Persistent Erythema, Telangiectases, and Facial Flushing After Carcinoid Tumor Excision

Barbara Giomi, MD, Carla Cardinali, MD, Marzia Caproni, MD, Paolo Fabbri, MD

Disclosures

Skinmed. 2003;2(4) 

Introduction

A 26-year-old woman with an uneventful family medical history presented for evaluation and treatment of a facial dermatosis of 6 years duration. Examination revealed an intense erythema symmetrically distributed over her face, with a particularly marked involvement of the forehead, nose, cheeks, and chin and an evident sparing around the eyes (Figure 1). On the zygomatic prominences, arborizing telangiectases could also be observed (Figure 2). Cervical and submandibular lymph nodes were not palpable. The patient complained of a burning sensation and referred to day-to-day fluctuation in reddening, together with recurrent severe flushing episodes of the same areas, sometimes induced by heat, emotion, or gustatory stimuli such as hot beverages and highly spiced foods. The persistent erythema had developed in the previous 4 months, while facial flushing, initially subsiding between attacks, had appeared first in 1995. In the same period, the patient had also suffered from abdominal pain, chronic watery diarrhea, and paroxysmal hypotension. One year later she had undergone appendectomy following acute appendicitis. Anatomicopathological and immunohistochemical assessments revealed the presence of a carcinoid tumor about 4 cm in diameter, showing positive staining for neuronal specific enolase, chromogranin, and synaptophysin. Shortly after surgical intervention, laboratory investigation documented normal plasma and platelet serotonin (5-hydroxytryptamine [5-HT]) and normal urinary 5-hydroxyindolacetic acid (5-HIAA) levels. Furthermore, computed tomography and magnetic resonance imaging excluded metastatic disease in the liver, and echocardiography was within normal limits. The patient observed a rapid improvement of systemic symptoms that vanished in a few weeks, but continued suffering from cutaneous flushing and progressively developed the facial erythrosis. During the hospitalization, serum levels of serotonin and its metabolite were repeatedly normal: total 5-HT=124 ng/mL (normal range, 90-180); platelet 5-HT=567 ng/109platelets (normal range, 200-600); urinary 5-HIAA=3.2 mg/24 hours (normal range, 2-6). Histamine also showed normal blood levels. Anti-Helicobacter pylori antibodies were slightly increased (30 U/mL; normal value <15 U/mL). Instrumental investigations (computed tomography of abdomen and chest) performed to discover metastatic spread or carcinoid multicentricity were all negative again. Based on the anamnestic and clinical findings, a diagnosis of facial flushing and erythemato-telangiectatic rosacea due to pre-existent carcinoid was established. The patient was started on metronidazole gel 1% and referred to an internal medicine follow-up program. After 1 month, the facial erythema had markedly reduced.

Intense erythema of the forehead, nose, cheeks, and chin with sparing around the eyes.

Arborizing telangiectases of the zygomatic prominences.

Flushing is a transient reddening of the face and, frequently, of other areas (neck, upper chest, epigastric areas) due to a transient vasodilatation and increase in cutaneous blood flow.[1] Flushing reactions can result from different causes and pathophysiologic mechanisms, so that they often represent a difficult diagnostic and management problem ( Table I ) Additionally, when frequent and intense, flushing can lead to a cluster of cutaneous stigmata, possibly identifiable in the erythrosis and telangiectases that characterize the second stage of rosacea.[2]

Carcinoid tumors are neoplasms that arise from neuroendocrine cells throughout the body, but are most prevalent in the gastrointestinal tract, pancreas, and pulmonary bronchi. Appendiceal tumors make up nearly one half of all carcinoids and represent incidental findings in 0.3%-0.7% of routine appendectomy specimens.[3] They are usually small, solitary, and benign. Local invasion is common but metastatic spread is rare, and the presence of a tumor does not appear to be associated with appreciable morbidity or mortality.

Since neuroendocrine tissues secrete a variety of mediators, tumors of these cells can produce syndromes of hormone excess, often long before local growth or metastatic spread is otherwise apparent. Manifestations of the carcinoid syndrome include the "classic" triad of cutaneous flushing, diarrhea, and valvular heart disease and, less commonly, telangiectases, wheezing, and hypotension.[3]

The diagnosis of carcinoid tumors is suggested by these presenting features ( Table II ) and is based on instrumental investigations (computed tomography, barium studies, endoscopy) that allow anatomic localization together with detection of increased levels of 5-HT (synthesized and secreted by the large majority of functional carcinoid tumors) and urinary 5-HIAA excretion. These last diagnostic tests also supply valuable information about the functional nature of the mass and/or its size, since hormone production is as high as more pronounced tumor growth and spreading.

In our patient, the suspicion of carcinoid-dependent flushing arose from the anamnestic data, although it is generally well known that appendiceal carcinoids do not cause systemic signs (i.e., carcinoid syndrome) because of liver metabolization of active substances. An explanation for this apparent contradiction could be found in the presence of liver metastases (repeatedly excluded in our case) or in the tumor dimension. In fact, those very rare neoplasms measuring 2 cm or more (4 cm in our patient) often behave as metastasizing carcinomas and should be treated with prompt surgical intervention.[4]

Interestingly, our patient was still complaining of facial flushing 6 years after carcinoid excision, despite the rapid and steady normalization of serotonin. In this respect, it has been suggested[1] that in susceptible persons, frequent, intense flushing may lead to loss of vascular tone of the superficial vessel plexus, resulting in a cluster of physical signs that strictly overlap those observed in early rosacea. This could be confirmed by the permanent erythrosis observed in our case and could be a reasonable explanation for the persistence of flushing, evoked at any given moment by otherwise insufficient stimuli. On the other hand, several authors[2,5] when testing facial vessels with vasoactive agents, observed that capacity of dilatation and constriction is maintained in rosacea patients after application of adrenaline, histamine, and dimethyl sulfoxide. There is little doubt that additional triggers, such as sunlight overexposure, can combine with repeated flushes to provoke erythrotic rosacea.[2,6]

Finally, it is remarkable that flushing, which is present in approximately 85% of patients with carcinoid syndrome, is also seen with many other conditions, including menopause, autonomic nervous system disfunction, ethanol ingestion, drug withdrawal, and a variety of hormone-secreting tumors like pheochromocytoma, vasoactive intestinal polypeptide(VIP) oma, and mastocytosis[3] ( Table I ). Distinguishing features to favor one possibility over another are few, but differential diagnosis and the understanding of the mechanisms involved are strictly necessary to drive correct management and to choose among the therapeutic options.[7,8] It can be helpful to remember that cutaneous manifestations of carcinoid syndrome are often multiple, and may include pellagra-like lesions (hyperkeratosis, xerosis, scaling of arms, legs, and trunk due to the excessive utilization of tryptophan by the carcinoid, leaving little for the daily niacin requirement), pruritus, cutaneous metastatic nodules,[9] pyoderma gangrenosum,[10] and erythema annulare centrifugum.[11] ( Table II )

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