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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.
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