© 1991 S. Karger AG, Basel 0301-1569/91/0534-0250S2.75/0

ORL 1991;53:250-258

Neurological Manifestations of Neuroendocrine Neoplasms of the Larynx D. Deleu3, F. De Geeterb d e p a rtm e n t of Neurology and b Department of Nuclear Medicine, University Hospital A.Z.-V.U.B., Vrije Universiteit Brussel, Belgium

Key Words. Typical carcinoid • Atypical carcinoid • Small cell neuroendocrine carcinoma • Central nervous system • Larynx • Paraganglioma • Neuroendocrine carcinoma • 1311-m-iodobenzylguanidine scintigraphy

Introduction Although small cell neuroendocrine carcinoma (oat cell carcinoma), carcinoid and atypical carcinoid, and paraganglioma may be grouped as neuroendocrine tu­ mors, they display important differences in biological and clinical behavior. For example, small cell neuroen­ docrine carcinomas are characterized by a rapidly pro­ gressive clinical course, which relies on early invasion and métastasés via the blood stream, the lymphatics and via perineural spread. Carcinoid tumors from laryngeal origin, in particular those with atypical histological ap­ pearance, appear to share the same clinically unfavor­ able characteristics. In contrast, other carcinoids tend to have a more favorable prognosis. The biological behav­ ior of laryngeal paragangliomas is usually benign [1],

Neurological Manifestations of Neuroendocrine Neoplasms in General Carcinoid Tumor Patchell and Posner [2] reported neurological mani­ festations in 16% of patients with carcinoid tumors. The types of neurological complications were similar to those

observed in other types of cancer, the most frequent complications being due to metastasis. The most com­ mon neurological complication of carcinoid tumor is metastatic epidural spinal cord compression secondary to vertebral body involvement. This complication has been observed in up to 6% of all patients with carcinoid tumor and 16% of patients with metastatic carcinoid [2], The pathophysiological process underlying this type of meta­ static lesion is hematogenous spread. Pain resulting from bone metastasis is often the first manifestation. Brain metastasis is the second commonest neurological com­ plication, occurring in almost 6% of all patients and 14% of patients with metastatic disease. The mechanism of spread is hematogenous or, especially with pelvic or abdominal tumors, via Batson’s venous plexus. Comput­ erized tomography is unable to distinguish these brain metastases from other types of tumors [3]. Leptomeningeal metastases are very rare in patients with carcinoid tumor. Thus far only 5 cases of dural metastatic carci­ noid have been reported, only 1 being of laryngeal origin [4-8], One of the patients presented with the atypical picture of subarachnoidal hemorrhage [4], These lesions are believed to be due to hematogenous spread. Involve­ ment o f the peripheral nervous system is exceedingly rare. Nonmetastalic neurological complications are also ex­

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Abstract. The neurological complications of carcinoid tumors, small cell neuroendocrine carcinoma and paragan­ glioma include metastatic and paraneoplastic manifestations.

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tremely rare with carcinoid tumors in general. Metabolic encephalopathy with stupor and depression are ascribed to lack of serotonin or its precursors in the brain. Em­ bolic infarction, superior sagittal sinus thrombosis, sei­ zures, and paraneoplastic complications, such as carci­ noid myopathy and polyneuropathy, have all been re­ ported.

artificial vertebra had to be removed. A spondylodesis L4-S1 was carried out using spongiosa of the ilium and allografts.

Small Cell Neuroendocrine Carcinoma Small cell neuroendocrine carcinoma (small cell carci­ noma) may be divided into oat cell, intermediate cell and combined cell carcinoma. Of these, oat cell carci­ noma is the most aggressive tumor, resulting in one of the highest mortality rates in man [9]. Its commonest site of origin is the lung, although extrapulmonary sites of origin have been reported: trachea, esophagus, breast, stomach, pancreas, uterine cervix, prostate and even skin [10-12]. One retrospective study revealed a serious neurological disorder in approximately 30% of patients with small cell lung carcinoma during the evolution of their disease [13]. Most of these neurological manifesta­ tions (63.8%) occurred in patients with extensive dis­ ease. Brain metastases were the most frequent complica­ tion, accounting for 75.7% of the neurological disorders and affecting 24.8% of all patients with small cell lung carcinoma. Other, less frequently observed, sites of me­ tastases in the central nervous system were epidural (11%), meningeal (5.7%), and intramedullary (2.4%). One report of leptomeningeal metastatic small cell carci­ noma [14] and 1 case of epidural metastasis of an atypi­ cal carcinoid of laryngeal origin have been described [15]. The most frequently occurring nonmetastatic ‘para­ neoplastic’ neurological complications in small cell lung carcinoma are Eaton-Lambert syndrome and the syn­ drome o f inappropriate secretion o f antidiuretic hormone (SIADH). The former is found in only 0.3% of patients [13], while the latter is known to occur in about 8% of patients, but it induces neurological problems in only 1.1 % of them [16].

Neurological complications of neuroendocrine tu­ mors of the larynx have only very seldom been reported. However, thus far both metastatic and nonmetastatic, so-called paraneoplastic, syndromes associated with la­ ryngeal neuroendocrine carcinoma have been described. Table 1 summarizes the reports of neuroendocrine neo­ plasms of the larynx associated with neurological mani­ festations or neuropathologic findings, described in the literature. Syndrome o f Inappropriate Secretion o f Antidiuretic Hormone In 1979, Trotoux et al. [18] described the case of a 61-year-old man, admitted with an acute confusional syndrome, preceded by headache, due to SIADH (Schwartz-Bartter syndrome) as a paraneoplastic mani­ festation of a small cell carcinoma of the subglottic larynx. Neurological examination revealed an abnormal mental state, characterized by temporospatial disorien­ tation and confusion. Generalized hyperreflexia was found in the absence of paresis or extensor plantar responses. Physical examination did not reveal any sign of primary tumor. Laboratory examination revealed marked hyponatremia (107 Eq/1) with hypochloremia (80 mEq/1), reduced plasma osmolarity compared to uri­ nary osmolarity and reduced hematocrit. The diagnosis of SIADH was subsequently confirmed by the negative free water clearance and considerably increased plasma antidiuretic hormone (ADH) levels. Thorough investiga­ tion could not reveal any primary tumor. Three months later, however, the patient developed dysphonia and a cervical lymph node was found on physical examination. Laryngoscopy disclosed a subglottic tumor of the larynx, which histologically corresponded to a small cell neu­ roendocrine carcinoma. Radiotherapy was followed by rapid clinical improvement. However, 7 months later the patient presented with icterus, and rapid clinical deterioration ensued. The patient succumbed 7 months after diagnosis. In 1989, Takeuchi et al. [19] described a case of SIADH resulting from an anaplastic small cell carci­ noma of the larynx. This 53-year-old man with a 5-

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Paraganglioma To our knowledge no neurological complications have been described in paraganglioma, except for the case reported by Riifenacht et al. [17] who described the history of a 36-year-old woman who developed a meta­ static lesion to the lumbar spine 16 years after diagnosis. The patient was suffering from lumbago, and the de­ stroyed vertebral body (5th lumbar) was excised and replaced by an artificial vertebra. Six months later the

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Table 1. Cases of neuroendocrine neoplasms of the larynx associated with neurological manifestations, based on literature survey Case No.

Ref. No.

Agc/sex

Small cell neuroendocrine carcinoma 14 1 52/m 2 15 53/m 61/m 3 18 4 53/m 19 5 20 60/f 64/f 6 21 7 26 47/m 53/m 8 26 9 27 47/m 10 28 40/f 11 29 69/m 13 30 42/m 14 30 46/f Atypical carcinoid 15 8 16 15 17 32

58/m 66/m 50/m

Interval between primary tumor and neurological manifestation

Type of neurological manifestation or pathology

Follow-up

3 months 6 months

mental deterioration seizures SIADH SIADH ectopic ACTH Eaton-Lambert syndrome occipital metastasis brain metastasis brain metastasis brain metastasis epidural metastasis spinal cord metastasis brain metastasis

DOD DOD DOD DOD DOD

-

5 months 7 years (?) -

3 years 9 months -

2.5 years -

22 months

dural metastasis epidural metastasis C? brain metastasis

in in in in in

2 months 1 year 7 months 7 months 11 months 2 weeks

in in in in in in in

4 years 1 year 7 months 1 year 2 months 6 months 10 months 6 years

-

DOD DOD DOD DOD DOD DOD DOD

DOD in 1 year DOD in 2 months DOD in 3 years

month history of increasing hoarseness presented with a swollen right jugulodigastric lymph node on physical examination. Laryngeal examination disclosed a tumor of the right false cord, which proved to be an anaplastic small cell carcinoma at biopsy. He received preoperative radiotherapy, followed by total laryngectomy and right neck dissection. Four months later he was readmitted with low back pain associated with a paresis of the lower limbs and recur­ rence of the tumoral mass in the right neck region. Lab­ oratory examinations revealed a marked hyponatremia (122 mEq/1) with hypochloremia (89 mEq/1), which per­ sisted despite the administration of salt supplements. No plasma ADH levels or free water clearance were determined. Bone scintigraphic scan revealed multiple bone metastases. The metastatic tumor was resistant to treatment with vincristine sulphate, cyclophosphamide and adriamycin. He succumbed 7 months later. Appar­ ently, this S1ADH was not associated with neurological manifestations. Weakness in the lower limbs could have been explained by compression of the lumbar spinal cord. SIADH is usually associated with small cell lung can­ cer but has also been described in carcinoid tumors, in tumors of the thymus, the endocrine pancreas, the blad­

der, the duodenum, in pleural mesothelioma, in Hodg­ kin’s disease, and in acute myelogenous leukemia. Pa­ tients with this syndrome may be asymptomatic. How­ ever, mental symptoms, including memory loss, apathy, and impairment of abstract thinking are likely to appear when plasma sodium decreases between 120 and 125 mEq/1. At levels below 115 mEq/1, asterixis, fatigue, lethargy, drowsiness, confusion, disorientation and fi­ nally coma may supervene. Generalized convulsions may occur in the terminal stages of the disease. Muscular weakness and fatigability are some of the complaints in less severely affected patients. Inappropriate high urine sodium or osmolarity in the presence of hyponatremia strongly suggests the diagnosis, which can subsequently be confirmed by the finding of inappropriately high plasma ADH. Removal of the primary tumor and suc­ cessful radiotherapy or chemotherapy are followed by excretion of large volumes of dilute urine and conse­ quent restoration of the plasma sodium to normal. How­ ever, while waiting for the response to the oncologic treatment, SIADH itself must be treated. Fluid restric­ tion is useful in less severe cases, but may take a few days before normal serum sodium levels are obtained. Severe symptomatic hyponatremia should be treated with hy­ pertonic saline solution (3% saline) and furosemide

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DOD = Dead of disease.

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(1 mg/kg body weight). With tumor relapse and recurrent SIADH, demeclocycline (600-1,200 mg/day in divided doses) is the treatment of choice. It brings about a dosedependent, reversible inhibition of arginine vasopressin in renal tubules.

history of hoarseness, sore throat and left-sided otalgia. Indirect laryngoscopy disclosed a large tumor mass in­ volving the left aryepiglottic fold, the left false cord and the infrahyoid epiglottis. Histopathological examination revealed a primary small cell neuroendocrine carcinoma of the larynx with cervical lymph node involvement. During the observation period this patient developed bilateral ptosis especially marked in the evening. In addition, neurological examination revealed proximal muscle weakness with absent deep tendon reflexes. Elec­ tromyography showed low-amplitude muscle action po­ tentials, evoked by stimulation at rest. During fast rate stimulation and strong voluntary contraction a marked increase in the amplitude of the action potentials (incre­ menting response) could be observed. These findings, characteristic of a presynaptic defect of neuromuscular junction, confirmed the diagnosis of Eaton-Lambert Syndrome. Radiotherapy and adjuvant chemotherapy were given. The primary tumor as well as the cervical lymph node metastases disappeared and the myasthenic syndrome vanished. However, a few months later diplo­ pia and seizures in association with the presence of wide­ spread metastatic disease suggested central nervous sys­ tem involvement. More than 50% of well-documented cases of paraneo­ plastic Eaton-Lambert syndrome have been reported in association with small cell lung carcinoma, and it has been estimated that the incidence of Eaton-Lambert syn­ drome in patients with this tumor may be as high as 3-6% [22], However, at least one third of patients with this syndrome never develop cancer even after long fol­ low-up periods. The Eaton-Lambert myasthenic syn­ drome is typically characterized by subacute or chronic proximal muscle weakness, predominantly involving the pelvic and shoulder girdle muscles. There is usually a progressive increase in motor power following attempted movement. Involvement of cranial muscles is rare and usually mild compared to myasthenia gravis. Symptoms of cholinergic dysautonomia, such as dryness of the mouth, metallic taste and impotence, occur in at least 50% of the patients. In contrast to myasthenia gravis, symptoms usually respond poorly to neostigmine. Mor­ phologically, the Eaton-Lambert syndrome is character­ ized by atrophic changes in terminal axons: an increase in the branching of the nerve terminals, and hypertrophy of the postsynaptic membrane. No changes are observed in the number of sensitivity of acetylcholine receptors in the muscle membrane or in the amount of transmitter available. Presynaptically, however, voltage-sensitive calcium channels (especially L-type channels) are scarce

Ectopic Adrenocorticotropic Hormone Syndrome In 1985, Bishop et al. [20] reported the first case of an ectopic adrenocorticotropic hormone (ACTH)-producing laryngeal oat cell tumor. The patient, a 60-year-old women, presented with severe weight loss and a 2-month history of hoarseness, dysphagia, odynophagia and a left cervical mass. She was a heavy smoker and had received 7 years earlier radiotherapy for a well-differentiated squamous cell carcinoma of unknown origin, metastatic to a left submandibular lymph node. Physical examina­ tion revealed a cachectic patient with hyperpigmentation of the skin and facial hirsutism. A 2-cm mass was found in the anterior left midcervical area. Laryngoscopy re­ vealed a supraglottic tumor of the larynx which proved to be an oat cell carcinoma on biopsy. The cell cytoplasm was immunoreactive for ACTH, GRP, neuron-specific enolase, P-endorphin, calcitonin and keratin, by indirect immunoperoxidase techniques. Laboratory investiga­ tions showed a severe hypokalemic (1.3 Eq/1) alkalosis, markedly increased plasma cortisol, serum ACTH, and 17-hydroxycorticosteroids. This was associated with loss of diurnal variation, which could not be suppressed by dexamethasone. Scintigraphic bone and liver scan sug­ gested metastatic involvement. Her clinical condition rapidly deteriorated and she died 2 weeks after presenta­ tion. Autopsy confirmed widespread (adrenal glands, lung, liver, bone, thyroid) metastatic involvement. Ectopic ACTH production due to bronchogenic carci­ noma is the most common cause of Cushing’s syndrome in men. Weight loss, skin pigmentation, hypertension hirsutism and peripheral edema are the most common clinical abnormalities in this syndrome. Muscle weak­ ness is the only common neurological manifestation of this syndrome, but was apparently not present in this patient. However, it should be borne in mind that this paraneoplastic syndrome may be one of the first indica­ tions of an underlying laryngeal small cell carcinoma. Eaton-Lambert Syndrome (Paraneoplastic Myasthenic Syndromej In 1984, Medina et al. [21] reported the case of a 64year-old women, who developed a paraneoplastic myas­ thenic syndrome or Eaton-Lambert syndrome during the course of her illness. Initially, she was admitted with a

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Neurological Manifestations of Laryngeal Neuroendocrine Tumors

and disorganized. Disruption of their function affects the evoked release of acetylcholine. Extensive investiga­ tions using passively transferred murine Eaton-Lambert syndrome indeed have shown that Eaton-Lambert syn­ drome IgG inhibits nerve-evoked calcium entry. Appar­ ently by inhibiting the function of presynaptic voltage­ gated calcium channels [23]. 3,4-Diaminopyridine, which gains access to central nervous system poorly [24] in contrast to 4-aminopyridine, has proven to be the most effective and least toxic treatment. It increases quantal release by blocking vol­ tage-dependent potassium conductance, thereby pro­ longing depolarization at the nerve terminal and enhanc­ ing voltage-dependent calcium influx [25], Central Nervous System Metastasis Leptomeningeal Metastasis. In 1989, Deleu et al. [8] described a case of dural metastasis of a malignant carci­ noid of the larynx. This 58-year-old man had a history of an atypical carcinoid of the larynx, with regional lymph node invasion. At initial diagnosis, left neck dissection had been performed in association with radiotherapy and adjuvant chemotherapy. Eighteen months later total laryngectomy had been performed because of tumor recurrence. One year later the patient presented with a 2-month history of progressive left hemiparesis. Neuro­ logical examination showed a left hemiparesis with cen­ tral type of facial palsy, hypotonia and extensor plantar response. No sensory abnormalities were observed. There were no symptoms or signs to suggest carcinoid syndrome. Skull X ray (fig. 1) revealed hyperostosis without cal­ cifications, in the region of the right parietooccipital part of the brain. Computerized tomographic scan of the brain without contrast enhancement showed a right pari­ etal hyperdense space-occupying lesion originating from the dural surface extending to the parietooccipital re­ gion, with mass effect and adjacent bone thickening (hy­ perostosis). The corresponding T2-weighted magnetic resonance image (fig. 2) revealed an extended area of hypointense signal, probably corresponding to chronic hemorrhage and necrosis. At its most occipital extreme, a small area of hyperintense signal was found, corre­ sponding to recent bleeding. There was no clear evidence of edema. Intraarterial digital subtraction angiography revealed the hypervascularity of the lesion. 123I-m-iodobenzylguanidine (MIBG) scintigraphy (fig. 3) disclosed intense tracer captation in the lesion, thereby confirming its neuroendocrine nature, and suggesting that it was a carcinoid metastasis. Levels of 5-hydroxyindole acetic

Deleu/De Geeter

acid (5-HIAA) and serotonin in blood and urine were repeatedly normal. Serum gastrin, insulin, glucagon, and parathormone levels during basal conditions and after provocation were normal. In contrast, somatostatin, cal­ citonin and neuron-specific enolase serum levels were increased. A thorough investigation did not reveal any other primary or metastatic tumor. At neurosurgery, the tumor appeared to be fixed to the dura but could easily and completely be removed since there was no invasion of the cortical surface. The histological features (fig. 4) and immunohistochemical stainings were consistent with an atypical carcinoid tu­ mor. There was no invasion of the overlying bone. Immunohistochemically the primary tumor as well as the cerebral metastasis were positive for cytokeratin CAM 5.2, carcinoembryonic antigen, calcitonin and so­ matostatin. Both were negative for serotonin, ACTH, Met-enkephalin, bombesin, neurotensin, insulin and glu­ cagon. Shortly after the intervention, chemotherapy was started because of skin metastasis. The patient died of tumor generalization more than 1 year after neurosur­ gery. Brain Metastasis and Spinal Cord. Several instances of secondary central nervous system involvement have been reported in the terminal stage of laryngeal small cell neuroendocrine carcinoma and carcinoid [15, 26-31]. Woodruff et al. [ 15] described the case of a 66-year-old man with a carcinoid tumor of the larynx, who devel­ oped an epidural metastatic lesion in the area of C7, whereas a spinal cord metastasis of a small cell carci­ noma has been described by Weidauer et al. [31], Sun et al. [14] described the history of a 52-year-old man, a heavy smoker, who was admitted with the neuro­ logical syndrome of mental deterioration (probably due to intracranial hypertension) associated with a 3-month history of hoarseness, neck pain and weight loss. Physi­ cal examination revealed bilateral cervical lymphadenopathy. Laryngoscopic examination disclosed a tumor of the left true vocal cord diagnosed as an oat cell carcino­ ma. Thorough investigation revealed a metastatic lesion in the left scapula. He received palliative radiotherapy, but his physical condition continued to deteriorate and he died 2 months after admission. Autopsy revealed widespread metastatic involvement of the central ner­ vous system, cerebral hemispheres, brainstem, cerebel­ lum, pituitary and pineal gland and leptomeninges. Sneige et al. [32] described a case of a 50-year-old man, a heavy smoker, who presented with a 3-month history of pain, dysphagia, and intermittent hoarseness

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3

1

4

2

with hemoptysis. Physical examination revealed a tu­ moral lesion of the left false cord-arytenoepiglottic fold region, diagnosed as amelanotic melanoma. He under­ went a partial supraglottic laryngectomy, which resulted in 19 months free of disease. At that time he was seen

for recurrence of the laryngeal tumor. Total laryngec­ tomy was performed and the tumor was histologically characterized as laryngeal paraganglioma, later being re­ classified as atypical carcinoid [1]. Eight months later métastasés developed in brain, cervical lymph nodes

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Fig. 1. Skull X ray showing hyperostotic bone change in the right parietooccipital region. Fig. 2. T2-weighted spin echo axial magnetic resonance image of the brain showing the tumoral lesion in the right parietal region as a large hypointense signal with at its occipital extreme a small hyperintense signal. Fig. 3. Transverse (upper left), frontal (lower left) and sagittal (lower right) slices of l23I-MIBG scintigraphy. MIBG is taken up in the tumor. This is evidence for its neuroendocrine nature, suggest­ ing that the lesion is a carcinoid metastasis. Fig. 4. Dural metastasis of atypical carcinoid of laryngeal origin. The tumor cells are arranged in a solid growth pattern with presence of a few acini. The cells are rather uniform and contain round to oval vacuolated nuclei with prominent nucleoli. HE. X 400.

and lungs. He died nearly 3 years after the initial diag­ nosis. In 1990, Smets et al. [33] described a case, of laryn­ geal carcinoid with metastasis to the brain, which was in fact a separate report of the same case reported by Deleu et al. [8], Erroneously, Baugh et al. [34] reported, in his literature review of carcinoid of the larynx, the presence of brain involvement in two of these reports [35, 36]; however, this could not be confirmed by us.

Central Nervous System Metastases from Neuroendocrine Tumor: Diagnostic Methods Biochemical Findings Biochemical abnormalities with neuroendocrine tu­ mors may either be tumor markers [e.g. neuron-specific enolase or endocrine secretions such as somatostatin and calcitonin in the case of Deleu et al., 8] or relate to sec­ ondary effects of tumoral secretions [e.g., hyponatremia in SIADH in the case of Trotoux et al., 18 and Takeuchi et al., 19], In connection with carcinoid tumors, the carcinoid syndrome deserves a special mention. It consists of alter­ nating diarrhea and constipation, abdominal distension, headache, flushing and paroxysmal dyspnea or bronchospasm. It is due to oversecretion of serotonin and other APUD products including bradykinin, prostaglandins and histamine [37], 5-Hydroxyindole acetic acid, a me­ tabolite of serotonin, may be increased in the urine, even in patients without symptoms of the carcinoid syn­ drome. The prevalence of carcinoid syndrome in pa­ tients harboring carcinoid tumors is generally accepted to be 4%. Most commonly this syndrome occurs only after the tumor has metastasized to the liver and at present this syndrome has occasionally been reported in association with laryngeal typical and atypical carcinoid [34, 38], Measurements of 5-HIAA and serotonin in the cerebrospinal fluid may be helpful in establishing the diagnosis of carcinoid meningitis [39], Radiological Findings As a large part of the neurological complications of neuroendocrine tumors is due to metastasis, the role of radiological methods in the workup of these problems is evident. In the case of brain metastasis, changes on plain films of the skull depend on the site of the lesion. Prob­ ably only metastases in the meninges can give rise to abnormalities. An example of such abnormalities was given in the case study of Deleu et al. [8], where hyperos­

Deleu/De Geeter

tosis was seen at the tumor site. This is a remarkable finding, since such hyperostotic bone changes have hith­ erto been considered as suggestive for meningioma. This differential diagnostic problem was further compounded by the hypervascularity on angiography. The appearance of brain metastases of neuroendocrine tumors on CT scan and M RI does not differ from that of other types of tumor. Myelography still remains an important diagnostic technique for the identification of epidural metastases and meningeal carcinomatosis. This technique will be replaced by MRI, once the technique is more readily available. Diagnostic Scintigraphy I23I- or 13II-MIBG have succesfully been used as trac­ ers for pheochromocytoma and neuroblastoma, as well as for some neural crest tumors. Their application has been diagnostic as well as therapeutic. Their mechanism of uptake in these tumors relates to their chemical nature as guanethidine derivatives. Not unlike norepinephrine, they are taken up in part by an active uptake mechanism, which prevails at low concentration (as in diagnostic scintigraphy), and in part by passive diffusion, which becomes more important at higher concentrations (as in therapeutic administration). A second active transport transfers the compound from the cytosol to the neuroen­ docrine storage granules. Unlike norepinephrine how­ ever, MIBG is not metabolized by either monoamine oxidase or catechol-O-methyl-transferase [40], The isotopic label permits visualization of the tracer distribution by means of a y-camera. In normal individ­ uals, it includes the salivary glands and nasopharynx, the liver, spleen and urinary bladder in all cases. The heart is clearly depicted in patients with normal catecholamine levels, but not if these levels are elevated. The adrenals are depicted in only 10-20% of patients studied with l3lI-MIBG, but in almost all studied with l23I-MIBG. The lung bases and bowel show some uptake in a minor­ ity of cases [41], In carcinoid tumors, the sensitivity of l31I-MIBG scintigraphy has been estimated from pooled data on 154 patients to be 62.5% [40]. There is no apparent cor­ relation between scintigraphic positivity and carcinoid symptomatology or urinary excretion of 5-HIAA [39]. The moderate sensitivity does not warrant the use of this method to first detect carcinoid or to rule out its pres­ ence [42], However, in selected cases, such as the one described by Deleu et al. [8], this method may be extremely helpful, as it permits ‘in vivo histochemistry’,

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confirming the neuroendocrine nature of tumoral de­ posits. Thirteen of a total of 15 collected cases of paragan­ glioma published have shown uptake of the tracer. In cases of small cell lung cancer on the other hand results of MIBG scintigraphy have been mostly false positive: 25 out of 27 published cases have shown no uptake in the tumor [40].

Neuroendocrine carcinomas of the larynx. A study of two types, one of which mimics thyroid medullary carcinoma. Am J Surg Pathol 1985;9:771-790. Lokich JJ: The frequency and clinical biology of the ectopic hor­ mone syndromes of small cell cancer of the lung. Cancer 1982; 50:2111-2114. Rüfenacht H, Mihatsch MJ, Jundt K, Gächter A, Tanner K, Heitz PU: Gastric epithelioid leiomyomas, pulmonary chondro­ ma, non-functioning metastasizing extra-adrenal paraganglioma and myxoma: A variant of Carney’s traid. Report of a patient. Klin Wochenschr 1985;63:282-284. Trotoux J, Glickmanas M, Sterkers O, Trousset M, Pinel J: Syn­ drome de Schwartz-Bartter: Rélévatcur d’un cancer laryngé sous-glottique à petites cellules. Ann Otolaryngol Chir Cervicofac 1979:96:1720-1726. Takeuchi K, Nishii S, Shun JINC, Ukay K, Sakakura Y: Ana­ plastic small cell carcinoma of the larynx. Auris Nasus Larynx 1989;16:127-132. Bishop J W, Osamura Y, T sutsumi Y : Multiple hormone produc­ tion in an oat cell carcinoma of the larynx. Acta Pathol Jpn 1985; 35:915-923. Medina JE, Moran M, Goepfert H: Oat cell carcinoma of the larynx and Eaton-Lambert syndrome. Arch Otolaryngol 1984; 110:123-126. Lambert EH: The Lambert-Eaton myasthenic syndrome: Clini­ cal features and pathophysiology. 7th International Conference on Myasthenia Gravis. New York, Academy of Sciences, 1986. Pascuzzi RM, Kim YI: Lambert-Eaton syndrome. Semin Neurol 1990;10:35-41. Lundh H, Nilsson O, Rosen I: Treatment of Lambert-Eaton syn­ drome: 3,4-Diaminopyridine and pyridostigmine. Neurology 1984;34:1324-1330. Murray NMF, Newsom-Davis J: Treatment with oral 4-aminopyridine in disorders of neuromuscular transmission. Neurology 1981;31:256-271. Ferlito A: Diagnosis and treatment of small cell carcinoma of the larynx: A critical review. Ann Otol Rhinol Laryngol I986;95: 590-600. Gnepp DR, Ferlito A, Hyams V: Primary anaplastic small cell (oat cell) carcinoma of the larynx. Review of the literature and report of 18 cases. Cancer 1983;51:1731-1745. Lindeil MM, Jung B, Mackay B: Primary oat cell carcinoma of the larynx. AJR 1981;137:555-557. Posner MR, Weichselbaum RR, Carrol E, Fabian RL, Miller D, Ervin TJ: Small cell carcinomas of the larynx: Results of com­ bined modality treatments. Laryngoscope 1983;93:946-948. Wenig BM, Hyams VJ, Heffner DK: Moderately differentiated neuroendocrine carcinoma of the larynx. A clinicopathologic study of 54 cases. Cancer 1988;62:2658-2676. Weidauer H, Biobel GA, Nemetschek-Gansler H, Gould VE, Mall G: Das neue-endokrine Larynxkarzinom vom kleinzelligen (Oat-Cell) Typ. Morphologische und immunohistochemische Befunde und ihre Bedeutung für die Therapie. Laryngol Rhinol Otol 1985;64:121-127. Sneigc N, Mackay B, Ordonze NG, Batsakis JB: Laryngeal para­ ganglioma. Report of two tumors with immunohistochemical and ultrastructural analysis. Arch Otolaryngol 1983; 109:113117. Smets G, Warson F, Dehou MF. Storme G, Sacré R, Van Belle S, Somers G, Gepts W, Klöppel G: Metastasizing neuroendocrine

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Acknowledgments We gratefully acknowledge the help of Dr. Anita Goossens in providing us with the necessary histopathological material. We thank Mrs. Yolande Hanssens and Linda Dewit for their editorial assistance.

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References 21

1 Barnes L: Paraganglioma of the larynx. A critical review of the literature. ORL 1991;53:220-234. 2 Patchell RA, Posner JB: Neurological complications of carci­ noid. Neurology 1986;36:745-749. 3 Patchell RA, Posner JB: Neurological complications of systemic cancer. Neurol Clin 1985;3:729-750. 4 Kovachev D, Ruseva B: Carcinoid of the stomach with métas­ tasés to the dura mater. Vutr Boles 1976;15:98-103. 5 Bouldin TW, Killebrew K, Boone SC, Gay RM: Metastasis of a rectal carcinoid to the posterior fossa. Neurosurgery 1979;5: 496-499. 6 Smith TW, Wans SY, Schoene WC: Malignant carcinoid tumor metastatic to a meningioma. Cancer 1981;47:1872-1877. 7 Murayama K, Shimura T, Isayama K, Matsumoto M, Ohwaki K. Nakazawa S: A case of skull and dural métastasés of carcinoid tumor of the urinary bladder. No Shinkei Geka 1983; 11:643649. 8 Deleu D, De Geeter F, Buisseret T, Goossens A, Caemaert J, EbingerG: Dural metastasis from laryngeal malignant carcinoid. Am J Med 1989;86:502-505. 9 Minna JD, Pass H, Glatstein E, Ihde DC: Cancer of the lung; in DeVita Vincent TJ, Heilman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, Lippincott, 1989, pp 591-705. 10 Richardson RL, Weiland LH: Undifferentiated small cell carci­ nomas in extrapulmonary sites. Semin Oncol 1982;9:484-496. 11 Ibrahim NBN, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 1984;54:1645-1661. 12 Fer MF, Oldham RK, Richardson RL, Hände KR, Greco FA: Extrapulmonary small cell carcinoma. Proc Am Assoc Cancer Res 1980;21:475. 13 Sculier JP, Feld R, Evans WK, Deboer G, Shepherd FA. Payne DG, Pringle JF, Yeoh JL, Quirt IC, Curtic JE. Myers R, Herman JG: Neurologic disorders in patients with small cell lung cancer. Cancer 1987;60:2275-2283. 14 Sun CCJ, Hall-Craggs M, Adler B: Oat cell carcinoma of larynx. Arch Otolaryngol 1981;107:506-509. 15 Woodruff JM, Huvos AG. Erlandson RA, Shah JP, Gerold FP:

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40 Hoefnagel CA: The Clinical Use of l3lI-Meta-Iodobenzylguanidine (MIBG) for the Diagnosis and Treatment of Neural Crest Tumors; doctoral thesis Amsterdam, 1989. 41 Shapiro B, Gross MD, Sandler MP: Adrenal scintigraphy revis­ ited: A current status report on radiotracers, clinical utility, and correlative imaging; in Freeman LM, Weissmann HS (eds): Nu­ clear Medicine Annual. New York, Raven Press, 1987, pp 193— 232. 42 Hoefnagel CA, den Haertog Jager FCA, Taal BG, Abeling NGGM, Engelsman EE: The role of I-131 -MIBG in the diagno­ sis and therapy of carcinoids. Eur J Nucl Med 1987; 13:187— 191.

Dirk Deleu, MD Department of Neurology University Hospital A.Z.-V.U.B. Laarbeeklaan 101 B-1090 Brussels (Belgium)

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carcinom of the larynx with calcitonin and somatostatin secre­ tion and CEA production, resembling medullary thyroid carci­ noma. Virchows Arch 1990;416:539-543. Baugh RF, Wolf GT, McClatcey KD, Lloyd RV, Evans DA: Car­ cinoid (neuroendocrine carcinoma) of the larynx. Ann Otol Rhinol Laryngol 1987;96:315-321. Cefis F, Cattaneo M, Marziano P, Ricci C, Frigerio B, Usellini L, Capella C: Primary polypeptide hormones and mucin-producing malignant carcinoid of the larynx. Ultrastruct Pathol 1983;5:4553. Pages A, Pignodel C, Ramos J: Carcinoïde du larynx. Etude ultrastructurale et immunofluorescence. Ann Pathol 1983;59— 64. Gillin JS, Winawer SJ: Malignant carcinoid syndrome: Manifes­ tations and management. Drug Therapy 1983;13:149-158. Wenig BM, Gnepp DR: The spectrum of neuroendocrine carci­ nomas of the larynx. Semin Diagn Pathol 1989;6:329-350. Nagoumey RA, Hedaya R, Linnoila M, Schein PS: Carcinoid carcinomatous meningitis. Ann Intern Med 1985; 102:779— 782.

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Neurological manifestations of neuroendocrine neoplasms of the larynx.

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