FLUSHING

Four different types of flushing have been described in the literature. The first type (Fig. 153-2) is the diffuse, erythematous flush, usually affecting the face, neck, and upper chest (i.e., normal flushing area). This flush is commonly of short duration, lasting from 1 to 5 minutes, and is related to early stages of malignant midgut carcinoids. The second type (Fig. 153-3) is violaceous flush, which affects the same areas of the body and has roughly the same time course or sometimes lasts a little longer. These patients also may have facial telangiectasia. This flush is related to the later stages of malignant midgut carcinoids and is normally not felt by the patients because they have become accustomed to the flushing reaction. The third type (Fig. 153-4) is prolonged flushing, lasting for hours up to several days. It sometimes involves the whole body and is associated with profuse lacrimation, swelling of the salivary glands, hypotension, and facial edema. These symptoms are usually associated with malignant bronchial carcinoids. Finally, the fourth type (Fig. 153-5) of flushing reaction is bright red, patchy flushing, which is seen in patients with chronic atrophic gastritis and ECLomas (derived from enterochromaffin-like cells) of the gastric mucosa, with evidence of increased histamine production.^33–38

FIGURE 153-2. Patient with midgut carcinoid and a typical flush (type 1).

FIGURE 153-3. Patient with midgut carcinoid with chronic flushing (type 2) and characteristic telangiectasia of the nose.

FIGURE 153-4. Patient with a lung carcinoid with production of histamine as well as serotonin. Notice the lacrimation and swollen lips in addition to the flush (type 3).

FIGURE 153-5. Patient with gastric carcinoid (enterochromaffin-like [ECL]-oma) with histamine production and typical bright-red flushing (type 4).

The facial flushing associated with carcinoid tumors should be distinguished from other causes of flushes (Tables 153-2 to 153-5). The carcinoid flush is provoked by spicy food, alcohol, and physical and psychological stress and is often worse in the morning. Patients with idiopathic flushes usually have a long history of flushing, starting rather early in life and sometimes with a family history without occurrence of a tumor. Menopausal flushes usually involve the whole body and might be related to release of calcitonin gene–related peptide (CGRP), with transient vasodilation, a so-called dry flush. Another type of menopausal symptom is the wet flush, which includes epinephrine-induced sweating.^39,40 Proposed mediators of flushing in the menopause are CGRP, histamine, prostaglandins, serotonin, lysyl-bradykinin, and substance P. Estrogen is known to have an impact on the production and release of different signaling substances such as noradrenaline and β-endorphin. Low estrogen levels cause lower β-endorphin activity, which in turn enhances the release of gonadotropin-releasing hormone (GnRH), which gives rise to high luteinizing hormone (LH) levels.⁴¹ Postmenopausal women in whom a true carcinoid syndrome is developing can tell the difference between the two types of flushes. Sometimes patients with medullary thyroid carcinoma have brief flushes provoked by alcohol. In patients with watery diarrhea, hypokalemia, achlorhydria syndrome (WDHA; vasoactive intestinal peptide [VIP]omas), a purple-red constant flushing of the whole body may develop. This flushing reaction is related to the vasodilator effects of VIP. Flushes seen in mastocytosis are related to release of histamine from mast cell granules. Mastocytosis is a rare disease of mast cell proliferation that occurs both cutaneously and systemically.^42,43 In addition to the content of histamine and heparin, the mast cell granules contain arachidonic acid, which can be released and metabolized to prostaglandin D₂ (PGD₂). Involvement of skin in mastocytosis causes urticaria pigmentosa, which is present in 99% of all mastocytosis (Darier’s sign). The diagnosis is based on urinary histamine metabolite determination, urinary PGD₂ metabolites, and a tissue biopsy.⁴⁴

Table 153-2. Flushing Reaction: Differential Diagnosis

Table 153-3. Drugs Causing Flushes

Table 153-4. Food Causing Flushes

Table 153-5. Neurologic Disorders Causing Flushes

The exact cause of flushing in the carcinoid syndrome is not yet fully elucidated. It was previously thought to be related to excess production of serotonin, but some patients with high levels of serotonin do not have any flushing, and serotonin antagonists such as methysergide, cyproheptadine, and ketanserin have little effect on the flushing.^34,35,38,45 In a study from our group in which we measured the release of tachykinins (neuropeptide K and substance P) during flushing provoked by pentagastrin or alcohol, a clear correlation was found between the onset and intensity of the flushing reactions and the release of tachykinins.⁸ Furthermore, when the release of the tachykinins was blocked by prestimulatory administration of octreotide, very little or no flushing was observed in the same patient.⁸ Others also reported tachykinins as possible mediators of the carcinoid flush.^46,47 Another mediator of the flushing reaction may be bradykinin, which also has been shown to be released during provoked flushing.^36,48 Histamine may be a mediator of the flushes seen in both lung carcinoids and gastric carcinoids. Tachykinins, bradykinins, and histamine are known vasodilators, and somatostatin analogs may relieve flushing by reducing circulating levels of these agents.⁴⁹ An interesting theory by Furschgott and Zawadski⁵⁰ is that indirect vasodilation is mediated by endothelium-derived relaxing factor or nitric oxide released by 5-HTP during platelet activation and may be a possible cause of flushing.⁵⁰

DIARRHEA

Diarrhea occurs in 30% to 80% of patients with the carcinoid syndrome. Its pathophysiology is poorly understood but is probably multifactorial. A variety of tumor products, including serotonin, tachykinins, histamine, kallikrein, and prostaglandins can stimulate peristalsis, electromechanical activity, and tone in the intestine. A secretory diarrhea may occur.^51,52 Malabsorption may result from intestinal resections, lymphangiectasia secondary to mesenteric fibrosis, bacterial overgrowth secondary to a tumor partially obstructing the small bowel, or rapid intestinal transit. Increased secretion by the small bowel, malabsorption, or accelerated transit may overwhelm the normal storage and absorptive capacity of the proximal colon and result in diarrhea, which may be aggravated if the reabsorptive function of the colon is impaired.⁵³ In patients with increased urinary 5-HIAA and carcinoid syndrome, the transit time in the small bowel and colon is reduced in comparison with that of normal subjects; the volume of the ascending colon is smaller than that in normal subjects, and the postprandial colonic tone is markedly increased. These findings indicate that in patients in whom the carcinoid syndrome is associated with diarrhea, major alterations in gut motor function occur that affect both the small intestine and colon.⁵⁴ Because many patients with carcinoid tumors undergo wide resection of the small intestine at an earlier stage, they may be affected by the symptoms of short bowel syndrome.

CARCINOID HEART DISEASE

Carcinoid heart disease occurs in 57% to 77% of patients with the carcinoid syndrome but is hemodynamically significant in a much smaller percentage (<10%). The carcinoid heart lesions are characterized by plaquelike fibrous and cardiac thickening that classically involves the right side of the heart (approximately 10% affecting the left side). The finding of new collagen beneath the endothelium of the endocardium is almost pathognomonic for carcinoid heart disease. Echocardiography can demonstrate early lesions in about 70% of patients with carcinoid syndrome, whereas routine clinical examination detects them in only 5% to 10%.^55–59 Currently, carcinoid heart disease is a rare event, possibly owing to earlier diagnosis of carcinoid tumors but also because of more effective treatment, such as somatostatin analogs and α interferons, which block the release of substances causing the fibrosis. The most common lesion is tricuspid insufficiency, followed by tricuspid stenosis, pulmonary regurgitation, and pulmonary stenosis. Patients with carcinoid heart disease have significantly higher 5-HIAA levels and tachykinin levels, suggesting that these substances released into the circulation might play a role.⁵⁵ Substances inducing fibrosis are thought to be released directly into the right side of the heart and then neutralized or degraded through the pulmonary circulation, because rather few patients have similar lesions on the left side. However, patients with lung carcinoid occasionally displayed the same fibrotic changes on the left side. Serotonin has been found to modulate cell proliferation in valvular subendocardial cells, and human heart valves have been shown to express serotonin receptors (-HT1B, 1D, 2A and 2B). Long-term administration of serotonin in rats gives rise to cardiac fibrosis.⁶⁰ The transforming growth factor β (TGF-β) family of growth factors is up-regulated in carcinoid fibrous plaques on the right side of the heart, and these growth factors are known to participate in matrix formation and collagen deposition.⁶¹ One substance that might induce TGF-β locally could be serotonin.⁶² Another possible mediator might be insulin-like growth factor 1 (IGF-1), which is released from carcinoid tumor cells. Treatment with somatostatin analogs down-regulates circulating IGF-1 and may prevent further development of carcinoid heart disease.

BRONCHIAL CONSTRICTION

True asthma is rare in patients with carcinoid syndrome. The causative agent for bronchial constriction is not known, but both tachykinins and bradykinins have been suggested as mediators. These agents can constrict smooth muscle in the respiratory tract and also cause local edema in the airways.^63,64

OTHER MANIFESTATIONS OF THE CARCINOID SYNDROME

Fibrotic complications other than heart lesions may be found in patients with carcinoid tumors. These include intraabdominal and retroperitoneal fibrosis, occlusion of the mesenteric arteries and veins, Peyronie’s disease of the penis, and carcinoid arthropathy. Intraabdominal fibrosis can lead to intestinal adhesions and bowel obstruction and is indeed a more frequent cause of bowel obstruction than is the primary carcinoid tumor. Retroperitoneal fibrosis can result in ureteral obstruction that impairs kidney function and sometimes requires treatment with ureteral stents. Narrowing and occlusion of arteries and veins by fibrosis is potentially life threatening. Ischemic loops of small bowel occasionally have to be removed, which ultimately causes short bowel syndrome. Other rare features of the carcinoid syndrome are pellagra-like skin lesions, with hyperkeratosis and pigmentation, myopathy, and sexual dysfunction.^65,66

BIOCHEMICAL DIAGNOSIS

In all types of carcinoid tumors, high levels of CgA, pancreatic polypeptide (PP), and α and β human chorionic gonadotropin subunits may be found.^{26,31,67–72} Patients with NE tumors of the midgut carcinoids have increased 5-HT production, and elevated 5-HT levels can be measured directly in the plasma or indirectly via the 5-HT metabolite, U5-HIAA, in the urine (Fig. 153-6).³² Elevated 24-hour urinary 5-HIAA levels have 73% sensitivity and 100% specificity in predicting the presence of a carcinoid tumor of the midgut area. Patients with foregut carcinoids rarely secrete 5-HT but may release ACTH, GHRH, histamine, and high levels of CgA.²⁶ Patients with hindgut carcinoids rarely have elevated levels of tumor markers, even in the presence of metastatic tissues. However, increased levels of PP and CgA are found in a majority of these patients.⁷³ Plasma CgA is increased in more than 80% of patients with NE GI tumors and is the best general tumor marker (Fig. 153-7). It also appears to correlate with tumor load and can therefore be used to predict prognosis, particularly in patients with classic midgut carcinoids.⁷⁴ Elevation of CgA levels can precede radiographic evidence of occurrence in different types of GI NE tumors. This may prove useful in diagnosis; CgA may be elevated in 93% of patients with metastatic pulmonary carcinoid.²⁶ The sensitivity and specificity are approximately 92% and 96%, respectively, which is better than for neuron-specific enolase (NSE) or α–human chorionic gonadotropin (hCG) testing.⁷⁵ False-positive tests can occur in patients with reduced kidney function or inflammatory bowel disease. Chronic atrophic gastritis also gives high CgA levels. It must be remembered that treatment with somatostatin analogs can reduce the levels of CgA but does not necessarily reduce the tumor mass.

FIGURE 153-6. Schematic drawing of serotonin synthesis.

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