1967 Unusual Endocrine Presentations of Nasopharyngeal Carcinoma Kathryn C. B. Tan, M.D.’ John Nicholls, F.R.c.P.A.’ Annie W. C. Kung, M.D.’ Liiian Leong, F.R.c.R.~ Karen S. L. Lam, M.D.’ ’ Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong. Department of Radiology, University of Hong Kong, Queen Mary Hospital, Hong Kong. BACKGROUND. Nasopharyngeal carcinoma is endemic in Southern China and the majority of patients present with local symptoms due to the tumor. METHODS. This report describes two unusual cases of occult nasopharyngeal carcinoma in which the patients initially presented with endocrine manifestations. RESULTS. The first patient presented with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone (ACTH)production. Nasolaryngoscopy showed a growth in the left nasal fossa and biopsy revealed a poorly differentiated nasopharyngeal carcinoma that exhibited positive immunostaining for ACTH. The second patient presented with a 10-month history of bone pain over both lower limbs. She was normocalcemic but her serum alkaline phosphatase was markedly elevated. A bone biopsy showed both osteoclastic and osteoblastic activity with widespread fibrosis suggestive of Paget’s disease. Three months later, she developed third cranial nerve palsy. Computed tomography investigation revealed a soft tissue mass filling the sphenoid and ethmoid sinuses. Biopsy showed a poorly differentiated nasopharyngeal carcinoma. The bone biopsy was reviewed and immunohistochemistry demonstrated the presence of cells positive for the epithelial marker AE1/3 within the fibrous stroma. Radio-labeled in situ hybridization showed that Epstein-Barr virus early RNA was present in these tumor cells and the bone lesions were in fact metastases. CONCLUSIONS. Nasopharyngeal carcinoma can present with rather atypical symptoms that may lead to a delay in diagnosis. Therefore, in high risk populations, it is important to consider nasopharyngeal carcinoma as a possible primary tumor in patients with occult carcinomas. Cancer 1996; 77:1967-72. 0 1996 American Cancer Society. KEYWORDS: nasopharyngeal carcinoma, ectopic ACTH syndrome, bone metastases, Epstein Barr virus. - N Address for reprints: Kathryn C.B. Tan, M.D., Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong. Received October 10 1995; revision received February 12, 1996; accepted February 12, 1996. 0 1996 American Cancer Society asopharyngeal carcinoma is a common tumor among Hong Kong Chinese and its incidence is approximately 10 to 50 times higher than that of Western countries. It is the third most common malignant tumor in males and the eighth most common in females in Hong Kong. The typical presenting symptoms are usually cervical lymphadenopathy, epistaxis and nasorespiratory symptoms, and audiologic or neurologic symptoms. Skinner et al.’ reported in their series that 43% of Hong Kong Chinese patients with nasopharyngeal carcinoma presented with lymphadenopathy, 31% with nasal symptoms, and 17% with aural symptoms. A small percentage of patients presented with neurologic symptoms or symptoms due to distant metastases. We report two unusual cases of patients with nasopharyngeal carcinoma seen in our unit recently who presented initially with symptoms attributed to endocrine diseases. 1968 CANCER May 15,1996 / Volume 77 / Number 10 Case Reports Case 1 A 48-year-old Chinese postmenopausal woman presented with a 5-month history of general malaise, anorexia, and proximal muscle weakness. She was cushingoid in appearance and her blood pressure was 150/90 mm Hg. Laboratory evaluation demonstrated fasting hyperglycemia and hypokalemic alkalosis. Plasma cortisol and adrenocorticotropic hormone (ACTH) levels were high (basal cortisol, 1573 nanomole [nmoll /L, normal: 150-720 nmol/L; ACTH, 152 picogram [pg]ImL, normal: 9-52 pg/mL) with loss of diurnal rhythm. Twenty-four hour urinary-free cortisol, plasma cortisol, and ACTH levels remained elevated despite low dose and high dose dexamethasone suppression. A stimulation test with ovine corticotrophin-releasing hormone (oCRH) showed only a 20% increase in peripheral plasma cortisol and a 48% increase in peripheral plasma ACTH. The results of the dynamic tests were suggestive of Cushing’s syndrome due to ectopic ACTH secretion.‘ A magnetic resonance imaging scan of the pituitary gland showed no evidence of a microadenoma. A computed tomography (CT) scan of the abdomen showed bilateral adrenal enlargement and there were no pancreatic or ovarian masses. Chest X-ray, CT scan of the thorax, and mammogram were normal. Selective venous sampling was performed to localize the site of ACTH secretion. The ratios of basal inferior petrosal sinus to peripheral ACTH were 1.26 on the right and 1.17 on the left; 5 minutes after oCRH stimulation, the ratios were 1.06 and 1.10, respectively. This confirmed that the hypercortisolism in this patient was not pituitary-mediated. Selective sampling of the peripheral veins did not reveal any gradient of ACTH levels. Because no occult tumor could be identified, metyrapone was used to control the patient’s hypercortisolism. Four months later, she was found to have an enlarged right cervical lymph node. Fine-needle aspiration of the lymph node yielded numerous malignant epithelial cells in a background of lymphoid cells consistent with metastatic carcinoma. The immunoglobulin A (I@) Epstein-Barr (EBV) antibody titre was not elevated (<1:lO). Nasolaryngoscopy showed a growth in the left nasal fossa. Biopsy revealed a nonkeratinizing nasopharyngeal carcinoma (Fig. 1). Using frozen material, immunostaining of the tumor was performed with an antibody to ACTH (BioGenix, San Ramon, CA) and the tumor exhibited positive immunostaining for ACTH (Fig. 2). Radiotherapy to the primary tumor and the lymph node metastases was given upon amelioration of her hypercortisolism. Case 2 A 58-year-old Chinese woman presented to an orthopedic surgeon with a 10-month history of bone pain over both FIGURE 1. Sheets of nonkeratinizing nasopharyngeal carcinoma in a desmoplastic strorna (H & E, x200). FIGURE 2. The tumor exhibited a positive reaction for adrenocorticotropic hormone using frozen material (H & E, x200). lower limbs affecting mainly the ankles and shins. Skeletal X-rays demonstrated the presence of diffuse osteosclerosis. Further skeletal radiographs showed a diffuse increase in bone density, involving both the axial and peripheral skeleton with bone destruction (Fig. 3). Sclerotic nodules and cortical thickening were prominent over some bones (Fig. 4). Bone scan showed widespread patchy increased uptake over the whole skeleton. The features were suggestive of a diffuse sclerotic bone disorder. The differential diagnosis at the time included myelofibrosis, osteoblastic metastases, sclerotic form of lymphoma or myelomatosis, and multifocal osteosarcoma. Her serum calcium and phosphate levels were normal but the serum alkaline phosphatase was elevated to 2030 U/L (normak34-104 U/L). The urinary hydroxyproline was also elevated to 2177 micromoles (,umol)/ Presentation of Nasopharyngeal Carcinoma/Tan et al. 1969 FIGURE 4. Mixed lytic and sclerotic lesions in both tibias with cortical thickening. FIGURE 3. Osteosclerosis of the lower thoracic and lumbar vertebrae day (normal:137-300 pmollday) with a free level of 116 pmol/day (normal:1.5-12 pmollday). Investigation of the gastrointestinal tract, lungs, breast, liver, and oropharynx showed no evidence of tumor and there was no evidence of lymphadenopathy. Serum carcinoembryonic antigen, a fetoprotein, and the immunoglobulin levels were normal. The IgA EBV antibody titre was not elevated (<l:lO). Bone trephine biopsy was therefore performed to exclude a diagnosis of malignancy. The biopsy showed the presence of both osteoclastic as well as osteoblastic activity with widespread fibrosis (Fig. 5). A provisional diagnosis of Paget’s FIGURE 5. Biopsy from the iliac crest showing diffuse sclerosis between the trabeculae of bone (H & E x80). 1970 CANCER May 15,1996 / Volume 77 I Number 10 FIGURE 6. Radiolabelled Epstein-Barr virus early RNA 1 and 2 riboprobe revealed a positive signal in atypical cells within the fibrous Stroma (H & E, x400). disease was made and the patient was started on a 5-day course of intravenous clodronate, which was subsequently repeated twice. Despite significant improvement in her bone pain, her alkaline phosphatase remained markedly elevated. The lack of response in the alkaline phosphatase level was unusual for Paget's disease and cast doubt on the diagnosis. Her serum lactic dehydrogenase was also elevated at 828 U/L (normal:200-360 UIL). Three months later, the patient developed third cranial nerve palsy. CT investigation showed that the sphenoid sinus and the posterior part of the ethmoid sinuses were filled with a soft tissue mass. A biopsy of the nasopharyngeal mass by flexible endoscope showed a nasopharyngeal carcinoma. She was given a course of palliative radiotherapy to the nasopharynx. Six months after the completion of radiotherapy, the patient required a diminished amount of analgesic and symptomatically improved. After the diagnosis of nasopharyngeal carcinoma, her iliac crest biopsy was reviewed. Within the fibrous stroma there were a number of moderately atypical cells present in clusters that initially had been interpreted as reactive. Immunohistochemistry for the epithelial marker AE1/3 was performed and showed weak cytoplasmic positivity. In situ hybridization using a "S-labelled riboprobe for the EpsteinBarr virus early RNA 1 and 2 (EBER 1 and 2) showed the presence of signal over these atypical epitheloid cells (Fig. 6). These findings in a patient with documented nasopharyngeal carcinoma were in keeping with a diagnosis of metastatic nasopharyngeal carcinoma with a desmoplastic response. DISCUSSION Although nasopharyngeal carcinoma is very common in Hong Kong, patients usually only present to an endocri- nologist when they develop hypopituitarism as a consequence of radiotherapy." The majority of patients present with local symptoms due to the tumor',' and it is extremely rare for patients with occult nasopharyngeal carcinoma to initially present with endocrine manifestations. The first patient in our report presented with Cushing's syndrome and initial dynamic endocrine tests suggested ectopic ACTH production. Our effort to localize the source of the ectopic ACTH production was unsuccessful despite extensive investigations. Localization of occult ACTH-secreting neoplasms can still be a major problem despite recent advances in imaging techniques. In some patients, the occult neoplasm may not become clinically apparent for as long as 12 years after the diagnoThe disis of Cushing's syndrome has been e~tablished.~ agnosis of nasopharyngeal carcinoma in our first patient was not made until she developed unilateral cervical lymphadenopathy. That the ectopic ACTH syndrome was caused by the nasopharyngeal carcinoma was supported by the positive staining of the tumor for ACTH on immunohistochemistry and the fact that the hypercortisolism promptly resolved after radiotherapy to the tumor and lymph node metastases. The most common cause of ectopic ACTH syndrome is either small cell carcinoma of the lung or various carcinoid tumors, especially bronchial and thymic. Other well documented causes include medullary carcinoma of the thyroid, pheochromocytoma, medullary paraganglioma, pancreatic islet cell tumors, melanoma, and tumors of the colon, ovary, and prostate."' This is the first documented case of ectopic ACTH syndrome caused by nasopharyngeal carcinoma, although ectopic ACTH syndrome caused by a squamous cell carcinoma of the larynx has been previously reported by Imura et al.,5 in which they described a Japanese patient who developed hypercortisolism after the primary laryngeal tumor metastasized to the liver. Bioassayable and radioimmunoassayable ACTH, as well as bioassayable melanocyte-stimulating hormone, were detected in the metastatic tumor tissue. Despite the absence of neuroendocrine tissue in the nasopharynx, tumors arising in this region seem to be able to secrete biologically active ACTH. It has recently been shown that normal nonpituitary cells from various organs and tissues, including the testis, ovary, liver, kidney, adrenal medulla, hypothalamus, lung, thymus, stomach, lymphocytes, and pancreas, express the propiomelanocortin (POMC)gene from which ACTH is derived."" Immunoreactive POMC peptides have been demonstrated in these tissues and mRNA for POMC has been demonstrated by techniques of in situ hybridization. These nonneoplastic, nonpituitary cells transcribe the POMC gene from a different promoter site that is downstream from the normal pituitary POMC promoter and express a truncated mRNA Presentation of Nasopharyngeal Carcinorna/Tan et al. species approximately 350 bases shorter than pituitary POMC mRNA. This truncated mRNA lacks the nucleotides coding for the signal peptide necessary for normal processing. Therefore, most ACTH immunoreactivity in normal nonpituitary cells is not secreted and is sequestered predominantly in the cytoplasm in an unprocessed form.” The ubiquitous nature of POMC gene expression most likely accounts for the wide variety of tumors responsible for the ectopic ACTH syndrome. The basic mechanisms involved in the ectopic production of ACTH by tumors are poorly understood and the dysdifferentiation hypothesis proposed by Baylin and Mendelsohn is the most widely accepted explanation.” Cells responsible for hormone production in these tumors represent relatively primitive cells that have been prevented from differentiation into mature non-ACTH producing cells as a result of neoplastic events. They therefore retain the ability to express and produce ACTH. Unlike normal nonpituitary cells, however, they mainly express a mRNA of 1150 base pairs, similar to normal pituitary tissue.” Whether this is the result of a genuine promoter switch in these nonpituitary tumour cells is unclear. Alternatively, these tumor cells may have arisen from a small subpopulation of cells that express a different transcript. Despite the presence of glucocorticoid receptors, tumor cells in ectopic ACTH syndrome have also lost the glucocorticoid-mediated mechanism for preventing continuous expression of the POMC gene.” The second patient presented with diffuse osteosclerotic bone lesions. The malignancy most commonly associated with osteosclerotic activity is prostatic carcinoma. Tumors of the breast, lung, and bladder, as well as carcinoids from the gastrointestinal tract, occasional testicular tumors, and melanomas may also produce a sclerotic presentation. Nasopharyngeal carcinoma is a relatively common cause of sclerotic metastatic bone lesions in Asian countries. A recent retrospective study of patients with nasopharyngeal carcinoma in Hong Kong showed that 20% of patients developed bone metastases mainly involving the axial skeleton during follow-up, with 21% of the bone lesions being sclerotic.” This case is interesting as it is the first time we have seen such widespread sclerosis associated with metastatic nasopharyngeal carcinoma due to an occult primary tumor. In metastatic bone disease, tumor cells are usually readily identified even in a setting of widespread sclerosis. However, the pagetoid characteristics in the bone biopsy of this patient were so dominant that the malignant cells were obscured by the secondary response and led to the initial mistaken diagnosis of Paget’s disease. A lymphocytic infiltrate has traditionally been associated with primary nasopharyngeal carcinoma resulting in the erroneous term of lympohoepithelioma,’4but this was not pres- 1971 ent in the bone lesion. This case illustrates the benefit of using EBER in situ hybridization as an indicator for nasopharyngeal carcinoma. The small, intranuclear EBERs are most abundant in latently infected cells with up to 1 million copies present. EBER is therefore sensitive for the detection of EBV but the specificity for nasopharyngeal carcinoma is not absolute because RNA has also been observed in lymphoepithelial- and nonlymphoepithelial-type carcinomas from the lung, stomach, thymus, and salivary gland.I5 It is not present in normal epithelium from these sites. The finding of EBER-positivetumor cells in a patient with metastatic lesions in these areas should therefore direct the clinician toward investigating these anatomic regions as a possible primary source. In this locality, nasopharyngeal carcinoma has the strongest association with the Epstein-Barr virus and EBER has been detected in greater than 95% of all nasopharyngeal carcinoma^.'^ In summary, nasopharyngeal carcinoma can present with rather atypical symptoms that may lead to a delay in diagnosis. Therefore, in high risk populations, it is important to consider nasopharyngeal carcinoma as a possible primary tumor in patients with occult carcinomas. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. Skinner DW. van Hasselt CA, Tsao SY. Nasopharyngeal carcinoma: modes of presentation. Ann Otol Rhino1 Laryngol 1991; 100~544-51. Kaye TB, Crapo L. The Cushing’s syndrome: an update on diagnostic tests. Ann Iiztern Med 1990;xx:434-44. Lam KSL, Tse VKC, Wang C, Yeung RTT. Ho IHC. Effects of cranial irradiation on hypothalamic-pituitary function - a five-year longitudinal study in patients with nasopharyngeal carcinoma. Q 1 Med 1991;78:165-76. Sham JS, Choy D. 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