Moderately differentiated neuroendocrine carcinoma in the floor of the mouth: A case report

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physiologic pathways. Drugs such as sympathomimetits cause elevation of temperature by directly altering the thermoregulatory mechanism.’ This occurs by increasing the metabolic rate and promoting heat dissipation. Antibiotics may cause an increase in temperature by the release of pyogenic endotoxins from the dying organisms such as Treponema and BorreZia8 The most common cause of drug-related fever is a hypersensitivity reaction to antibiotics.’ This occurs by metabolite formation inducing an immunoglobulin G response, thereby increasing temperature.* The clinical features of drug-related fever can follow multiple courses. The course of the fever may be remittent, intermittent, or erratic. Remittent patterns appear as constantly elevated temperatures above lOl.O”F. Intermittent patterns present as daily episodes of fever spikes, which then return to normal. Erratic patterns seem to have no confirmable course. They present as more than 2 episodes of temperature elevation within a 24-hour period.8 Many factors may indicate the likelihood of a drug-related fever. Males and the elderly appear more prone to this condition,5 as well as patients with the complicated medical histories, autoimmune diseases such as systemic lupus erythematosus, or a history of using multiple pharmacologic agents.* Drug-related fever may present as a single symptom, or it may be associated with other clinical signs and symptoms, the most common being pruritus and

urticaria.s In the presence of drug-related fever, the signs and symptoms may differ from those ordinarily expected. Although tachycardia is most commonly seen with fever, the heart rate can remain normal despite temperatures greater than lOl.O”F during episodes of drug-related fever. Chills and myalgia ordinarily seen with fever are,also notably absent with drug-related fever, and leukocytosis and eosinophilia appear only sporadically in these patients.5 In most instances, individuals experiencing drug-related fever have a clinical sense of well-being,’ contrasted with the usual malaise seen during febrile illnesses.

References 1. Redon J, Pasqual JM, Michavila J, et al: Drug fever. Ann Intern Med 107:264,1987 2. Fonseca RJ, Walker RV: Oral and Maxillofacial Trauma. Philadelphia, PA, Saunders, 1987, pp 1159-l 162 3. Isselbacher KJ, Braunwald E, Wilson JD, et al (eds): Harrison’s Principles of Internal Medicine (ed 13). New York, NY, McGrawHill, 1994, p 551 4. Isselbacher KJ, Braunwald E, Wilson JD, et al (eds): Harrison’s Principles of Internal Medicine (ed 13). New York, NY, McGrawHill, 1994, p 1141 5. Mackawiak P, LeMaistre C: Drug fever: A critical appraisal of conventional concepts. Ann Intern Med 106:728, 1987 6. Hanson MA: Drug fever: Remember to consider it In diagnosis. Postgrad Med 89:167, 1991 7. Johnson DH, Cunba BA: Drug fever. Infect Dis Clin North Am 10:85, 1996 8. Lipsky BA, HirscbmannJV: Drug fever. JAMA 245:851, 1981 9. Cunha B: Drug fever: The importance of recognition. Postgrad Med 80:123,1986

J Oral Moxillofac Surg 57: 1 143-l 147, 1999

Moderately Differentiated Neuroendocrine Carcinoma in the Floor of the Mouth: A Case Report Patricia

Baker, MD, * and Antonio

Moderately differentiated neuroendocrine carcinoma is an uncommon but well-documented tumor of the larynx.lJ Review of the English language MEDLINE, CANCER-CD, and Current Contents did not reveal a

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from

Department

University

of Manitoba,

of Pathology, Winnipeg,

Health

Manitoba,

Sciences

Centre,

tprofessor. Garcia: Sherbrook

correspondence Department

of Pathology,

St, Winnipeg,

D 1999 American Association 0278-239

l/99/5709-002

and Manitoba,

reprint

requests

Health

Sciences Canada.

of Oral and Maxillofacial 1$3 00/O

to Dr Alguacil-

R3A lR9,

MDf

case of moderately differentiated neuroendocrine carcinoma arising in the oral cavity. We report a case arising in the floor of the mouth.

Report

of Case

A 49-year-old man presented to his family physician with a 3-month history of discomfort in the right side of his mouth and swelling in the right neck region. He had smoked 1

Canada.

*Resident. Address

Alguacil-Garcia,

Surgeons

Centre,

820

package of cigarettes per day since the age of 20 years and had a history of heavy alcohol consumption. Physical examination showed an ulcerating tumor 4.5 cm in greatest dimension in the right anterolateral side of the floor of the mouth as well as a firm 4- to 5-cm mass in the right submandibular triangle. A computed tomography scan

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showed a large mass in the right anterior half of the floor of the mouth intimately apposed to the inner mandibular surface. Multiple lymph nodes, including the right submandibular, upper posterior cervical, and upper jugulo-digastries, were enlarged, and some showed central necrosis (Fig 1). A small, superficial biopsy specimen of the oral lesion was interpreted as an infiltrating, poorly differentiated squamous cell carcinoma, with an underlying small cell carcinoma. The patient underwent a composite resection of the right anterior floor of the mouth and a right standard neck dissection and marginal mandibulectomy. Reconstruction was done with a radial forearm flap. The postoperative course was complicated by a coagulopathy, hepatic ins&% ciency, gram-negative sepsis, and seizures with progressive worsening of his neurologic status. The patient died 10 days after surgery, and an autopsy was done.

PATHOLOGIC FINDINGS The surgical specimen consisted of a right radical neck dissection, the right side of the floor of the mouth, and a portion of the right mandible. An ulcerating mass measuring 3.7 X 2.4 X 1.4 cm was present in the floor of the mouth. The submandibular gland was almost entirely replaced by a multinodular tumor measuring 2.5 X 1.7 X 2.7 cm. Multiple, enlarged, right upper and lower cervical lymph nodes were identified. Microscopic examination showed an invasive, moderately differentiated neuroendocrine carcinoma showing a vague organoid pattern, with largely solid cell nests and focal trabeculae delineated by thin fibrovascular septa. Occasional glandular lumina and areas of necrosis were present (I9gs 2,3). The tumor cells showed 2 distinct morphologiespolygonal and spindle cells. Most areas were composed of polygonal cells with large, generally round to oval nucleus; hyperchromatic, coarsely granular, chromatin with prominent large nucleolus; and ample eosinophilic cytoplasm (Fig 2). In other areas, the tumor cells appeared spindle shaped with elongated nucleus. In these areas, the chromatin pattern was similar to that of the polygonal cells. However, the nucleolus appeared less conspicuous (Fig 3). The mitotic rate was high in both cell populations. Immunoperoxidase stain (avidin-biotin peroxidase complex method) was positive for the neuroendocrine markers chromogranin (Fig 4A), synaptophysin, and calcitonin, as well as low-molecular-weight cytokeratin in both the polygonal and spindle cells. Ultrastructural examination showed abundant neurosecretory granules in both the spindle and polygonal cells (Fig 4B). The squamous mucosa overlying the infiltrating neuroendocrine carcinoma was largely ulcerated. A small microscopic focus of squamous cell carcinoma “in situ” was identified at the previous biopsy site. There was extension into the underlying submucosal glands (Fig 5) without invasion or connection to the underlying neuroendocrine carcinoma. This small superficial squamous cell carcinoma stained immunohistochemically for low- and high-molecularweight cytokeratin, but not for the neuroendocrine markers. The surgical margins of resection were free of tumor; however, vascular/lymphatic invasion was present. The submandibular gland was largely replaced by metastatic tumor. Several nodes from levels I through lV showed metastatic tumor and extranodal, soft tissue extension. At autopsy, metastatic neuroendocrine carcinoma was found in the lower lobe of the right lung (small 0.7-cm

FIGURE 1. CT scan showing a large tumor in the right anterolateral floor of mouth (long arrow) and an enlarged, centrally necrotic, lymph node (short arrow).

nodule), in several mediastinal lymph nodes, and in the liver (3.0-cm nodule). The histology of the metastases was similar to the moderately differentiated neuroendocrine component, with a predominance of spindle cells. The cause of death was determined to be multiorgan failure and extensive hepatic necrosis.

Discussion Neuroendocrine tumors show a wide spectrum of differentiation, and the nomenclature of their classification is somewhat confusing. In a clinicopathologic study of 54 cases of moderately differentiated neuroendocrine carcinoma in the larynx, Wenig et al, classified neuroendocrine tumors as 1) well-differentiated neuroendocrine carcinoma (carcinoid), 2) moderately differentiated neuroendocrine carcinoma (atypical carcinoid), and 3) poorly differentiated neuroendocrine carcinomas (small cell carcinoma). As defined by Wenig et al, well-differentiated neuroendocrine carcinoma (carcinoid) shows an organoid pattern with nests of uniform bland cells separated by a fibrovascular or hyalinized connective tissue stroma. Mitoses and necrosis are absent. Small cell carcinoma is characterized by sheets of small to intermediate cells with minimal cytoplasm, hyperchromatic nuclei, prominent necrosis, and high mitotic activity. Moderately differentiated neuroendocrine carcinoma shows features intermediate to these 2, with retention of some degree of an organoid pattern. The cells are approximately twice the size of those seen in small cell

FIGURE Hinher orizinal

FIGURE shows

2. Photomicrographs of the tumor. A, Organoid arrangement composed of nests of polygonal cells separated by thin fibrovascular sepia. maanification reveals the ~olvaonul cell m~~nholoav. with orominent nuc/eo/us and ample cytoplasm. Mitoses are present [Hematoxylin-eosin, mggnifications X 125 a;d kzO0).

3. Photomicrographs of ihe tumor. A, Organoid arrangement spindled cells with inconspicuous nucleolus (Hematoxyl~neos~n,

of spindle cells showing a trabecular architecture. original magnikations, x 12.5 and x/100).

5, Higher

magnification

A,

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carcinoma, with variable but usually little necrosis and infrequent mitoses. Typical carcinoids are usually indolent, with infrequent metastases. Small cell carcinomas, in contrast, have an aggressive course with widespread metastases and a generally poor outcome. The prognosis of atypical carcinoid is alleged to be intermediate to these 2, in keeping with its intermediate degree of differentiation. l Wenig et al also state that moderately differentiated neuroendocrine carcinomas of the larynx have a better prognosis than small cell carcinomas. We believe this case to be a primary, moderately differentiated, neuroendocrine carcinoma arising in the floor of the mouth. That this is a primary tumor is supported by the presence of an in situ squamous component, by the large size of the oral tumor, as well as by the extensive metastatic involvement of the ipsilateral cervical lymph nodes and submandibular gland. The small tumor deposits identified at autopsy in the right lung, mediastinal lymph nodes, and liver

CARCINOMA

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FLOOR

OF THE

MOUTH

are believed to represent metastases from the large oral tumor rather than primary tumor. The architectural and cytologic pattern of the tumor was not consistent with small cell carcinoma or with carcinoid. It was pleomorphic, with frequent mitotic figures and necrosis, whereas carcinoids show a uniform cell population. Additionally, most carcinoids are slow growing and surgically resectable, whereas this tumor had widespread metastasis. The tumor was not a small cell carcinoma because the polygonal cells were large, with abundant cytoplasm and often prominent nucleolus. The pattern was organoid, with the presence of occasional small glandular lumina. The presence of necrosis and the high mitotic activity in this tumor suggest commonality with the so-called large cell neuroendocrine carcinomas.2-4In fact, one may argue that large cell neuroendocrine carcinomas are at the “atypical” end of the spectrum of the moderately differentiated neuroendocrine carcinomas as described by Wenig et al. The neuroendocrine nature of this tumor was

FIGURE 4. Photomicrograph A, showing polygonal tumor cells with positive black staining of cytoplasmic granules for chromogranin A (arrows) (Hematoxylin-eosin, original magnification x400). 5, El ec t ron micrograph showing abundant neurosecretorygranules (arrows) in the cytoplasm of the tumor cells (original magnification X 12,000].

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FIGURE 5. Photomicrographs showing A, ulcerated surface of floor of mouth with some normal squamous mucosa (arrowhead) and a small superficial squamous carcinoma “in situ” with extension into the underlying submucosal gland [short arrows). A small submucosal focus of infiltrating neuroendocrtne carcinoma is also present (long arrow). 5, Higher magnification displaying the squamous cell carcinoma “In situ” extension into the submucosal aland duct Is/tori arrowi and the focus of infiltratina ” neuroendocrine carcinoma (long WOW) (Hematoxylin-eosin, original magnifications x40 and ~7251.

confirmed by the immunohistochemical demonstration of neuroendocrine markers (chromogranin, synaptophysin, and calcitonin) as well as by the ultrastructural presence of neurosecretory granules. The presence of a squamous cell carcinoma component is well documented in some neuroendocrine tumors, but it was not found in the cases of moderately differentiated carcinoma of the larynx reported by Wenig et al.’ The small, superficial focus of squamous cell carcinoma may conceivably be interpreted as an incidental unrelated synchronous lesion. However, it also may be considered as an example of the multidirectional differentiation seen in neuroendocrine tumors. Although moderately differentiated neuroendocrine carcinoma of the larynx is well documented in the literature, its presentation as a primary tumor in other areas of the head and neck has not been reported to our knowledge.

This case represents an example of moderately differentiated neuroendocrine carcinoma arising in the floor of the mouth, suggesting that neuroendocrine carcinoma may originate in any area of the oropharyngeal tract. Recognition of its occurrence in this area may lead to more cases being classified as neuroendocrine carcinoma in the future.

References Wenig B, Hymas J, Heffner D: Moderately differentiated neuroendocrine carcinoma of the larynx. Cancer 62:2658, 1988 Woodruff JM, Huvos AG, Erlandson RA, et al: Neuroendocrine carcinomas of the larynx: A study of two types, one of which mimics thyroid medullary carcinoma. Am J Surg Path01 9:771, 1985 Chetty R, Batitang S, Govender D: Large cell neuroendocrine carcinoma of the thymus. Histopathology 31:274, 1997 Travis WD, Linnoila RI, Tsokos MG, et al: Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Path01 15:529, 1991