Typical carcinoid tumor of the larynx occurring with otalgia: A case report. (Original Article).

Abstract

Neuroendocrine neoplasms of the larynx comprise a rare group of tumors that have a controversial history with regard to their classification. The World Health Organization categorizes these tumors as typical carcinoids, atypical carcinoids, small-cell neuroendocrine carcinomas, and paragangliomas. A typical carcinoids and small-cell neuroendocrine carcinomas are the more common. Only 13 cases of typical carcinoid have been reported. Local excision is sufficient for typical carcinoids and paragangliomas, but atypical carcinoids require neck dissection because of their tendency to metastasize. Small-cell neuroendocrine carcinomas are not cured by local excision, and these patients have the worst prognosis (5-year survival: 5%); their treatment is limited to chemo- and radiotherapy. Because of these variations in tumor behavior and treatment, it is essential that otolaryngologists and pathologists be able to correctly identify the specific type of tumor in order to optimize patient treatment and survival. We rep ort a case of typical carcinoid and review the pertinent literature on this subject.

Introduction

Neuroendocrine carcinomas of the larynx comprise a rare group of neoplasms. They are classified into four categories: typical carcinoids, atypical carcinoids, small-cell neuroendocrine carcinomas, and paragangliomas. Histologic differentiation of these neoplasms is essential because the treatment options and prognoses differ drastically. Among the four types of tumor, typical carcinoids are the most rare; only 13 previous cases have been reported in the literature. (1-6) In this article, we report a new case of typical carcinoid tumor, which was characterized by referred otalgia, and we review the pertinent literature on this subject.

Case report

A white 52-year-old man, well developed and well nourished, referred himself to our institution for evaluation of a 3-year history of an intermittent, sharp, burning pain in his left ear. The pain usually lasted 15 to 20 seconds then resolved spontaneously. The pain occasionally radiated down the left side of his neck inferiorly. At first, the episodes occurred once or twice per month, but during the 6 months prior to our evaluation, their frequency had increased and they began occurring four or five times per hour.

The patient denied otorrhea, tinnitus, and hearing loss, but he did report a sensation of pressure in his left ear that was not associated with his pain. He denied an nasal obstruction, nasal purulence, decreased sense of smell, swallowing difficulty, or change in voice or speech. He had not undergone any recent dental procedures. The patient also denied any significant past medical or surgical problems. He had smoked one-half pack of cigarettes per day for 17 years before he quit at age 31. He drank alcohol occasionally, and he denied any other drug use.

On physical examination, the auricles, external auditory canals, and tympanic membranes were clear. The temporomandibular joint on the left was not tender to palpation. The anterior nasal cavity was remarkable only for a left inferior septal deviation. The oral cavity and oropharynx were clear.

Indirect laryngoscopy revealed the presence of a lesion on the superior surface of the left arytenoid cartilage. Fiberoptic direct laryngoscopy also detected this lesion, as well as a vocal process ulcer on the left. Based on a presumptive diagnosis of gastroesophageal reflux, the patient was prescribed a trial of a proton-pump inhibitor and scheduled for follow-up.

The patient returned 2 months later and reported no improvement during the interim, although he did note that his pain could be relieved by swallowing, chewing, or speaking. Examination again required the use of the fiberoptic nasopharyngoscope, which revealed some enlargement of the left arytenoid cartilage, as well as the previously noted ulcer. The patient was scheduled to undergo computed tomography (CT) and direct microlaryngoscopy with biopsy. CT findings were negative for laryngeal or thyroidal masses. The patient's serum calcitonin level was normal. The biopsy specimen yielded what was initially interpreted as a neuroendocrine neoplasm suggestive of a poorly differentiated neuroendocrine carcinoma of the larynx; staining revealed that the specimen was positive for cytokeratin, carcinoembryonic antigen, chromogranin, synaptophysin, and calcitonin. However, after the case and pathology were subsequently reviewed by an otolaryngologic pathologist, a final diagnosis of well-differentiated neuroendocrine c arcinoma (typical carcinoid) was made (figure).

The patient underwent repeat direct microlaryngoscopy and resection with clear margins. Following surgery, the otalgia resolved and the patient remains symptom-free.

Discussion

Neuroendocrine neoplasms of the larynx were first described in 1955 by Blanchard and Saunders. (1) Since then, more than 500 cases of neuroendocrine carcinoma of the larynx have been reported. (1-13)

A great deal of confusion and controversy exists with respect to the proper classification of these tumors." (1-3,6,7,9,12,13) At one time, some authors believed that these tumors represented an extrathyroidal medullary carcinoma; this belief was based on the histologic similarities among extrathyroidal medullary carcinomas, atypical carcinoids, and paragangliomas. (1,2,7,10,14) Later, the World Health Organization (WHO) developed a classification system for neuroendocrine tumors of the larynx, (1,2,6) modifications of which were proposed by Gould et al (15) and by Wenig and Gnepp (16) (table).

The WHO classification system

In this section, we briefly outline the four types of laryngeal neuroendocrine tumors and discuss some of their usual and unusual characteristics.

Typical carcinoids. The 13 cases of typical carcinoid that have been previously reported have primarily occurred in male (3:1) smokers in the sixth to eighth decade of life. (1-6) These tumors usually appear in the supraglottic region, and they can be accompanied by a lump or discomfort in the throat, hoarseness, dysphagia, dysphonia, and pain. (5,6,8)

Histologically, these tumors are made up of sheets and nests of uniform cells with small, round or oval, centrally placed nuclei in a poorly delineated clear or slightly granular eosinophilic cytoplasm. (1-3,6) Mitoses are rare, and the stroma is frequently hyalinized. (1,2) Staining can reveal neuron-specific enolase, calcitonin, somatostatin, carcinoembryonic antigen, chromogranin, serotonin, and cytokeratin. (1,2,4,8) These tumors rarely metastasize to local lymph nodes (four of the 13 cases), and only one of the 13 patients died as a result of the disease. (3)

The treatment of choice is local excision. (1-3,6) There is usually no need to perform neck dissection unless symptoms indicate a possible metastasis. (1-3,6) Likewise, adjuvant chemotherapy or radiation is also unnecessary. Prognosis is excellent following complete excision with clear margins. (1,2,6)

Atypical carcinoids. Atypical carcinoids are the most common of the neuroendocrine tumors of the larynx, with approximately 300 cases reported in the literature. (1,2,6) Like typical carcinoids, atypical carcinoids have a predilection for the supraglottis and for male smokers; they also tend to occur with a local mass effect. (1-4,6,8,9)

Atypical carcinoids are characterized microscopically by polygonal cells with amphophilic or eosinophilic cytoplasm that contains centrally or eccentrically placed nuclei. (1,2) The cells are arranged in a variety of configurations, including nests, ribbons, trabeculne, acini, and even a pseudo-Zellballen pattern that mimics a paraganglioma. (1,2,6) Their vascularity, the presence of amyloid, and positive calcitonin staining have led some to confuse atypical carcinoid with medullary carcinoma of the thyroid. (1,2,10) In fact, many early cases that were reported to be extrathyroidal medullary carcinomas were almost certainly atypical carcinoids. These tumors can stain for the same cytologic markers as typical carcinoids, but calcitonin staining is almost universal. (1,2) Unlike typical carcinoids, atypical carcinoids are much more aggressive and have a propensity to metastasize (45%).

Treatment consists of excision with neck dissection, along with a radical or modified radical neck dissection if nodes are positive. (1) Five- and 10-year survival rates are only 48 and 30%, respectively. (1,2,6)

Small-cell neuroendocrine carcinomas. The second most common of the neuroendocrine tumors of the larynx, small-cell neuroendocrine carcinomas have been reported in approximately 160 patients. (1,2,6) Again, they are usually found in older men who have a history of smoking.

These tumors are made up of sheets or cords of small, hyperchromatic, undifferentiated cells that feature scant cytoplasm. (1-3,6) Mitoses are common, as are necrosis and vascular invasion. (3,6) As is the case with patients who have small-cell carcinoma of the lung, the prognosis is extremely poor and unrelated to tumor size. (1-3,6,14) Approximately 50% of such patients have cervical lymph node metastasis. (3)

Because of the high rate of metastasis, surgery is rarely curative and therefore not indicated. The combination of chemotherapy and radiation is the mainstay of treatment. Yet despite treatment, the mean survival after diagnosis is, less than 10 months, and 5-year survival is a dismal 5%. (1-3,6)

Paragangliomas. Paragangliomas are made up of cells that originate in the branchiomeric paraganglionic system and that develop in close relationship to the laryngeal arteries. (3,6) This association might account for the tumor's high degree of vascularity. Paragangliomas are the only laryngeal neuroendocrine tumors that have a female preponderance (3:1). (1-3,6)

Paragangliomas are made up of chief cells arranged in clusters and nests (the classic Zellballen pattern (1,14) that are surrounded by a highly vascular stroma. (1) Mitoses and necrosis are uncommon, as is invasion. Metastasis is rare, as only one case has been reported. (1) The difficulty with this tumor is in distinguishing it from the more aggressive atypical carcinoid. (1,2) The chief cells produce all of the general neuroendocrine markers, but unlike a typical carcinoids, they are usually negative for epithelial staining (cytokeratin, carcinoembryonic antigen). (1,2) These tumors must also be differentiated from melanomas which are chromogranin-negative, (1) and from renal cell carcinomas, which are negative for chromogranin and neuron-specific enolase. (1)

The prognosis following local excision is excellent, and there is usually no need for neck dissection. (1,6)

While the controversy over the classification of these tumors might seem like nothing more than an exercise in semantics, making the distinction among them is essential in light of the vastly different treatment modalities for each. The universal adoption of the WHO classification guidelines by pathologists and otolaryngologists would lessen some of the confusion and misinterpretation and allow for better and more prompt treatment of affected patients. The fact that our patient had referred otalgia emphasizes the need to be suspicious of any pharyngeal, hypopharyngeal, or laryngeal lesion in any patient who manifests ear pain without obvious ear pathology. (11)

From the Division of Otolaryngology--Head and Neck Surgery, Department of Surgery, University of Kentucky College of Medicine, Lexington (Dr. Cuzzourt), the Division of Otolaryngology, Department of Surgery, University of Alabama, Birmingham (Dr. Pezold), and the Ear, Nose, and Throat Center of Central Georgia, Macon (Dr. Dunn).

References

(1.) Ferlito A, Barnes L, Rinaldo A, et al. A review of neuroendoerine neoplasms of the larynx: Update on diagnosis and treatment. J Laryngol Otol 1998;112:827-34.

(2.) Ferlito A, Friedmann I. Review of neuroendocrine carcinomas of the larynx. Ann Otol Rhinol Laryngol 1989;98:780-90.

(3.) Batsakis JG, el-Naggar AK, Luna MA. Neuroendocrine tumors of larynx. Ann Otol Rhinol Laryngol 1992;l0l:710-4.

(4.) Dictor M, Tennvall J, Akerman M. Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the supraglottic larynx. A report of two cases including immunohistochemistry and aspiration cytology. Arch Pathol Lab Med 1992:116:253-7.

(5.) Stanley RJ, DeSanto LW, Weiland LH. Oncocytic and oncocytoid carcinoid tumors (well-differentiated neuroendocrine carcinomas) of the larynx. Arch Otolaryngol Head Neck Surg 1986; 112:529-35.

(6.) McBride LC, Righi PD, Krakovitz PR. Case study of well-differentiated carcinoid tumor of the larynx and review of laryngeal neuroendocrine tumors. Otolaryngol Head Neck Surg 1999:120:536-9.

(7.) el-Naggar A. Laryngeal neuroendocrine carcinoma. Victims of semantics, Arch Pathol Lab Med 1992;116:237-8.

(8.) Laccourreye O, Brasnu D, Carnot F, et al. Carcinoid (neuroendocrine) tumor of the arytenoid. Arch Otolaryngol Head Neck Surg 1991;] 17:1395-9.

(9.) Overholt SM, Donovan DT, Schwartz MR, et al. Neuroendocrine neoplasms of the larynx. Laryngoscope 1995:105:789-94.

(10.) Sweeney EC, McDonnell L, O'Brien C. Medullary carcinoma of the thyroid presenting as tumours of the pharynx and larynx. Histopathology 1981;5:263-75.

(11.) Cummings CW, ed. Otolaryngology--Head and Neck Surgery. 2nd ed. St. Louis: Mosby, 1993:1314-5.

(12.) Romero JM, Bori MA, Lacasa M, et al. [Neuroendocrine carcinoma of the larynx. Review of literature in reference to one case report]. An Otorrinolaringol Ibero Am 1998;25:105-11.

(13.) Vilde F, Arkwright 5, Paoli C, et al. [Neuroendocrine carcinoma of the larynx with secretion of calcitonin: Primary tumor or metastasis of the medullary thyroid carcinoma]? Ann Pathol 1996; 16: 104-7.

(14.) Cotran RS. Robbins Pathologic Basis of Disease. 5th ed. Philadelphia: W.B. Saunders, 1994:1140-2.

(15.) Gould VE, Banner BF, Baerwaldt M. Neuroendocrine neoplasms in unusual primary sites. Diagn Histopathol 1981:4:263-77.

(16.) Wenig BM, Gnepp DR. The spectrum of neuroendocrine carcinomas of the larynx. Semin Diagn Pathol 1989;6:329-50.

Table

World Health Organization classification of neuroendocrine carcinoma
(NEC) of the larynx (*)

Tumor                            Prevalence  Predominance  Metastasis

Epithelial origin
Typical carcinoid                    +           Male         Rare
(well-differentiated NEC)
Atypical carcinoid                  ++++         Male         45%
(moderately differentiated NEC)
Small-cell NEC                      +++          Male         50%
(poorly differentiated)
Neural origin
Paraganglioma                        ++         Female     Very rare

Tumor                               Treatment     Prognosis

Epithelial origin
Typical carcinoid                Local excision     Good
(well-differentiated NEC)
Atypical carcinoid                Excision with   Moderate
(moderately differentiated NEC)  neck dissection
Small-cell NEC                     Chemo- and     Very poor
(poorly differentiated)           radiotherapy
Neural origin
Paraganglioma                    Local excision   Excellent

(*)System proposed by Wenig and Gnepp. (16)