients presenting with skin lesions that reflect an underlying endocrine disorder not commonly seen in daily practice. Some of these endocrine disorders include glucagonoma, neurofibromatosis type 1, McCune-Albright syndrome, multiple endocrine neoplasia, the Carney complex, carcinoid tumors, and mastocytosis. The clinical syndrome classically associated with glucagonoma includes necrolytic migratory erythema, weight loss, diabetes mellitus, anemia, cheilitis, venous thrombosis, and neuropsychiatric symptoms. The hallmarks of neurofibroma- tosis type 1 are the multiple café-au-lait spots and associated cutaneous neurofibromas. Other presenting features include freckling, peripheral neurofibromas, Lisch nodules, bone abnormalities, tumors, neurologic abnormalities and hypertension. McCune-Albright syndrome is characterized by café-au-lait spots, polyostotic fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands. Multiple endocrine neoplasia type 2A is characterized by medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. In some patients with multiple endocrine neoplasia type 2A, cutaneous lichen amyloidosis may also be present. Multiple endocrine neoplasia type 2B is characterized by medullary thyroid cancer and pheochromocytoma but not hyperparathyroidism. The syndrome also includes mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas and a marfanoid habitus. Multiple endocrine neoplasia type 1 is an autosomal dominant predisposition to tumors of the parathyroid glands (four-gland hyperplasia), anterior pituitary, and pancreatic islet cells; hence, the mnemonic device of the “3 Ps”; multiple cutaneous lesions (angiofibromas and collagenomas) are frequent in patients with multiple endocrine neoplasia type 1. Carney complex may be viewed as a form of multiple endocrine neoplasia because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocortical disease (some with Cushing’s syndrome), pituitary adenoma, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts. Additional unusual manifestations include psammomatous melanotic schwannoma, breast ductal adenoma, and a rare bone tumor, osteochondromyxoma. Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elaborated by some carcinoid tumors; the major manifestations are diarrhea, flushing, bronchospasm, and cardiac valvular lesions. Mast cell diseases include all disorders of mast cell proliferation. These diseases can be limited to the skin, referred to as “cutaneous mastocytosis,” or involve extracutaneous tissues, called “systemic mastocytosis.” Patients present with urticaria pigmentosa, mastocytoma, or diffuse cutaneous mastocytosis. Systemic involvement may be gastro- intestinal, hematologic, neurologic, and skeletal. @ 2006 Elsevier Inc. All rights reserved.
* Corresponding author. Tel .: +1 215 9555564; fax: +1 215 9283160.
E-mail address: serge.jabbour@jefferson.edu (S.A. Jabbour).
Glucagonoma and necrolytic migratory erythema
Introduction
Necrolytic migratory erythema (NME) was first de- scribed by Becker et al1 (of Becker’s nevus) in 1942 in a woman with an islet-cell type of pancreatic carcinoma that was revealed only postmortem. Only in 1966,2 the hyper- glycemic potential of the neoplasm was identified, and glucagon was discovered at high levels within the neoplasm. In 1974,3 the term glucagonoma syndrome was introduced to describe an alpha-cell pancreatic tumor with its characteristically associated rash, NME.
Glucagonomas are rare tumors, which originate in the alpha cells of the pancreas.4,5 These tumors demonstrate the typical characteristics of islet-cell tumors; they vary in size from 2 to 25 cm and occur most often in the tail of the pancreas.5 Despite their benign histologic appearance, most glucagonomas are malignant, as defined by their pro- pensity for metastasis, and usually present at the time of diagnosis.4,5
Patients typically present in their fifth decade with even distribution between males and females.4 Rarely, glucago- noma may be associated with the multiple endocrine neoplasia (MEN) syndrome type 1.
Clinical presentation
The clinical syndrome classically associated with gluca- gonoma includes NME, weight loss, diabetes mellitus, anemia, cheilitis, venous thrombosis, and neuropsychiatric symptoms. Necrolytic migratory erythema and weight loss are the most prevalent symptoms, occurring in approxi- mately 65% to 70% of patients by the time of diagnosis.4 Diabetes mellitus occurs in 75% to 95% of patients with glucagonoma. The hyperglycemia is usually mild, easily controlled by diet and oral agents, and is not associated with diabetic ketoacidosis because beta-cell function is preserved.6
Gastrointestinal symptoms associated with glucagonoma include abdominal pain, anorexia, diarrhea, and constipation.
Venous thrombosis occurs in up to 30% of patients with glucagonoma.6
Neurologic symptoms may include ataxia, dementia, optic atrophy, and proximal muscle weakness. 4-6
A normochromic normocytic anemia is common, being present in up to 90% of patients in some series; it is probably due to the anemia of chronic disease.5 Amino acid levels are markedly diminished in the serum of patients with glucagonoma. Glucagon, acting on the liver, increases amino acid oxidation and gluconeogenesis from amino acid substrates.7 Multiple hormones can be cosecreted with glucagon, including gastrin, insulin, pancreatic polypeptide, vasoactive intestinal peptide, and adrenocorticotropic hor- mone (ACTH).
Cutaneous manifestations
Necrolytic migratory erythema characteristically begins as erythematous papules or plaques involving the face, perineum, and extremities. The eruption usually occurs in periorificial, flexural, and acral areas and closely resembles the lesions associated with a zinc deficiency.
Over the ensuing 7 to 14 days, the lesions enlarge and coalesce. Central clearing then occurs, leaving bronze- colored, indurated areas centrally, with blistering, crusting, and scaling at the borders. The affected areas are often pruritic and painful4-7 (See Fig. 1).
Skin biopsies obtained from the edge of the lesions reveal superficial necrolysis with separation of the outer layers of the epidermis and perivascular infiltration with lympho- cytes and histiocytes. Multiple biopsies may be required to demonstrate these diagnostic findings. The same process often affects the mucous membranes, resulting in glossitis,
angular cheilitis, stomatitis, and blepharitis. Hair thinning and dystrophic nails are also commonly observed.4-7
The rash may occasionally appear before the onset of systemic symptoms, but most patients usually have weight loss, diarrhea, sore mouth, weakness, mental status changes, or diabetes mellitus.4 The etiology of NME could be the hypoaminoacidemia; in one patient, amino acid infusion led to an improvement in the rash.
Although NME is often the clue that leads to the correct diagnosis, it is not completely pathognomonic for glucago- noma; it can be seen in the absence of pancreatic, glucagon- secreting tumor (termed pseudoglucagonoma syndrome). In these cases, the underlying diseases are celiac and malab- sorption, in addition to cirrhosis, nonislet-cell tumors and other conditions such as zinc deficiency, pellagra, kwash- iorkor, pancreatitis, toxic epidermal necrolysis, pemphigus foliaceus, and pustular psoriasis.4-7,9
Diagnosis
Many of the symptoms of glucagonoma are nonspecific; even NME is not completely pathognomonic. When there is a constellation of symptoms discussed above, mainly with NME, further workup is necessary.
Serum glucagon
Many conditions other than glucagonoma can induce “physiologic” elevations in the serum glucagon concentra- tion. These include hypoglycemia, fasting, trauma, sepsis, acute pancreatitis, abdominal surgery, Cushing’s syndrome, and renal and hepatic failure. These conditions, however, are associated with only moderate elevations of glucagon, usually less than 500 pg/mL (upper limit of normal <100 pg/mL).4 In addition, other neuroendocrine tumors, such as carcinoid tumors, insulinomas, and gastrinomas, can secrete glucagon, although rarely in levels high enough to cause the classic clinical syndrome.10
Glucagonoma, in contrast to the above conditions, is associated with markedly elevated serum concentrations of glucagon (>500 pg/mL), multiple molecular weight forms of glucagon, and the classic clinical syndrome. Glucagon levels are generally highest in patients with NME and diabetes mellitus due to glucagonoma.
Some glucagonomas, however, are associated with serum levels of the peptide in the “physiologically elevated” range, even in the presence of NME. Thus, in patients with the classic syndrome, a serum glucagon concentration below 500 pg/mL does not exclude a glucagonoma. On the other hand, concentrations above 1000 pg/mL are virtually diagnostic of glucagonoma.
Abdominal computed tomographic scan
Clinical and/or laboratory abnormalities suggesting the presence of glucagonoma should be followed by attempts to localize the tumor. Abdominal computed tomographic (CT) scanning is the initial imaging procedure of choice. Because the primary tumor is usually large by the time of
diagnosis, it is localizable by CT in most cases (86% in the most recent series).4 Intravenous contrast enhances the CT detection of smaller lesions, especially when images are obtained during the arterial phase. Computed tomography is also useful in identifying metastatic disease.
Endoscopic ultrasonography
Endoscopic ultrasound (EUS) can detect pancreatic tumors as small as 2 to 3 mm, provides accurate information on the local extent of disease, and allows transmucosal needle biopsy of pancreatic lesions. In the largest published series to date, EUS had a sensitivity of 82% and a specificity of 95% for the detection of islet-cell tumors too small to be visualized by CT; one of the 37 patients in this series had a small glucagonoma, which was accurately localized by EUS.11
Some experts proceed with this diagnostic modality in either of two situations. After CT has revealed an apparently localized pancreatic tumor, EUS is useful for further examination of the regional extent of disease and for obtaining biopsy material. Even more importantly, when CT is unrevealing in a patient with clinical evidence of glucagonoma, EUS is the modality of choice for detecting and biopsying islet cell tumors too small for CT visualization.
Other imaging modalities
Other imaging modalities are less useful for the diagnosis of glucagonoma4-6:
· Angiography is highly sensitive for islet-cell tumors given their hypervascularity, but it has largely been superseded as a diagnostic test by the improvements in contrast CT imaging. Angiography is now per- formed almost exclusively for embolization and/or infusion of chemotherapy via the hepatic artery.
· Transabdominal ultrasound is often able to visualize larger islet cell tumors but lacks sensitivity, especially for smaller and more distal tumors.
· Somatostatin receptor scintigraphy using radiolabeled octreotide is very sensitive for islet-cell tumors, including glucagonomas.12 Because glucagonomas, however, unlike other gastrointestinal neuroendocrine tumors, are usually large by the time of diagnosis, somatostatin receptor scintigraphy is rarely required for localization.
Biopsy
Once the primary tumor and/or metastases have been localized by CT or EUS, we proceed with needle biopsy to confirm the diagnosis. Endoscopic ultrasound-guided biopsy is the preferred method for localized disease. In com- parison, a CT-guided liver biopsy is performed if liver metastases are present. The histology will be diagnostic of an islet-cell tumor. Immunoperoxidase staining is required to confirm the presence of glucagon in the tumor cells. Because
of heterogeneous expression of glucagon, however, small needle biopsies may occasionally yield negative immuno- peroxidase stains for glucagon.
Brief overview on management
The prevalence of metastatic disease at the time of diagnosis varies from series to series, ranging from 50% to 100%.4,6 The most common site of metastasis is the liver, followed by regional lymph nodes, bone, adrenal gland, kidney, and lung. Glucagonomas are generally slow- growing but usually advanced by the time of diagnosis. Once the tumor is metastatic, cure is rarely, if ever, achieved. Despite the presence of metastases, however, many patients are able to experience prolonged survival with a combination of therapeutic modalities.
Resection
For the minority of cases in which the tumor remains localized at the time of diagnosis, resection of the primary pancreatic tumor is indicated because it offers the chance of complete cure. Whether a simple enucleation, focal pancreatic resection, or Whipple procedure is performed is dictated by the site and extent of the tumor at the time of laparotomy.
Rapid resolution of hyperglucagonemia and NME are typical after resection.13 Even in cases deemed to be localized preoperatively, however, resection results in a complete cure rate of only about 30%.14
Other modalities
When the tumor is unresectable because of metastatic disease, treatment with octreotide, interferon-«, or chemo- therapy may be considered. In patients with liver metastases, embolization or chemoembolization can result in palliation of symptoms.
Amino acid, zinc, and essential fatty acid supplementa- tion has improved the NME despite high glucagon levels, suggesting a role of these secondary consequences of hyper- glucagonemia in its pathogenesis.15
Neurofibromatosis type 1 Introduction
Classically, there are two types of neurofibromatosis
- Neurofibromatosis (NF) type 1 or von Recklinghau sen’s disease, which we will discuss in this article, is an autosomal dominant genetic disorder with an incidence of approximately 1 in 3000 individuals. Approximately one-half of the cases are familial; the remainder are new mutations.
- Neurofibromatosis type 2 is an autosomal dominant disorder predisposing to multiple neoplastic lesions. The pathognomonic findings are bilateral acoustic neuromas (schwannomas). Astrocytomas, multiple meningiomas, and occasional ependymomas are also encountered in persons with NF2.18
Additional forms of NF have been described: types 3 (mixed) and 4 (variant) are autosomal dominant genetic disorders, which resemble type 2 but may have more numerous cutaneous neurofibromas. There is also a greater risk for developing optic gliomas, neurilemomas, and meningiomas in these patients.
Type 5, dermatomal (segmental) NF, probably arises from a postzygotic somatic mutation and therefore is not generally heritable.19
Type 6 NF has no neurofibromas, only café-au-lait spots (CALS), and must occur in two generations to be diagnosed.
Type 7 NF, late onset NF, begins to manifest only when the patients are in their twenties. It is not yet known whether it is inherited.
Clinical presentation
The hallmarks of NF1 are the multiple CALS and associated cutaneous neurofibromas.20-22 Other presenting features include freckling, peripheral neurofibromas, Lisch nodules, bone abnormalities, tumors, neurologic abnormal- ities and hypertension.
Café-au-lait spots, freckling, and cutaneous neuro- fibromas will be discussed in the next section on cuta- neous manifestations.
The other features are briefly reviewed:
Peripheral neurofibromas
Neurofibromas are benign tumors that are composed of a mixture of Schwann cells, fibroblasts, and mast cells.
The four types of neurofibromas are the following:
· Cutaneous: most common type (see Fig. 2)
· Subcutaneous: these lesions present as firm, tender nodules along the course of peripheral nerves. On palpation, they are described as feeling like a “bag of worms.”
· Nodular plexiform: nodular plexiform neurofibromas appear as complex clusters along proximal nerve roots
and major nerves. They are similar to subcutaneous neurofibromas. They can cause vertebral erosion that may result in compression of the spinal cord.
· Diffuse plexiform: these lesions usually involve multiple nerve fascicles, with serpiginous growth and significant vascularity, rendering complete surgi- cal resection extremely difficult, if not impossible, to accomplish.23 Plexiform neurofibromas also can undergo malignant transformation to malignant pe- ripheral nerve sheath tumors.
Lisch nodules
Lisch nodules characteristically are raised, often pig- mented hamartomas of the iris and represent a relatively specific finding for NF1. They almost never cause signif- icant disease.24 They may be seen with a direct ophthal- moscope if the nodules are large or numerous, and the iris is light, but usually, a thorough slit-lamp examination by an ophthalmologist is needed to detect the lesions.
Bone abnormalities
Bony abnormalities in NF1 include pseudoarthrosis and bone dysplasia, which are part of the National Institutes of Health Consensus Conference criteria for the disease,20-22 as well as short stature and scoliosis.
A pseudoarthrosis, or false joint, is formed because of nonunion of bone fragments. Pseudoarthrosis in NF1 results from impaired healing because of bone dysplasia.25 Pseudo- arthrosis typically presents in infants or young children as bowing of the tibia, which progresses to thinning of the cortex and fracture. It has a male predominance (1.7:1).26 The diagnosis may be overlooked until pathologic fractures
occur with weight-bearing or when walking is first attempted. Approximately one-half of fractures occur before the patient is 2 years of age.26
Tumors
Patients with NF1 develop benign and malignant tumors at increased frequency throughout life.23 Optic pathway gliomas are the predominant type of intracranial neoplasms, but other central nervous system (CNS) and non-CNS tumors can occur. The overall risk of malignancy in NF1 is estimated at 2% to 10% of affected individuals.
Optic pathway gliomas (OPGs) occur in 15% of children younger than 6 years of age with NF1.27 With magnetic resonance imaging (MRI), they appear as an enlargement of the optic nerve or chiasm. These tumors, which are typically low-grade gliomas, may arise anywhere along the anterior visual pathway to the optic radiations and involve the optic nerves, chiasm, and postchiasmal optic tracts. Many children with NF1 and OPGs have normal vision. A minority of children, however, become symptomatic with progressive vision loss associated with an expanding lesion. Children with tumors involving the optic chiasm occasion- ally present with either premature or delayed puberty caused by hypothalamic involvement.28 Detecting precocious puberty early in patients with NF1 is important because it may indicate the presence of an optic pathway glioma. In addition, treatment can minimize the complications of accelerated linear bone growth and premature development of secondary sexual characteristics.
In addition to OPGs, individuals with NF1 are at in- creased risk for developing other CNS neoplasms, par- ticularly astrocytomas and brainstem gliomas.29,30 As discussed earlier, plexiform neurofibromas can undergo malignant transformation to malignant peripheral nerve sheath tumors, which are also called neurofibrosarcomas or schwannomas. Neurofibromatosis type 1 patients have an increased risk of certain other malignancies, including chronic myeloid leukemias of childhood, rhabdomyosarco- ma, and pheochromocytoma.31
Children with NF1 are 200 to 500 times more likely to develop malignant myeloid disorders. The presence of juvenile xanthogranuloma, a rare, benign cutaneous abnor- mality that occurs in 1% of young children with NF-1, should raise special concern because there may be an excess of juvenile chronic myelogenous leukemia in children with these lesions. 32,33
Neurologic abnormalities
Neurologic abnormalities include cognitive deficits with IQ scores 5 to 10 points lower than the general population, learning disabilities, seizures, macrocephaly and rarely peripheral neuropathy.34
Hypertension
Hypertension is a frequent finding in adults with NF1 and may develop during childhood. Hypertension is con- sidered essential in most cases, but vascular lesions pro-
ducing renovascular hypertension are more frequent in NF1 patients.38 Renovascular lesions can be detected in patients who are still normotensive; the frequency with which such patients will develop hypertension is not known. A much less common cause of hypertension in NF1 is pheochromo- cytoma, which has been clinically identified in 0.1% to 5.7% of patients.39 The mean age at diagnosis was 42 years.
Cutaneous manifestations
Café-au-lait spots
Café-au-lait spots are flat, uniformly hyperpigmented macules (see Fig. 3), which appear during the first year after birth and usually increase in number during early childhood. The number of CALS then stabilizes over time. As many as 25% of the normal population will have one to three CALS. The presence of six or more CALS, however, is highly suggestive of NF1.20-22
In a child with a negative family history and no other diagnostic features, CALS alone are insufficient to make a diagnosis of NF1. These children should be followed up clinically for the appearance of other manifestations because a definitive diagnosis usually can be made by the time the child is 4 years of age. In one report of 41 children 1 month to 14 years of age with six or more CALS on the initial visit, a diagnosis of NF1 eventually was made in approximately 50%.40
Approximately 95% of adults with NF1 have CALS, but they tend to fade later in life and may be difficult to distinguish in elderly individuals, particularly in African Americans. A Wood’s lamp often is useful to visualize these macules when they are not readily discernible by gross inspection.4
Freckling
Freckling is a diagnostic criterion distinct from CALS. It occurs mostly in regions of skin apposition, especially the axillary and groin areas. Freckling usually is not apparent at birth but often appears during early childhood. The occurrence of freckling in other intertriginous areas, such as the neckline or inframammary areas in women, suggests that these cutaneous lesions may be modulated by the local environment.25
Cutaneous neurofibromas
The most common type of neurofibromas consists of soft fleshy tumors arising from cells in the peripheral nerve sheath.42 They can invaginate into the underlying dermal defect with light digital pressure (“button-holing”). This feature is a useful sign in distinguishing the lesions of this disease from other surface tumors, for example, multiple lipomas.
In general, these dermal lesions begin to appear just before or during adolescence. They tend to increase in size and number with age. They vary in number from just a few to several hundred, with the highest density occurring over the trunk. Cutaneous neurofibromas are benign and do
not carry an increased risk of developing malignant trans- formation. However, they often represent a major cosmetic problem in adults. Pruritus associated with accelerated growth of neurofibromas may be a prominent and distress- ing symptom.
Neurofibromas of the areola occur in most women with this disease.43 Pregnancy can affect the number and size of neurofibromas, suggesting that these tumors have a hor- mone-responsive component. In a report of 247 pregnancies in 105 women, growth of new lesions and enlargement of existing lesions was reported in 60 and 55% of cases, respectively.44
Cutaneous pigmentation
There are two basic types of NF1 hyperpigmentation abnormalities: focal and diffuse. The latter involves virtually all the skin.19
Diagnosis
The diagnostic criteria developed by the National Institutes of Health Consensus Conference in 1987 and updated in 1997 are based upon specific clinical features of NF1.20-22 According to these criteria, at least two of the following clinical features must be present to make the diagnosis of NF1:
· Six or more café-au-lait macules of greatest diameter higher than 5 mm in prepubertal and higher than 15 mm in postpubertal individuals
· Two or more neurofibromas of any type or one plexiform neurofibroma
· Freckling in the axillary or inguinal regions
· Optic glioma
· Two or more Lisch nodules (iris hamartomas)
· A distinctive bony lesion such as sphenoid dysplasia or thinning of the long bone cortex with or with- out pseudoarthrosis
· A first-degree relative (parent, sibling, or offspring) with NF1 based upon the above criteria
Brief overview on management
Treatment is targeted to the organ involved, mainly surgery in the case of neurofibromas, pseudoarthrosis, and tumors.
With regard to optic gliomas, because of the variable natural history of these tumors, all children with NF1 should undergo thorough ophthalmologic evaluation and regular growth assessments using standard growth charts.45 The evaluation should begin when NF1 first is suspected and be repeated at annual intervals or when symptoms develop. Some experts recommend systemic surveillance with MRI of the brain and orbits before 6 years of age because of the difficulty assessing vision in this age group.46
Children with NF1 should be monitored for develop- mental progress. A careful neurologic examination should be part of the evaluation performed at yearly intervals. A developmental history should be obtained and school
progress reviewed. If areas of concern are identified, a formal educational assessment should be performed.34
All patients with NF1 or at risk for having the disorder must have regular blood pressure monitoring and/or periodic ambulatory blood pressure monitoring.47 Patients with severe hypertension should be evaluated for renal artery stenosis and pheochromocytoma.
McCune-Albright syndrome
Introduction
McCune-Albright syndrome48,49 is a sporadic disease, which occurs twice as often in girls as in boys and is due to somatic activating mutations in the gene (GNAS1) that encodes the a subunit of the trimeric guanosine trip- hosphate-binding protein (Gsx) that stimulates adenyl- ate cyclase.
Clinical presentation
This syndrome is characterized by CALS, polyostotic fibrous dysplasia, sexual precocity, and hyperfunction of multiple endocrine glands.49 Café-au-lait spots will be discussed in the next section on cutaneous manifestations.
The other features are briefly reviewed:
1. Polyostotic fibrous dysplasia: this can involve any bone and is frequently associated with facial asym- metry and hyperostosis of the base of the skull. The skeletal lesions are dysplastic and are filled with spindle cells with poorly organized collagen support; they take the form of scattered cystic areas of rarefaction on radiography and often result in pathologic fractures and progressive deformities.50,51 Bone lesions can be detected by technetium bone scan before they are visible radiographically. If the skull is involved, the optic or auditory nerve foramina may be compressed and lead to blindness, deafness, facial asymmetry, and ptosis.
2. Sexual precocity: the sexual precocity in girls, the onset of which is often in the first 2 years of life and is frequently heralded by menstrual bleeding, is due to autonomously functioning luteinized follicular cysts of the ovary.5º Serum estradiol is elevated, and the luteinizing hormone (LH) response to LH- releasing hormone (LHRH) is prepubertal, consis- tent with LHRH-independent puberty. When the bone age approaches 12 years, the LHRH pulse generator becomes operative, and ovulatory cycles ensue.52 Sexual precocity is rare in boys with McCune-Albright syndrome.50
3. Endocrine hyperfunction: autonomous hyperfunc- tion most commonly involves the ovary, but other endocrine involvement includes the thyroid (nodular hyperplasia with thyrotoxicosis53), adrenal (multiple hyperplastic nodules with Cushing’s syndrome54),
pituitary (somatotrope adenoma or hyperplasia with gigantism and acromegaly and hyperprolactine- mia55), and parathyroids (adenoma or hyperplasia with hyperparathyroidism5º). In addition, hypophos- phatemic vitamin D-resistant rickets or osteomalacia can also occur.56
Cutaneous manifestations
Café-au-lait spots are pale brown macules that vary in size from 0.5 to 20 cm and can be found on any cutaneous surface. As opposed to the CALS with smooth regular borders (shaped like the “coast of California”) in NF, the CALS in McCune-Albright syndrome have a more irregular border (shaped like “the coast of Maine”).
The CALS in this syndrome may not be conspicuous in infancy. They usually do not cross the midline, are usually located on the same side as the main bone lesions, and have a segmental distribution.57 The CALS involve the forehead, nuchal area, and buttocks most commonly. They may follow the lines of Balschko. Spotty pigmentation may also occur periorally.58
Diagnosis
Asymptomatic sites of fibrous dysplasia can be detected with bone scanning. Positive sites on bone can then be confirmed as fibrous dysplasia by means of radiogra- phy.50,51 Finding these sites when gonadotropin-indepen- dent precocious puberty is also present can confirm the diagnosis of McCune-Albright syndrome.
Precocious puberty in McCune-Albright syndrome is gonadotropin-independent.50,52 Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropins is diagnostic of gonadotropin-independent puberty. Frequently, however, estrogen secretion is epi- sodic in McCune-Albright syndrome, so that multiple assays over time may be necessary to demonstrate an elevation in estradiol levels. In difficult cases, a LHRH stimulation test can help to differentiate between central gonadotropin-dependent and gonadotropin-independent precocious puberty. Serum is sampled for LH and follicle stimulating hormone (FSH) after administration of LHRH. Suppressed or undetectable levels of LH and FSH after administration of LHRH are consistent with McCune- Albright syndrome.
If hyperthyroidism is suspected, thyroid stimulating hormone (TSH) should be done; if suppressed, free T4 and T3 levels are obtained. To screen for Cushing’s syndrome, an overnight dexamethasone suppression test or urine free cortisol can be used. For somatotrope adenomas, insulin-like growth factor-1 is the best screening test.
Brief overview on management
Precocious puberty in McCune-Albright syndrome is gonadotropin-independent and, therefore, does not respond
to the gonadotropin-releasing hormone agonist therapy that is so successful with gonadotropin-dependent central preco- cious puberty. The aromatase inhibitor testolactone59 has been the mainstay of therapy in girls with persistent estradiol ele- vation. Aromatase inhibitors block the conversion of testos- terone to estradiol, thus lowering circulating estrogen levels.
Symptomatic fibrous dysplasia is difficult to treat medi- cally.60,61 Currently, no clinically proven medical therapies exist. Recent studies using bisphosphonates are encouraging. Although bisphosphonates60 may not heal or prevent fibrous dysplasia, they do seem to make the lesions less painful. Fracture is the primary indication for surgical treatment of dysplastic lesions. Most fractures are treated with traction. Proximal fractures of the femur, however, may require sur- gically placed fixation devices. Rarely, severe and progres- sive malformation of the femur can occur. These lesions usually are painful because of the multiple small fractures associated with them and may need to be removed surgically. Routine removal of most polyostotic dysplastic lesions generally is not warranted and can result in the lesion recurring at the same site.
Hyperthyroidism due to functional thyroid follicular ade- nomas can be treated medically. Antithyroid medications, such as propylthiouracil and methimazole, can be used to decrease thyroid hormone production. Unlike Graves’ disease, hyperthyroidism secondary to an activating Gsx mutation is unlikely to go into remission.62 Therefore, patients probably should use antithyroid drugs indefinitely. Consider a more permanent treatment of the hyperthyroid- ism, including I131 therapy or thyroidectomy, if a diagnosis of McCune-Albright syndrome is confirmed.
No effective long-term medical treatment of ACTH- independent Cushing’s syndrome exists, and the current recommendation for treatment is bilateral adrenalectomy.6 During the adrenalectomy and afterward, the patient needs replacement of glucocorticoid and mineralocorticoid in appropriate amounts.
Medical treatment is the most effective for growth hormone (GH)-producing adenomas.64,65 Radiation therapy may cause sarcomatous changes in the surrounding dysplas- tic bone if fibrous dysplasia is present. Octreotide, the long- acting somatostatin analogue, has been used with variable success in decreasing GH secretion from these tumors. Octreotide has been successful in lowering GH levels in many cases but rarely has normalized GH secretion. Com- bination octreotide and bromocriptine therapy was successful in normalizing GH in one case when octreotide alone was not adequate. Consider surgical removal only if the tumor is threatening vision because removal is rarely curative.
Multiple endocrine neoplasia
Introduction
The coexistence of tumors of the parathyroids, pancre- atic islets, and pituitary was first noted in autopsy studies of
patients with acromegaly in 1903.66 Not until 1954, when Wermer67 described a family with four daughters and a father manifesting multiple parathyroid, pancreatic islet, and pituitary tumors, was the autosomal dominant genetic basis of the disease recognized. This condition was later termed the Wermer syndrome or multiple endocrine adenomatosis, but MEN-1 is now the preferred term, whereas Sipple’s syndrome is currently termed MEN-1A and Wagenmann-Froboese syndrome, MEN-2B (previously known as MEN-III).68
Multiple endocrine neoplasia type 2A is an autosomal dominant disorder characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary parathy- roid hyperplasia. In some patients with MEN-2A, cutaneous lichen amyloidosis (CLA) may also be present.
Multiple endocrine neoplasia type 2B is also an autosomal dominant disorder characterized by MTC and pheochromocytoma, but not hyperparathyroidism. The syndrome also includes mucosal neuromas, typically involving the lips and tongue, intestinal ganglioneuromas, and a marfanoid habitus.
Multiple endocrine neoplasia type 1 is an autosomal dominant predisposition to tumors of the parathyroid glands (four-gland hyperplasia), anterior pituitary, and pancreatic islet cells; hence, the mnemonic device of the “3 Ps.” The most common pancreatic islet cell tumor is gastrinoma, followed by insulinoma; glucagonoma is a rare finding in MEN-1 (see section on glucagonoma).
Clinical presentation
Cutaneous lichen amyloidosis will be discussed in the section on Cutaneous manifestations.
Medullary thyroid cancer
Multicentric hyperplasia of the parafollicular C-cells is the hallmark of MEN-2, with a penetrance approaching 100%, and nearly all patients develop clinically apparent MTC, often early in life; the risk is even greater in MEN- 2B.69 If diagnosed as an index case, the clinical presentation and manifestations of MEN-2-associated MTC are similar to those of sporadic MTC, most often as a thyroid nodule or as cervical lymphadenopathy. Less common presentations include recognition during a search initiated after an associated disease, such as pheochromo- cytoma, or hyperparathyroidism becoming apparent, diar- rhea caused by gastrointestinal secretion of fluid and electrolytes, and flushing due to the secretion of other peptides by the tumor. In rare cases, MTC causes Cushing’s syndrome due to ectopic production of cortico- tropin (ACTH).70,71
Pheochromocytoma
Pheochromocytoma occurs in approximately 40% of pa- tients with MEN-2A and, probably, a similar percentage in MEN-2B. Sporadic pheochromocytomas are almost always unilateral.72 In contrast, pheochromocytomas in MEN-2A have been reported to be bilateral73 in approximately one
third to, in one study from Spain, 100% of patients.74 Extra- adrenal pheochromocytoma is rare in MEN-2.
It is unusual for pheochromocytoma to precede the development of MTC and be the initial manifestation of MEN-2. In patients who have undergone regular screening, pheochromocytomas have usually become evident about 10 years later than C-cell hyperplasia or MTC.75
Pheochromocytomas in MEN-2 are usually identified during screening or through heightened vigilance for symp- toms in patients with known or suspected MEN-2. The patients may report anxiety, headache, diaphoresis, palpita- tions, or tachycardia, such as patients with sporadic pheo- chromocytomas. In one report, however, only about one third had hypertension at the time of diagnosis.7
Primary hyperparathyroidism
Primary hyperparathyroidism in MEN-2A is almost always multiglandular. It has been reported in 10% to 25% of patients.69,76 Hyperparathyroidism is not associated with MEN-2B. The hyperparathyroidism in MEN-2A is often clinically occult. The diagnosis is established by finding high (or inappropriately normal) serum parathyroid hormone concentrations in the presence of hypercalcemia.
Pituitary adenomas
Seen in MEN-1, the most common type of pituitary tumor in is a prolactinoma, but growth hormone-producing, corticotropin (ACTH)-producing, gonadotroph, and clini- cally nonfunctioning tumors can also occur. Patients with prolactinomas present with galactorrhea and hypogonadism. In macroadenomas, compressive symptoms can occur, such as visual abnormalities and headaches.
The presentation of acromegaly and Cushing’s syndrome is reviewed elsewhere in this issue.
Pancreatic islet cell tumors
The most common cause of symptomatic disease is the Zollinger-Ellison (gastrinoma) syndrome, leading to multi- ple peptic ulcers. Symptomatic insulinomas also occur with moderate frequency, whereas VIPomas and glucagonomas are rare.
Cutaneous manifestations
Cutaneous lichen amyloidosis is a rare skin condition, and can occur sporadically and as a familial disease. The hereditary forms are transmitted in an autosomal dominant fashion, and an association between CLA and MEN-2A has been established in some families.77
The skin lesion is usually described as pruritic, scaly, papular, and pigmented and located in the interscapular region or on the extensor surfaces of the extremities.77,78 Amyloid deposition has been documented histologically.79
Although only recently reported,80 multiple cutaneous lesions (angiofibromas and collagenomas) are frequent in MEN-1 patients, and it was proposed that their discovery suggested the diagnosis. In a recent study81 on the frequency and sensitivity/specificity of various cutaneous criteria for
MEN-1, angiofibromas or collagenomas (single or multiple) had 50% to 65% sensitivity for MEN-1 and 92% to 100% specificity. The combination criterion of multiple angio- fibromas (more than three) and any collagenomas had the highest sensitivity (75%) and specificity (95%). This cri- terion has even greater sensitivity than pituitary or adrenal disease and is comparable with hyperparathyroidism in some studies of patients with MEN-1. Dermatologists should, therefore, be aware of this cutaneous sign, which are underreported in the dermatologic literature.
Diagnosis
Basal serum calcitonin concentrations usually correlate with tumor mass and are almost always high in patients with a palpable tumor. In patients with small tumors and those with C-cell hyperplasia, the values may be normal but rise excessively after calcium infusion.82 Fine needle aspiration of any thyroid nodule (palpable or seen on ultrasound) is also helpful; however, cytologists will usually recognize fine needle aspiration from MTC as suspicious but will not always make the diagnosis preoperatively.8 The cells frequently disperse, and are characterized by eccentrically placed nuclei and cytoplasmic tails. Immu- nocytologic staining for calcitonin confirms medullary cancer. Staging of MCT is done by performing ultrasono- graphy or CT scanning of the neck and CT of the chest and upper abdomen.
Biochemical screening to detect pheochromocytomas in MEN-2 patients may be done by measuring urinary catecholamines and metanephrines. Plasma free metanephr- ines are recommended by investigators at the National Institutes of Health as the most sensitive diagnostic test84; however, investigators at the Mayo Clinic85 have found that plasma metanephrines lack the specificity to recommend it as a first-line test in adults. When the biochemical diagnosis is made, localization of the tumor is done by a CT or MRI of the abdomen; rarely, 123-I-metaiodobenzylguanidine scin- tigraphy or 111-Indium pentetreotide (Octreotide) scintigra- phy may be helpful.
In primary hyperparathyroidism, the diagnosis is estab- lished by finding high (or inappropriately normal) serum parathyroid hormone concentrations in the presence of hypercalcemia. Because primary hyperparathyroidism is almost always multiglandular, there is no need for localiza- tion studies.
In pituitary adenomas, prolactinomas are diagnosed by a high serum prolactin after excluding other causes of hyperprolactinemia (drugs, hypothyroidism, pregnancy, etc). The diagnosis of Cushing’s syndrome and acromegaly is reviewed elsewhere in this issue.
Fasting serum gastrin should be measured in any patient suspected of having the Zollinger-Ellison syndrome. In the presence of gastric acid (ie, a gastric pH below 5.0), a serum gastrin value greater than 1000 pg/mL (475 pmol/L) is virtually diagnostic of the disorder. Insulinomas are diag- nosed by measuring serum insulin (high) and C-peptide
(high) at the time of documented hypoglycemia after excluding surreptitious sulfonylurea intake.
Multiple endocrine neoplasia type 2A and MEN-2B are inherited in an autosomal dominant pattern with very high penetrance. The genetic defect in these disorders in- volves the RET protooncogene on chromosome 10.86 The RET protein is a receptor tyrosine kinase that appears to transduce growth and differentiation signals in several tissues. Modern screening with molecular methods for the RET protooncogene should permit an early diagnosis of the MEN-2 syndromes.
Multiple endocrine neoplasia type 1 is also inherited in an autosomal dominant pattern. Because the MEN1 gene has been cloned, direct DNA testing for inherited MEN1 mutations has become possible. The proper role of such testing in screening and clinical management, however, remains to be determined.
Brief overview on management
With regard to MTC, total thyroidectomy with central lymph node dissection should be performed.87 Patients with MTC should be evaluated for possible pheochromo- cytoma before thyroidectomy; if one is found, it should be removed first.
Medullary thyroid cancer in patients with MEN-2B is more aggressive than in MEN-2A or familial MTC, and surgery is often not curative.70,88 Radiation therapy can also be used to diminish the tumor burden in the neck and to prevent local recurrence. Whether morbidity or mortality is improved remains questionable87; as a result, radiotherapy cannot be strongly recommended. The response of patients with metastatic MTC to chemotherapy or radioactive iodine treatment has usually been poor.8
An important issue is the optimal time of surgery in children identified as carrying a RET mutation by genetic screening. Although there is no universal agreement, a reasonable approach in these children (which is in agree- ment with guidelines from an MEN consensus meeting in 200171) is to perform thyroidectomy and central node dissection at age 4 to 6 years.75 Even earlier thyroidectomy is justified in MEN-2B,69 given that metastatic disease has been reported in 1-year-old children with the disease and that later surgery is often not curative.
Surgery for pheochromocytoma should be performed only after adequate «-blockade. A ß-adrenergic blocker may then be added to overcome tachycardia, but it should never be started first because blockade of vasodilatory peripheral ß- adrenergic receptors with unopposed a-adrenergic receptor stimulation can lead to a further elevation in blood pressure. The patient should be ready for surgery in 10 to 14 days.
Once the biochemical diagnosis of primary hyperpara- thyroidism is confirmed in a patient known or presumed to have MEN-2A, the indications for surgical intervention are similar to those in patients with sporadic primary hyper- parathyroidism. These include symptomatic or marked hypercalcemia, nephrolithiasis, major hypercalciuria, and
evidence of bone disease. Evidence of pheochromocytoma should be sought before parathyroidectomy, and if present, the pheochromocytoma(s) should be removed before the parathyroid surgery. Preoperative localization studies are not indicated in patients with MEN-2A who have not had previous neck surgery. Bilateral neck exploration in an attempt to find all glands should always be performed in patients with known or suspected MEN-2A. Beyond that, controversy exists as to the ideal surgical approach. Some experts prefer subtotal parathyroidectomy (usually removal of 3 1/2 glands) to total parathyroidectomy with forearm autotransplantation (which carries a higher risk of hypo- parathyroidism). Centers using either approach, however, report excellent and equivalent results.89,90
The Carney complex
Introduction
The complex of “spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas” or Carney complex is an autosomal dominant, multiple neoplasia syndrome that was initially described in 1985 under the rubric “the complex of myxomas, spotty pigmentation, and endocrine overactivity.”91 Isolated patients with some components of the complex, in particular, cardiac myxomas and pigmentary anomalies, had previously been described under the acronyms NAME (nevi, atrial myxomas, and ephelides) and LAMB (lentigines, atrial myxomas, and blue nevi).92,93 Today, it is accepted that most, if not all, of these patients had Carney complex.
Clinical presentation
Carney complex may be viewed as a form of MEN because affected patients often have tumors of two or more endocrine glands, including primary pigmented nodular adrenocorti- cal disease (some with Cushing’s syndrome), pituitary ade- noma, testicular neoplasms, thyroid adenoma or carcinoma, and ovarian cysts.94 Additional unusual manifestations in- clude psammomatous melanotic schwannoma, breast ductal adenoma, and a rare bone tumor, osteochondromyxoma.94
In an analysis of 338 patients from a worldwide collection of affected patients, the following clinical manifestations were recorded: spotty skin pigmentation (77%), heart myxoma (53%), skin myxoma (33%), pigmented nodular adrenocortical disease (26%), and testicular neoplasms (33% of male patients).94 The same analysis enabled also to present diagnostic criteria, according to which a patient is considered to have Carney complex if two major criteria out of a list of 12 are present or, alternatively, if one major criterion is present and a first-degree relative has Carney complex.
Cutaneous manifestations
Carney complex shares clinical features with several other “familial lentiginoses,” such as Peutz-Jeghers syn- drome, Cowden disease, and Bannayan-Zonana syndrome,
all of them associated with mucocutaneous lentigines, multiple neoplasms in particular endocrine tumors, and auto- somal dominant inheritance. Lentigines in Peutz-Jeghers syndrome are indistinguishable from those of Carney complex: their presence, particularly in the mucosae, serves to identify families affected with any of the lentiginoses.95
Diagnosis and management
Depending on the clinical presentation, testing should be directed toward the suspected pathology (adrenal Cushing’s, pituitary tumors, thyroid nodules, etc), and appropriate treatment should be instituted once the diagnosis is con- firmed. Discussion related to these topics is reviewed elsewhere in this issue.
Carcinoid tumors
Introduction
The first description of a carcinoid tumor was by Lubarsch96 in 1988. The name carcinoid was applied by Obendorfer97 in 1907, but the exact nature of the tumor was not determined until 1928 when Masson98 described its origin as the chromaffin cell.
Although malignant carcinoid neoplasms are not rare (incidence, 1.5 per 100,000 of the population99), the carcinoid syndrome is occurring in less than 10% of patients with the tumor. 99-101
Carcinoid tumors are rare. The age distribution of carcinoid tumors ranges from the second to the ninth decade, with the peak incidence occurring between 50 and 70 years of age.102 Most carcinoids are located in the gastrointestinal tract (55%) and bronchopulmonary system (30%).103 Within the gastrointestinal tract, most carcinoids arise in the small intestine (45%; most commonly in the ileum), followed by rectum (20%), appendix (16%), colon (11%), and stomach (7%).
Carcinoid tumors were so named because they seemed morphologically different and clinically less aggressive than the more common intestinal adenocarcinoma.104 Carcinoids arise from enterochromaffin cells of the gastrointestinal tract. The term enterochromaffin refers to the ability to stain with potassium chromate (chromaffin), a feature of cells that contain serotonin.
Clinical presentation
Carcinoid syndrome is the term applied to a constellation of symptoms mediated by various humoral factors elabo- rated by some carcinoid tumors. These tumors synthesize, store, and release a variety of polypeptides, biogenic amines, and prostaglandins. Some of these tumor products are responsible for the carcinoid syndrome, but the relative contributions of each and specificity of any for particular components of the syndrome are uncertain.
Carcinoid tumors may arise anywhere in the gastrointes- tinal tract, in the bronchi, and occasionally elsewhere.
The liver inactivates the bioactive products of carcinoid tumors. This may explain why patients who have gastroin- testinal carcinoid tumors have the carcinoid syndrome only if they have hepatic metastases, resulting in the secretion of tumor products into the hepatic veins.105 In contrast, bronchial and other extraintestinal carcinoids, the bioactive products of which are not immediately cleared by the liver, can rarely cause the syndrome in the absence of metastatic disease because of their direct access to the systemic circulation.106
Seventy-five to eighty percent of patients with the carcinoid syndrome have small bowel carcinoids; however, the expression is variable in individual patients. 107
Cutaneous flushing and venous telangiectasia will be discussed in the section on cutaneous manifestations.
Diarrhea
Secretory diarrhea occurs in 80% of patients and is often the most debilitating component of the syndrome. Stools may vary from few to more than 30 per day, are typically watery and nonbloody, and can be explosive and accompanied by abdominal cramping. The abdominal cramps may be a consequence of mesenteric fibrosis.
The diarrhea is usually unrelated to flushing episodes. Transit time through the intestine may be extremely short108; as a result, opacification of the entire small bowel and even the colon may be evident fluoroscopically at a time when a patient is completing an initial barium drink.
Bronchospasm
Ten to twenty percent of patients with the carcinoid syndrome have wheezing and dyspnea, often during flushing episodes. Carcinoid wheezing should not be mistaken for bronchial asthma because treatment with ß-agonists can trigger intense, prolonged vasodilation.106
Cardiac valvular lesions
Carcinoid heart disease is characterized by pathogno- monic plaquelike deposits of fibrous tissue. These deposits occur most commonly on the endocardium of valvular cusps, the cardiac chambers, and occasionally, on the intima of the pulmonary arteries or aorta. The valves and endocardium of the right side of the heart are most often affected because inactivation of humoral substances by the lung protect the left heart.105,107
Others
There is an increased incidence of peptic ulcer in patients with metastatic carcinoid tumors, occurring in those with and those without the carcinoid syndrome.109 Diversion of dietary tryptophan for synthesis of large amounts of sero- tonin can result in the development of pellagra,110 man- ifested by rough scaly skin, glossitis, angular stomatitis, and mental confusion. Poor dietary intake and diarrhea or mal- absorption can augment this process. Muscle wasting may occur because of poor protein synthesis. In addition to the mesenteric fibrosis associated with carcinoid tumors,
extensive fibrosis can occur in the retroperitoneal area and other sites, causing ureteral obstruction or Peyronie’s disease. 111,112
In the case of bronchial carcinoids, fatal pulmonary edema can occur with left-sided lesions. Hemoptysis may be massive or recurrent. In addition, bronchial carcinoids may result in Cushing’s syndrome from ACTH production by the tumor.113
Cutaneous manifestations
1. Cutaneous flushing: episodic flushing is the clinical hallmark of the carcinoid syndrome and occurs in 85% of patients. The typical flush associated with midgut carcinoids (jejunum, ileum, and appendix) begins suddenly and lasts 20 to 30 seconds. It primarily involves the face (see Fig. 4), neck, and upper chest, which become red to violaceous or purple, and is associated with a mild burning sensation. Severe flushes are accompanied by a fall in blood pressure and rise in pulse rate. As the disease progresses, the episodes may last longer, and the flushing may be more diffuse and cyanotic. Most flushing episodes occur spontaneously, but they can be provoked by eating, drinking alcohol, defecation, emotional events, palpation of the liver, and anes- thesia.115,116 Episodes induced by anesthesia may last hours and be accompanied by severe hypotension (“carcinoid crisis”). In patients with the gastric carcinoid variant, the flushes are patchy, sharply demarcated, serpiginous, and cherry red; they are also intensely pruritic. In patients with the bronchial carcinoid variant, the flushes can be very severe and
prolonged, lasting hours to days.117 They may be associated with disorientation, anxiety, and tremor. Periorbital edema, lacrimation, salivation, hypoten- sion, tachycardia, diarrhea, dyspnea, asthma, edema, and oliguria are other components of this variant.
2. Edema: persistent brawny edema of the face and, to a lesser degree, of the extremities may be an advanced manifestation of the syndrome in some patients with severe flushing attacks. This is particularly true for those with foregut carcinoids.117
3. Venous telangiectasia: these purplish vascular lesions, similar to those seen in acne rosacea, appear late in the course of the carcinoid syndrome. They are due to prolonged vasodilatation and most often occur on the nose, upper lip, and malar areas.
4. Additional skin manifestations associated with carci- noid syndrome include sclerodermalike changes, probably due to impairment of tryptophan metabo- lism and often associated with fibrotic heart dis- ease,99,118,119 rare cases of cutaneous metastatic nodules,120 and others.
Diagnosis
The most useful initial diagnostic test for the carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid (HIAA), which is the end pro- duct of serotonin metabolism.121 This test has a sensitivity of 75% and specificity of up to 100%121 but is fraught with errors that may be induced by the ingestion of certain drugs and foods. The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/d (10-42 umol/d). Values of up to 30 mg/d (157 umol/d) may be found in patients with malabsorption syndromes such as celiac and Whipple’s disease, as well as after the ingestion of large amounts of tryptophan-rich foods. Although some patients with the carcinoid syndrome have similar modest elevations, most have values for urinary 5-HIAA excretion above 100 mg/d (523 umol/d). Measure- ment of urinary 5-HIAA excretion may not be useful in foregut carcinoids (bronchial and gastric), which often lack aromatic amino acid decarboxylase. Many patients with these tumors have minimal or no elevations in urinary 5-HIAA excretion. Instead, the tumors produce 5-hydroxy- tryptophan. In one series, 5-hydroxytryptophan was detected in the urine of 60% of patients with foregut carcinoids.122
Determination of the whole blood serotonin concentra- tion is often helpful when urinary 5-HIAA testing yields equivocal results. Provocation of flushing using epinephrine or pentagastrin are useful in evaluating patients who describe flushing but have normal or only marginally elevated bio- chemical markers.
Once the biochemical diagnosis of the carcinoid syn- drome is confirmed, usually by an elevated 24-hour excretion of 5 HIAA, the tumor must be localized. Two techniques, abdominal CT and octreotide imaging) have a complemen- tary role in this pursuit; abdominal CT with intravenous and oral administration of radiographic contrast agents has a
sensitivity of 87%123 for identifying liver metastases, mesenteric stranding due to tumor spread admixed with a fibrotic response, and mesenteric lymph node enlargement and the primary tumor. Imaging using octreotide124 is a useful technique for tumor localization because tumor cells almost always contain somatostatin receptors, a property shared with other neuroendocrine neoplasms. Octreotide imaging has a sensitivity greater than 90% for identifying carcinoid tumors in patients with carcinoid syndrome.
Brief overview on management
The treatment of choice for a patient who has a localized carcinoid tumor102 is surgery. The extent of the surgical resection depends on the site of origin and size of the primary tumor.
Patients with the carcinoid syndrome105,107 may benefit from therapies for the different components of the syndrome:
1. The patient should be advised to avoid factors that induce flushing episodes, such as alcohol ingestion or specific forms of physical activity that involve pressure or trauma to the right upper quadrant.
2. Mild diarrhea may respond to codeine phosphate.
3. Asthma can be treated with theophylline or the B-2 adrenergic agonist albuterol (which does not precip- itate flushing attacks).
Surgery plays a limited role in the treatment of patients with the carcinoid syndrome because almost all have extensive metastatic disease. Curative surgery can be offered only to the rare patient with resectable nodal, hepatic, or isolated brain metastasis or to patients with extraintestinal primary tumors such as bronchial and ovarian carcinoids that cause the carcinoid syndrome without metastasis. Resection is also recommended for small intestinal carcinoids, even in the presence of metastases, to prevent the development of fibrosing mesenteritis.
Surgical procedures in patients with carcinoid syndrome are potentially hazardous due to the precipitation of carcinoid crisis during induction of anesthesia or surgical manipulation of tumors. This complication can be pre- vented by pretreatment with octreotide, which should be used prophylactically.
A large number of drugs have some efficacy for patients with flushing or more severe diarrhea. In patients with severe symptoms, the only drug that is likely to be effective with acceptable toxicity is the somatostatin analog octreotide. 125
For patients with metastatic disease, interferon-«, che- motherapy, embolization, and chemoembolization have been tried with variable success. 126,127
Carcinoid tumors are characterized by slow growth. Even when metastases are present, survival is measured in terms of years rather than months. The prognosis of carcinoids is largely based upon the size, invasiveness, and histology of the primary tumor; those that are judged to have a typical (vs atypical) histology have a better prognosis.12
Mastocytosis Introduction
Urticaria pigmentosa was first described by Nettleship in 1869 when he presented “an unusual form of urticaria” in a 2-year-old girl. The name “urticaria pigmentosa” was suggested by Sangster in 1878. The 23-year-old Paul Ehrlich (1877), while still a student, showed that the cytoplasmic granules of certain connective tissue cells possessed meta- chromatic properties, and he separated these cells out into a special type. Two years later (1879), he called these cells “Mastzellen,” implying that they were “overnourished” cells. 129
Mast cell diseases include all disorders of mast cell proliferation. These diseases can be limited to the skin, referred to as “cutaneous mastocytosis,” (CM) or involve extracutaneous tissues, called “systemic mastocytosis” (SM)130:
1. Cutaneous mastocytosis consists of different disor- ders: urticaria pigmentosa (eg, maculopapular CM), diffuse CM, or mastocytomas. This is a benign disease.
2. There are multiple forms of SM. They are distin- guished by clinical presentation, degree and type of extracutaneous organ involvement, and associated hematologic syndromes or malignancies.
Disease manifestations result from several pathogenic mechanisms.131 These include increased numbers of mast cells in one or more tissues, effects of local mast cell mass, tissue response to cellular infiltration, and local and distant effects of released mast cell mediators.
Clinical presentation
Gastrointestinal
Symptoms and abnormalities include abdominal pain, diarrhea, nausea, vomiting, peptic ulcer disease, and gas- trointestinal bleeding. Precipitation of symptoms is com- mon with the administration of drugs (such as narcotics, aspirin and nonsteroidal anti-inflammatory drugs, procaine, and penicillin), exposure to cold or hot temperature, barium enemas, trauma, stress, exercise, alcohol, and medical procedures (including bone marrow biopsy, lapa- rotomy, or endoscopy).
Steatorrhea, malabsorption, hepatomegaly, splenomega- ly, and lymphadenopathy may occur via the infiltration of mast cells into the intestine, liver, or spleen.132
Lymphoid tissue and spleen
Lymph nodes and spleen are the organs most commonly infiltrated in all types of SM133:
- Central and peripheral lymphadenopathies are noted in 20 to 60% of patients.
- Splenomegaly is observed in 50% of patients.
Hematologic
The most common hematologic abnormality is mild to moderate anemia, which occurs in up to 50% of patients.134 Eosinophilia is found in 25% of patients, with eosinophils exhibiting the same phenotype as those in the hyper- eosinophilic syndrome (hypogranular and hypersegmented nuclei). Myeloproliferative or myelodysplastic diseases can be associated with SM.
Bleeding, which has been reported in some patients, may be due to the high levels of heparin released from mast cells and a prolonged bleeding time in skin areas infiltrated by mast cells.135 Malabsorption of vitamin K can also contri- bute to a systemic bleeding diathesis.
Skeletal
Osteolytic and osteopenic lesions can be observed, which is manifested as bone pain or fracture.136 Skeletal scintigraphy is necessary to identify the extent of disease. Long bones and the spine are affected.
Neurologic
Frequently ignored and untreated, neurologic manifes- tations of SM include depression, mood changes, lack of concentration, increased somnolence, irritability, and emo- tional instability.”
Cutaneous manifestations
Urticaria pigmentosa
Urticaria pigmentosa (UP) is the most common manifes- tation of mastocytosis in children and adults.138 It is found in more than 90% of patients with systemic indolent mastocytosis but in less than 50% of those with mastocy- tosis associated with a hematologic malignancy.
Lesions among those with UP are characterized by small yellow-tan to reddish brown macules or slightly raised papules (see Fig. 5). Nodules or plaquelike lesions may also occur. The upper and lower extremities are most commonly affected followed by the thorax and abdomen. The palms, soles, face, and scalp remain free of lesions. These cutaneous mast cell accumulations can be identified by Darier’s sign, which is characterized by urticaria and erythema upon rubbing, scratching, or stroking affected skin.139 Pruritus associated with UP is exacerbated by changes in temperature, local friction, ingestion of hot beverages, spicy food, ethanol, or certain drugs. Bullous eruptions with hemorrhage can also occur.
Mastocytomas
Solitary or multiple mastocytomas are rare lesions that occur before 6 months of age and are usually localized in the skin. Other organs, however, can be affected. Lesions are similar in quality to those of UP but can be larger (up to several centimeters).139 Bullae may be present, with typical localization in the extremities but rarely on the palms or soles. Flushing may also occur. Spontaneous involution is frequently observed; surgical removal is curative if required.
Diffuse CM
Diffuse CM is the result of a diffuse mast cell infiltration in the dermis. Involvement of the whole skin can be observed. Discrete lesions are not described. Diffuse CM presents before 3 years of age, with the skin being normal in color or possibly yellowish brown with increased thickness. The diagnosis is made by biopsy, which demonstrates a diffuse increase of mast cells. 139
Pseudoxanthomatous mastocytosis (xanthelasoidea)
A rare variant described by Tilbury Fox in 1875. Pale yellow nodules 1 mm to 2 cm in diameter usually are present in perfusion at birth. Rubbing provokes erythema but not urtication. 140
Erythrodermic mastocytosis
A rare variant of diffuse CM manifesting in generalized erythroderma and the skin has a lichenified leathery appear- ance. Urtication can be provoked over the entire surface.141
Telangiectasia macularis eruptive perstans
This rare form of asymptomatic cutaneous disease (fewer than 1%) is observed exclusively in adults. It appears as tan to brown macules and patchy erythema with little telangi- ectasias. In most cases it is a benign disorder of cosmetic importance only. Bone lesions and peptic ulcer, however, may occur. Darier’s sign may not be demonstrable. 142
Diagnosis
The measurement of serum concentrations of tryptase is used for the diagnosis of mastocytosis.143 There are two principal forms of tryptase, « and mature. The predominant serum form in healthy donors is a tryptase, which is usually found in normal individuals at serum levels up to 11 ng/mL. Levels of a tryptases are therefore released in serum in normal individuals, reflecting mast cell numbers.
By comparison, elevations of mature tryptase are only observed during acute anaphylactic events. During such an event, elevations of mature tryptase can be detected 30 to 60 minutes after the event, can persist several hours depending upon the magnitude of the elevation, and can be
associated with elevations of total tryptases. The normal ratio between total and mature tryptase is usually less than 20.144
Measurement of mature and total tryptases (a plus mature forms) most accurately reflects overall mast cell burden and activation. Systemic mastocytosis is strongly suspected in patients with baseline levels of total tryptases of greater than 20 ng/ml and with a ratio of greater than 20 between total tryptase and mature tryptase.14
The measurement of histamine in a 24-hour urine collection has been used in the diagnosis of SM, particularly before the availability of tryptase measurements.146 A urinary histamine concentration of up to 30 ng/ml is considered normal. Levels of histamine are elevated in adults with SM but not in those with skin-limited disease.
Other testing includes bone marrow biopsy in SM; histologic evaluation of cutaneous and extracutaneous organs; and imaging studies such as CT scan, bone scan, and endoscopies.
Brief overview on management
Treatment varies with the extent of organ involvement. Patients with disease largely limited to the skin are prin- cipally treated by avoiding triggering events and adminis- tering agents aimed at symptomatic relief. By comparison, those with significant extracutaneous involvement are, in addition to the previous measures, given agents aimed at decreasing the number of infiltrating mast cells. In addition, patients with mastocytosis and a hematologic syn- drome or malignancy are treated in the same way as those with such hematologic disorders but without a diagnosis of mastocytosis.
Cutaneous mastocytosis
Several forms of therapy have been used to decrease the number of mast cells in skin:
- Psoralen-ultraviolet A therapy is efficient at decreas- ing the number of mast cells and at controlling pruritus.147 Long-term use is associated with an increased risk of skin cancer.
- Topical corticosteroids are effective at decreasing the number of skin mast cells. Beclomethasone is admin- istered once or twice a day to affected areas. Long-term side-effects, however, may include cutaneous atrophy, adrenal suppression, osteoporosis, and aseptic necrosis of the femoral head.139 Systemic corticosteroids are ineffective in patients with disease limited to the skin.
Systemic mastocytosis
There is currently no cure or standard of care for SM. Symptomatic treatment includes the following:
- Blockade of H1 histamine receptors to prevent flushing and itching-appropriate agents may there- fore include oral cetirizine, hydroxyzine (25 mg every 6 hours), or doxepin (50 to 100 mg/d).148
- Blockade of H2 histamine receptors is aimed at controlling peptic ulcer disease, cramping, and/or diarrhea. The choice of administered agent includes oral ranitidine (150 mg every 12 hours), famotidine (10 mg every 12 hours), or cimetidine (400 mg twice daily). 148
- Aspirin (up to 500 mg every 6 hours) is administered to control flushing.
- Disodium cromolyn (100 to 200 mg four times a day), which is an inhibitor of mast cell degranulation, is used for gastrointestinal symptoms.14
- Epinephrine is used for anaphylactic events.150
- Ketotifen, which is not available in the United States, is used to control mast cell activation and is a first- line agent in Canada and Europe. The oral dose is 2 to 4 mg per 12 hours.151
In addition to the avoidance of precipitating factors and the administration of symptomatic therapy, patients with SM associated with hematologic disorder (myeloproliferative or myelodysplastic) are treated based upon their associated hematologic syndrome or malignancy.152 Patients with aggressive SM are commonly treated with interferon alfa- 2b and/or glucorticoids or cladribine.153 Some clinicians suggest that corticosteroids (40 to 60 mg/d of oral prednisone for 2 to 3 weeks) may be effective in patients with severe malabsorption or ascites.154 Splenectomy is also indicated when hypersplenism occurs in association with severe anemia and thrombocytopenia.155 Patients with mast cell leukemia are treated similarly as those with acute leukemia.
The outcome of patients with CM is excellent. The outcome of patients with SM varies with the disease type.
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