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Paraneoplastic syndromes in patients with nasopharyngeal cancer
Auris Nasus Larynx 36 (2009) 513–520 www.elsevier.com/locate/anl
Paraneoplastic syndromes in patients with nasopharyngeal cancer C. Toro a, A. Rinaldo b, C.E. Silver c, M. Politi a, A. Ferlito b,* a
Department of Surgical Sciences, Maxillofacial Surgery Clinic, University of Udine, Udine, Italy b Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy c Departments of Surgery and Otolaryngology-Head and Neck Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Received 22 August 2008; accepted 14 October 2008 Available online 27 December 2008
Abstract Paraneoplastic syndromes (PNS) represent the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products. Paraneoplastic effects are not directly mediated by tumor invasion of normal tissue, or by the disruption of normal function of the involved organ, or by distant metastases. More than 260 cases of nasopharyngeal carcinoma (NPC) associated with PNS have been reported in the literature. These syndromes can be divided into six main groups: cutaneous or dermatologic, endocrine, hematologic, osteoarticular or rheumatologic, neurologic, and ocular. The most common dermatologic manifestation is dermatomyositis, while the syndrome of inappropriate secretion of antidiuretic hormone and occasionally Cushing’s syndrome due to ectopic ACTH production are the endocrinologic manifestations. Tumor fever and leukemoid reaction, osteoarticular or rheumatic syndromes, including clubbing of the fingers and toes, sensory neuropathy and demyelinating motor polyneuropathy, and rarely optic neuritis represent the most prominent examples of the other groups of syndromes. PNS may occur before the NPC is manifest, or while it is in an occult stage, and thus the possibility of NPC should be considered in patients with these various disorders. While some PNS will respond to direct treatment, most often the PNS subsides in parallel to response of the NPC, and thus may be useful for monitoring tumor response or recurrence. # 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Nasopharyngeal carcinoma; Paraneoplastic syndromes; Early detection; Pathogenesis; Treatment; Hormones
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Nasopharyngeal carcinoma . . . . . . . . . . . . . . . . . . . . . . Paraneoplastic syndromes . . . . . . . . . . . . . . . . . . . . . . . Paraneoplastic cutaneous or dermatologic syndromes . . . . Paraneoplastic endocrine syndromes. . . . . . . . . . . . . . . . Paraneoplastic hematologic syndromes . . . . . . . . . . . . . . Paraneoplastic osteoarticular or rheumatologic syndromes. Paraneoplastic neurologic syndromes . . . . . . . . . . . . . . . Paraneoplastic ocular syndromes . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Nasopharyngeal carcinoma * Corresponding author at: Department of Surgical Sciences, ENT Clinic, University of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail address: [email protected] (A. Ferlito).
Nasopharyngeal carcinoma (NPC) is relatively uncommon in Western countries, but is 10–50 times more common
0385-8146/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2008.10.006
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in the Far East, and is endemic in the Southern parts of China with the yearly incidence rate varying between 15 per 100,000 and 50 per 100,000 [1]. In Hong Kong, NPC is the third most common malignancy in male and the fifth in female patients with an incidence of 27.5 and 11.2 per 100,000, respectively [2]. The particularly high frequency of malignancies of the nasopharynx in the Far East is not well understood, although metaplasia and eventual carcinoma in situ is associated with chronic sinusitis, which is extremely common in southeast Asian countries [3]. A spectrum of risk factors has been described including environmental carcinogenesis from inhaled or chewed tobacco, racial factors, hereditary trends, and infection with the Epstein–Barr virus (EBV). Undifferentiated carcinoma is the only EBV related NPC. The undifferentiated NPC was initially designated lymphoepitelioma by Schminke [4] and Regaud and Reverchon [5] because of the mixture of lymphoid and epithelial cells seen in the primary tumor. It has subsequently been established that only the epidemoid cells are neoplastic, as evidenced by the absence of lymphoid tissue in metastatic lesions. Thus, undifferentiated NPC is an epidermoid-lineage cancer, and because of various unique features constitutes a clinical entity different from other head and neck squamous cell carcinomas. The typical presenting symptoms of NPC are usually cervical lymphadenopathy, epistaxis, audiologic or neurologic symptoms, and nasorespiratory symptoms. A small percentage of patients present with the clinical manifestation of the indirect and remote effects produced by the tumor.
2. Paraneoplastic syndromes Paraneoplastic syndromes (PNS) represent the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products. Paraneoplastic effects are not directly mediated by the invasion of normal tissue, or by the disruption of normal function of the involved organ, or by distant metastases [6]. PNS occur in 1–7.4% of all cancer patients [7]. Different terms such as paraneoplastic effects, remote effects, paraneoplastic events, non-metastatic syndromes, paraneoplastic manifestations, paraneoplastic phenomena, and paraneoplastic disturbances have all been employed as synonyms to the term ‘‘paraneoplastic syndrome.’’[8]. The mechanism of most PNS is not well known. Only few cases clearly demonstrate an etiologic or a pathogenetic factor. PNS can precede, follow or be concurrent to the diagnosis of a malignancy. Physicians who deal with cancerassociated syndromes should be able to differentiate the PNS from the benign disorders that mimic them. PNS associated with NPC can be divided into six main groups: cutaneous or dermatologic, endocrine, hematologic, osteoarticular or rheumatologic, neurologic, and ocular. The exact incidence of PNS associated with NPC is not known, because numerous ‘‘false-PNS’’ have been reported in
which symptoms are directly related to the invasion of normal tissue by the tumor or by distant metastases [9]. Moreover, sometimes the same cases have been reported in different journals (for example: Botsios et al. [10] and Botsios et al. [11]. We have reviewed the literature in order to underline the various PNS related to NPC and their relevance to the diagnosis.
3. Paraneoplastic cutaneous or dermatologic syndromes First described in 1916 by Stertz [12], the association of connective tissue diseases, particularly dermatomyositis (DM) and scleroderma, with a variety of malignancies has been reported frequently in recent decades. DM seems to have a robust association with malignancy, with studies showing a frequency of cancer of 15–34% in some medical centers. In the upper aerodigestive tract, this phenomenon is seen most commonly with NPC [13]. DM is a severe systemic disorder characterized by typical cutaneous lesions and an inflammatory myopathy. The five main diagnostic findings of DM include: (1) systemic proximal muscle weakness, with or without dysphagia or respiratory muscle involvement; (2) abnormal muscle biopsy findings; (3) elevated skeletal muscle-derived enzymes; (4) abnormal electromyographic findings; and (5) a typical skin eruption (Gottron papules) overlying the knuckles, elbows, and knee joints. Special skin features include a characteristic heliotropic rash on exposed surfaces, periungual telangiectasia, and poikiloderma. The first cases of NPC associated with a dermatologic syndrome were reported in 1969 [14]. Since that time, more than 100 such cases have been reported. NPC has long been reported as the predominant type of cancer associated with DM in several Asian countries, including Hong Kong, Singapore, and Southern-China [15]. Although in the Orient NPC is more frequently found in the general population and in patients with DM, the proportion of individuals with both NPC and DM is approximately 3–4 times greater than in the general population [16]. Ang et al. [17] reported 28 cases with DM from the National Skin Centre of Singapore; malignancies were detected in 12 patients, half of which were NPC. They concluded that screening for malignancies, especially NPC, is recommended for all DM patients. In Hong Kong, 10 of 1154 patients with NPC developed DM [18]. Leow and Goh [19] reported 38 cases of DM in patients affected by cancer, 5 of which were NPC. A photodistributed urticarial vasculitis with DM was described as the presentation of a NPC [20]. The autoimmune basis of DM was confirmed by the presence of a lymphoplasmic cellular infiltrate of the muscular interstices. This clinical entity has mainly been described in patients from southern Chinese groups, and there are fewer reported
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instances among patients in the West. However, Ferris and Koch [13] reported two sporadic cases of DM coincident with NPC in a Western population of 94 patients from the United States. Botsios et al. [11] and Martini et al. [21] reported two cases of caucasian Italian patients with DM associated with NPC. Among caucasian patients, a variety of malignancies are associated with DM, but NPC is sporadically found. In a review of the literature encompassing 590 Western patients with DM, 92 (16%) had associated malignancy. Cancer of the lung and stomach were most frequent among men in this group, whereas women were most likely to have breast or ovarian cancer [22,23]. There are several ways in which mechanistic factors may link paraneoplastic dermatologic syndromes with NPC. They may result from immune disregulation, leading to aberrant recognition of normal tissues after viral-mediated transformation and tumor formation. One potential pathway for a linkage may be the production of a tumor-related antigen that induces an autoimmune response because of the homologous sequence with some normal antigen (‘‘molecular mimicry’’). EBV is widely accepted as an etiologic agent in NPC tumorigenesis. Activation of an immune response to a ‘‘cryptic’’ epitope, not produced or exposed before viral infection, may result from the matching of a viral epitope to a mutated or endogenous antigen. The unmasking of cryptic immune epitopes in the setting of EBV infection may enable the activation and expansion of autoreactive immune response, perhaps through the dysfunction of suppressor T cells, leading to clinical connective tissue manifestations (antibodyantigen complex deposition, complement fixation, and tissue damage) [13]. In a woman with a primary NPC associated with hypertrophic osteoarthropathy (HOA) and cutaneous vasculitis, the serum contained antibodies to EBV and U1 Ribonucleic Protein (RNP) antigens. Cryoproteins isolated from her serum contained antibodies to U1 RNP and a protein with a molecular weight of 32 kD, which reacted specifically with antibodies to U1 RNP. HLA typing revealed HLA-B7 and DR1, and these have been reported to be increased in Japanese patients with rheumatic diseases who have autoantibodies to U1 RNP. These findings indicated that some features of the PNS in this patient might have been caused by immune complexes, part of which were formed by specific autoantibodies produced under genetically controlled conditions of immune responsiveness [24]. Stone [25] proposed multiple trigger mechanisms caused by malignancy to account for the onset of DM. He cited the changes in extracellular membrane around tumors with entry into the circulation of altered glycosaminoglycans. The secretion of biologically active molecules by the transformed NPC cells may be another factor, resulting in a paraneoplastic phenomenon inducing connective tissue diseases. In most reported cases, the course of the PNS precedes the diagnosis of NPC [26], and then runs parallel to
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the cancer, with improvement of the DM after chemotherapy and radiation therapy of the tumor [27]. Several researchers have suggested that patients with DM be screened for the possible presence of NPC [28]. An unfavourable prognosis is suggested when DM is associated with NPC [18].
4. Paraneoplastic endocrine syndromes Patients affected by NPC usually consult the endocrinologist when they develop hypopituitarism as a consequence of radiotherapy. The majority of patients present with local symptoms due to the tumor and it is rare for patients with occult NPC to present initially with endocrine manifestations. Paraneoplastic endocrine syndromes result from aberrant production of protein hormones, hormone precursors, or hormone-like substances by tumors. Ectopic or inappropriate hormone secretion causing clinically manifest syndromes is uncommon in patients with cancer of the head and neck [29]. The most important of these is the syndrome of inappropriate secretion of arginine vasopressin, known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or as Schwartz–Bartter syndrome. SIADH was first described in association with bronchogenic carcinoma [30]. The condition also has been reported to occur in various other types of malignant neoplasms, in central nervous system disorders, with numerous cardiopulmonary diseases, and in drug-related iatrogenic cases. Of particular interest is the SIADH associated with ectopic secretion of vasopressin by tumor cells. However, this condition has been associated only rarely with tumors of the head and neck. Only in 1981, 24 years after the first description of SIADH, was it found in association with a sarcoma of the epipharynx [31]. Hayes et al. [32] proposed that SIADH observed after induction chemotherapy for squamous cell carcinoma of the head and neck might be produced by the rapid lysis of cancer cells by cytotoxic agents, thus releasing vasopressin or some other substance capable of producing SIADH. An entirely different pathophysiologic explanation was offered by Wenig and Heller [33], who analyzed six cases of SIADH after radical neck dissection for cervical metastases; five of the six patients also received radiation therapy. It was suggested that impaired venous return led to increased intracranial pressure, indirectly causing SIADH. The oral cavity is the most common primary tumor site of the head and neck in paraneoplastic SIADH, and squamous cell carcinoma is the most common histological type in these cases. Kavanagh et al. [34] observed a patient with undifferentiated NPC whose clinical presentation, results of laboratory studies, and clinical response to water deprivation suggested the presence of SIADH. This was the first report of pathologic confirmation of the syndrome with the use of
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both molecular and immunologic probes. Histologic examination of the nasopharyngeal mass with the use of in situ hybridization and immunohistochemical techniques confirmed expression of the messenger RNA for the vasopressin precursor, propressophysin, and its translated peptide products in the biopsy sample. Talmi et al. [35] reported a retrospective review of 1436 patients with head and neck malignancy. In 43 of these patients (3%), SIADH was found to be associated with the cancer of the head and neck, and six of these primary tumor were detected in the nasopharynx. Antidiuretic hormone (ADH) or its biologically active form in human, i.e., arginine vasopressin, is normally synthesized in the hypothalamus and then transported through the hypothalamic-neurohypophyseal stalk to the posterior pituitary, where it is stored and finally released. ADH physiologically participates in maintaining a constant serum osmolarity and intravascular volume, acting on the renal tubular apparatus by retaining water and concentrating urine. The SIADH is characterized by excessive blood levels or actions of vasopressin associated with hyponatremia without edema. The inability to excrete a diluted urine implies a subsequent retention of ingested fluids, with expansion of the extracellular fluid volume. Hyponatremia is due to higher urinary excretion caused by decreased reabsorption of sodium—both factors contribute to the syndrome. Diagnostic criteria for SIADH are: hyponatremia (<135 mEq/L), serum hypo-osmolarity (<280 mOsm/kg), urine concentration or specific gravity greater than expected for serum osmolarity (continued urinary excretion of sodium, urine osmolarity of >500 mOsm/kg or >300 mmol/Kg, urinary concentration of sodium of >20 mEq/L), no edema, orthostatic hypotension, or features of dehydratation, no evidence of volume depletion, normal renal, adrenal, and thyroid function, elevated plasma concentration of vasopressin, hypouricemia due to increased renal clearance, hypocreatininemia and hypoalbuminemia [29]. The syndrome may precede the presentation of the cancer by a few weeks or months. Identification of endocrine syndromes is important because they cause symptoms which are frequently treatable. In SIADH, appropriate treatment consists on the treatment of the primary tumor and restriction of fluid intake. In severe cases this syndrome should be treated with hypertonic saline solution (3% saline) and furosemide. The treatment of choice in tumor relapse and recurrent SIADH is demeclocycline (600–1200 mg/d in divided doses) [36]. The prognosis depends on the underlying malignancy and its treatment. Tan et al. [37] reported the first case of occult NPC initially presented with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production. Cushing’s syndrome, accompanied by high plasma levels of ACTH, hypokaliemia and increased serum and urine cortisol concentrations, is a common example of a paraneoplastic
endocrine disorder linked to a malignancy. Ectopic ACTH syndrome is most commonly associated with small cell carcinoma of the lung or various carcinoid tumors; particularly bronchial and thymic. Other well documented causes include medullary carcinoma of the thyroid, pheocromocytoma, medullary paraganglioma, pancreatic islet cell tumors, and tumors of the colon, prostate, and ovary. 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 been shown that normal non-pituitary cells from various organs and tissues, express the proopiomelanocortin gene from which ACTH is derived [38]. Immunoreactive proopiomelanocortin peptides have been demonstrated in these tissues. The ubiquitous nature of proopiomelanocortin gene expression most likely accounts for the wide variety of tumors responsible for the ectopic ACTH syndrome. The basic mechanism involved in the ectopic production of ACTH by tumors is poorly understood and the dysdifferentiation hypothesis proposed by Baylin and Mendelsohn [39] 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.
5. Paraneoplastic hematologic syndromes Tumor fever and leukemoid reaction are associated with NPC as PNS. They are usually observed in patients with metastatic disease. Tumor fever is frequently associated with other PNS, of which leukemoid reaction is the most common. These remote effects are not produced as a direct effect of the tumor or its metastasis. A single case of hematologic syndrome was reported in 1985 by Maalej et al. [9]. In 1993, Cvitkovic et al. [40] reported a cohort of 255 patients affected by undifferentiated NPC. Forty-seven of the 255 patients had paraneoplastic hematologic syndromes. Fever of unknown origin was found in 23 patients, and in 17 patients it was associated with leukemoid reaction. Leukemoid reaction was observed in 41 cases. Isolated leukemoid reaction was observed in 17 patients. Liaw et al. [41] reported on 67 patients with NPC proven to have developed paraneoplastic tumor fever. All 67 patients had metastases when tumor fever occurred. The most common metastatic sites were bone and liver. The time between the first febrile episode and the confirmation of tumor fever ranged from 1 week to 3 months. Fever in cancer patient is often the result of infection. However, paraneoplastic fever may be caused by malignant disease, in the absence of infection. Standard antipyretic drugs and antibiotics are usually ineffective. The evaluation of fever in cancer patients, should include a careful clinical history, complete physical examination,
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complete blood count, blood culture, chest X-ray, urine, and other relevant material examination. The criteria for tumor fever include all of the following: (1) temperature exceeding 38 8C at least once; (2) fever duration of at least 1 week; (3) negative clinical and radiological examination for infectious disease; (4) negative blood cultures and urine examination; (5) persistent fever despite adequate antibiotic treatment [41]. Leukemoid reaction is characterized by the elevation of peripheral count to more than 20,000/ml without infection or leukemia. In some cases, symptoms result from neutrophilic leukemoid reactions, which are characterized by the presence of immature white blood cells in the blood-stream, and may be accompanied by hypereosinophilia and itching. These reactions typically are observed in patient with lymphomas; however, they have also been reported in association with NPC. Cvitkovic et al. [40] also observed a 16% rate of leukemoid reaction in undifferentiated NPC. The paraneoplastic origin of these phenomena suggested taking into account the absence of infection and/or tumor necrosis. In addition, the lack of relationship between the leukemoid reaction and the tumoral mass also favored the hypothesis of a dysregulation of the immune response. Granulocytemacrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFa) and interleukin-1 alpha (IL1a) are involved in the generation of the inflammatory response and the synthesis and the differentiation of neutrophilic leukocytes. IL-1a is an essential mediator of the immune response and IL-1a, directly produced by tumoral cells of a thyroid squamous cell carcinoma, has been reported to be responsible for paraneoplastic fever and hyperleucocytosis [42]. In undifferentiated NPC, different immunoregulatory molecules produced and released by the malignant cells could attract and locally stimulate T cells to produce cytokines. Conversely, in a case of paraneoplastic leukemoid reaction associated with an undifferentiated NPC reported by Saussez et al. [43] serum IL-1a and TNFa, remained undetectable suggesting that these factors were not involved in the occurrence of the paraneoplastic leukemoid syndrome. In paraneoplastic fever standard antipyretic drugs and antibiotics are usually ineffective. Naproxene, indometacin, and systemic chemotherapy all are effective in ameliorating tumor fever. Successful treatment of local or metastatic disease consistently reverses both the fever and peripheralblood profile, although they can reappear with tumor relapse. Systemic metastases should be suspected in patient with NPC who have fever of unknown origin. Paraneoplastic hematologic syndromes could be important both in the diagnosis and follow-up of patients with NPC. They could also simulate or evoke metastatic dissemination and could occasionally prevent patients from having potentially curative therapy. The hematologic leukemoid syndrome must be clearly distinct from leukoerythroblastosis, secondary to bone
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marrow invasion, which occurs in the late evolution of various malignancies.
6. Paraneoplastic osteoarticular or rheumatologic syndromes The real incidence of paraneoplastic osteoarticular syndromes is difficult to determine, because NPC can be associated with finger clubbing as a part of a paraneoplastic condition or as an external manifestation of occult pulmonary metastases [44]. Many ‘‘false-paraneoplastic’’ osteoarticular syndromes are reported in the head and neck literature, in which symptoms were related to direct disruption of the normal function of the lungs by distant metastases. Indeed, the most common site of distant metastases associated with finger clubbing is pulmonary. At present, primary carcinoma of the lung is the entity most frequently associated with this condition. HOA without pulmonary metastases in NPC is unusual. In 1977, Zornoza et al. [45] reported two cases of NPC associated with HOA, one without pulmonary metastases. Isolated HOA with NPC without digital clubbing was also reported [46]. HOA in malignancy is very rare in children, but most of the reported HOA associated with NPC involve young patients [47,48]. Digital clubbing is a clinical sign resulting from the overgrowth of fibroblasts and neovasculature at the pulp of the nail bed. HOA may be associated with soft tissue swelling of the extremities and clubbing of the fingers and toes. HOA is characterized by periosteal reactions of long bones. It is usually associated with pulmonary, cardiac or hepatic disease. HOA has three characteristic features: (1) clubbing of the fingers and toes; (2) pain and swelling at the distal ends of the limbs; and (3) periosteal proliferation, mainly involving the distal ends of the bones of the extremities. These characteristics commonly are symmetrical. According to accepted pathophysiology, in finger clubbing there may be an increase in blood flow to the nail bed resulting from increased circulation, rather than to neovascularization. In HOA, the periosteal new bone is smooth at first and is undulating and rough later. It may be deposited most conspicuously on the concavity of long bones. The mechanism by which pulmonary metastases results in clubbing might be due to anoxia. The histopathological features include an inflammatory cell reaction with round cell infiltration and, later, periosteal new bone formation. Recently, vascular endothelial growth factor and plateletderived growth factor were suggested for their role in the pathogenesis of digital clubbing which is a condition frequently associated with HOA [49]. Differential diagnosis between HOA and coexisting bone metastasis must be made with caution. Bone scintigraphy seems to be the most sensitive tool to distinguish between these two diseases. Intense symmetrical uptake of radio-
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isotope along the cortex of long bones, the so-called ‘‘parallel tract sign’’, is typical. Plain radiographs demonstrating prominent periosteal reaction are also effective for this [50]. HOA may develop even before there is radiographic evidence of lung metastases, and it may precede pulmonary symptoms by several months. These features may persist for quite some time or may resolve spontaneously. However, a striking feature is the reversibility of these signs after successful treatment of the primary cancer [51,52]. The treatment of paraneoplastic osteoarticular or rheumatic syndromes consists of therapy for the underlying malignancy and symptomatic treatment with non-steroidal anti-inflammatory drugs or corticosteroids. Development of finger clubbing during or after treatment for NPC heralds imminent pulmonary metastasis. The development of finger clubbing in NPC is rapid and the progression halts after the suppression or elimination of the malignant process.
The most common paraneoplastic ocular syndromes in head and neck cancer are cancer-associated retinopathy and melanoma-associated retinopathy [56]. These have been occasionally reported in association with cancer of the larynx and hypopharynx. NPC is commonly manifest as a neck mass, nasal obstruction, nasal bleeding, and occasionally hearing loss. NPC typically presents to ophthalmologists with one or more cranial nerve palsies. The fifth and sixth nerves are the most commonly affected. These are primarily due to tumor invasion of the cavernous sinus and/or skull base. However, early invasion of the optic nerve is very rare. Three cases of optic neuritis as paraneoplastic ocular syndromes associated with NPC are reported [57,58] with no evidence of a tumor mass around the optic nerve or any histological evidence of tumor infiltration. A possible remote effect of NPC was postulated.
7. Paraneoplastic neurologic syndromes
9. Conclusions
Paraneoplastic neurologic syndromes are believed to be autoimmune and due to activation of the immune system to destroy distant tumors. The neural tissues are damaged by immune-mediated inflammation as they express onconeural proteins coexpressed by tumors [53]. Both the central and peripheral nervous systems can be affected. Sensory neuropathy is a classical paraneoplastic neurologic syndrome affecting the peripheral nervous systems associated with solid tumors, mostly common small cell lung carcinoma seropositive for anti-Hu antibody (antineuronal nuclear antibody type 1 [ANNA-1]) [54]. Paraneoplastic, predominantly motor, acute inflammatory demyelinating polyradiculoneuropathy compatible with Guillain–Barre´ syndrome, and chronic inflammatory demyelinating polyneuropathy have been reported associated with certain lymphomas, B-cell acute lymphoblastic leukemia and renal clear cell carcinoma. These syndromes have been occasionally described in association with head and neck cancer, although only two cases are available in the literature. Baijens and Manni [26] reported a case that presented with a neurologic syndrome before the diagnosis of NPC; the patient manifested progressive weakness in the upper extremities and episodes of mental confusion. A poliomyelitis-like clinical manifestation with neuronal loss in the anterior and posterior horns was diagnosed, with deterioration of the sensibility of both feet. Serum anti-Hu antibodies were positive. Chan et al. [55] reported a case with simultaneous paraneoplastic predominantly motor polyneuropathy/polyradiculoneuropathy and inflammatory myopathy upon relapse of a NPC. The paraneoplastic anti-neural autoantibodies can more specifically lead to the diagnosis of the underlying primary malignancy or recurrent tumor.
PNS may precede the clinical manifestation of a persistent or recurrent tumor or of asymptomatic metastases [59]. In the literature PNS are mostly described in case reports or review articles. Excluding false-paraneoplastic cases, more than 260 NPC have been reported with PNS (Table 1). The exact incidence of PNS in association with head and neck cancer is not known, but it is surely underestimated, because many cases are not reported in the literature or they are not well recognized. The incidence does not appear related to the age of the patients. The majority of patients present with local symptoms due to the tumor, but it is not rare for patients with occult NPC to initially present with systemic manifestations. PNS often represents the only signal of a silent neoplasm and sometimes it precedes the tumor itself. The predominant histological type of NPC associated with PNS is squamous cell carcinoma. Because of their protean manifestation, they should be evaluated by a coordinated multidisciplinary team, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, dermatologists, and ophthalmologists. In addition to their association with EBV, NPC display a series of immunologic and humoral characteristics that have no equivalent among other head and neck carcinomas. An awareness of the association of these diseases in the West is of particular importance to head and neck surgeons, who are responsible for early cancer diagnosis and implementation of appropriate therapy. These syndromes can follow the clinical course of the tumor and thus be useful for monitoring its evolution.
8. Paraneoplastic ocular syndromes
C. Toro et al. / Auris Nasus Larynx 36 (2009) 513–520 Table 1 Paraneoplastic syndromes occurring in patients with nasopharyngeal carcinoma. Source
Patients no.
Cutaneous or dermatologic syndromes Wong [14] Miyachi et al. [24] Teo et al. [18] Peng et al. [16] Hu et al. [28] Leow and Goh [19] Boussen et al. [27] Ang et al. [17] Ferris and Koch [13] Botsios et al. [11] Wang et al. [20] Martini et al. [21] Baijens and Manni [26]
9 1 10 17 61 5 3 6 2 1 1 1 1
Endocrine syndromes Yokokawa et al. [31] Kavanagh et al. [34] Talmi et al. [35] Tan et al. [37] Baijens and Manni [26] Hematologic syndromes Maalej et al. [9] Cvitkovic et al. [40] Saussez et al. [43] Liaw at al. [41]
1 1 6 1 1 1 47 1 67
Osteoarticular or rheumatologic syndromes Zornoza et al. [45] Wollner et al. [51] Vera Sempere et al. [47] Tan et al. [37] Wang et al. [50] Varan et al. [46] Biswal et al. [44] Sohn et al. [48] Ulusakarya et al. [52] Baijens and Manni [26]
2 1 1 1 2 1 2 1 1 1
Neurologic syndromes Baijens and Manni [26] Chan et al. [55]
1 1
Ocular syndromes Hoh et al. [57] Tsai et al. [58]
1 2
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Paraneoplastic syndromes in patients with nasopharyngeal cancer C. Toro a, A. Rinaldo b, C.E. Silver c, M. Politi a, A. Ferlito b,* a
Department of Surgical Sciences, Maxillofacial Surgery Clinic, University of Udine, Udine, Italy b Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy c Departments of Surgery and Otolaryngology-Head and Neck Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA Received 22 August 2008; accepted 14 October 2008 Available online 27 December 2008
Abstract Paraneoplastic syndromes (PNS) represent the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products. Paraneoplastic effects are not directly mediated by tumor invasion of normal tissue, or by the disruption of normal function of the involved organ, or by distant metastases. More than 260 cases of nasopharyngeal carcinoma (NPC) associated with PNS have been reported in the literature. These syndromes can be divided into six main groups: cutaneous or dermatologic, endocrine, hematologic, osteoarticular or rheumatologic, neurologic, and ocular. The most common dermatologic manifestation is dermatomyositis, while the syndrome of inappropriate secretion of antidiuretic hormone and occasionally Cushing’s syndrome due to ectopic ACTH production are the endocrinologic manifestations. Tumor fever and leukemoid reaction, osteoarticular or rheumatic syndromes, including clubbing of the fingers and toes, sensory neuropathy and demyelinating motor polyneuropathy, and rarely optic neuritis represent the most prominent examples of the other groups of syndromes. PNS may occur before the NPC is manifest, or while it is in an occult stage, and thus the possibility of NPC should be considered in patients with these various disorders. While some PNS will respond to direct treatment, most often the PNS subsides in parallel to response of the NPC, and thus may be useful for monitoring tumor response or recurrence. # 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Nasopharyngeal carcinoma; Paraneoplastic syndromes; Early detection; Pathogenesis; Treatment; Hormones
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Nasopharyngeal carcinoma . . . . . . . . . . . . . . . . . . . . . . Paraneoplastic syndromes . . . . . . . . . . . . . . . . . . . . . . . Paraneoplastic cutaneous or dermatologic syndromes . . . . Paraneoplastic endocrine syndromes. . . . . . . . . . . . . . . . Paraneoplastic hematologic syndromes . . . . . . . . . . . . . . Paraneoplastic osteoarticular or rheumatologic syndromes. Paraneoplastic neurologic syndromes . . . . . . . . . . . . . . . Paraneoplastic ocular syndromes . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Nasopharyngeal carcinoma * Corresponding author at: Department of Surgical Sciences, ENT Clinic, University of Udine, P.le S. Maria della Misericordia, 33100 Udine, Italy. E-mail address: [email protected] (A. Ferlito).
Nasopharyngeal carcinoma (NPC) is relatively uncommon in Western countries, but is 10–50 times more common
0385-8146/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.anl.2008.10.006
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in the Far East, and is endemic in the Southern parts of China with the yearly incidence rate varying between 15 per 100,000 and 50 per 100,000 [1]. In Hong Kong, NPC is the third most common malignancy in male and the fifth in female patients with an incidence of 27.5 and 11.2 per 100,000, respectively [2]. The particularly high frequency of malignancies of the nasopharynx in the Far East is not well understood, although metaplasia and eventual carcinoma in situ is associated with chronic sinusitis, which is extremely common in southeast Asian countries [3]. A spectrum of risk factors has been described including environmental carcinogenesis from inhaled or chewed tobacco, racial factors, hereditary trends, and infection with the Epstein–Barr virus (EBV). Undifferentiated carcinoma is the only EBV related NPC. The undifferentiated NPC was initially designated lymphoepitelioma by Schminke [4] and Regaud and Reverchon [5] because of the mixture of lymphoid and epithelial cells seen in the primary tumor. It has subsequently been established that only the epidemoid cells are neoplastic, as evidenced by the absence of lymphoid tissue in metastatic lesions. Thus, undifferentiated NPC is an epidermoid-lineage cancer, and because of various unique features constitutes a clinical entity different from other head and neck squamous cell carcinomas. The typical presenting symptoms of NPC are usually cervical lymphadenopathy, epistaxis, audiologic or neurologic symptoms, and nasorespiratory symptoms. A small percentage of patients present with the clinical manifestation of the indirect and remote effects produced by the tumor.
2. Paraneoplastic syndromes Paraneoplastic syndromes (PNS) represent the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products. Paraneoplastic effects are not directly mediated by the invasion of normal tissue, or by the disruption of normal function of the involved organ, or by distant metastases [6]. PNS occur in 1–7.4% of all cancer patients [7]. Different terms such as paraneoplastic effects, remote effects, paraneoplastic events, non-metastatic syndromes, paraneoplastic manifestations, paraneoplastic phenomena, and paraneoplastic disturbances have all been employed as synonyms to the term ‘‘paraneoplastic syndrome.’’[8]. The mechanism of most PNS is not well known. Only few cases clearly demonstrate an etiologic or a pathogenetic factor. PNS can precede, follow or be concurrent to the diagnosis of a malignancy. Physicians who deal with cancerassociated syndromes should be able to differentiate the PNS from the benign disorders that mimic them. PNS associated with NPC can be divided into six main groups: cutaneous or dermatologic, endocrine, hematologic, osteoarticular or rheumatologic, neurologic, and ocular. The exact incidence of PNS associated with NPC is not known, because numerous ‘‘false-PNS’’ have been reported in
which symptoms are directly related to the invasion of normal tissue by the tumor or by distant metastases [9]. Moreover, sometimes the same cases have been reported in different journals (for example: Botsios et al. [10] and Botsios et al. [11]. We have reviewed the literature in order to underline the various PNS related to NPC and their relevance to the diagnosis.
3. Paraneoplastic cutaneous or dermatologic syndromes First described in 1916 by Stertz [12], the association of connective tissue diseases, particularly dermatomyositis (DM) and scleroderma, with a variety of malignancies has been reported frequently in recent decades. DM seems to have a robust association with malignancy, with studies showing a frequency of cancer of 15–34% in some medical centers. In the upper aerodigestive tract, this phenomenon is seen most commonly with NPC [13]. DM is a severe systemic disorder characterized by typical cutaneous lesions and an inflammatory myopathy. The five main diagnostic findings of DM include: (1) systemic proximal muscle weakness, with or without dysphagia or respiratory muscle involvement; (2) abnormal muscle biopsy findings; (3) elevated skeletal muscle-derived enzymes; (4) abnormal electromyographic findings; and (5) a typical skin eruption (Gottron papules) overlying the knuckles, elbows, and knee joints. Special skin features include a characteristic heliotropic rash on exposed surfaces, periungual telangiectasia, and poikiloderma. The first cases of NPC associated with a dermatologic syndrome were reported in 1969 [14]. Since that time, more than 100 such cases have been reported. NPC has long been reported as the predominant type of cancer associated with DM in several Asian countries, including Hong Kong, Singapore, and Southern-China [15]. Although in the Orient NPC is more frequently found in the general population and in patients with DM, the proportion of individuals with both NPC and DM is approximately 3–4 times greater than in the general population [16]. Ang et al. [17] reported 28 cases with DM from the National Skin Centre of Singapore; malignancies were detected in 12 patients, half of which were NPC. They concluded that screening for malignancies, especially NPC, is recommended for all DM patients. In Hong Kong, 10 of 1154 patients with NPC developed DM [18]. Leow and Goh [19] reported 38 cases of DM in patients affected by cancer, 5 of which were NPC. A photodistributed urticarial vasculitis with DM was described as the presentation of a NPC [20]. The autoimmune basis of DM was confirmed by the presence of a lymphoplasmic cellular infiltrate of the muscular interstices. This clinical entity has mainly been described in patients from southern Chinese groups, and there are fewer reported
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instances among patients in the West. However, Ferris and Koch [13] reported two sporadic cases of DM coincident with NPC in a Western population of 94 patients from the United States. Botsios et al. [11] and Martini et al. [21] reported two cases of caucasian Italian patients with DM associated with NPC. Among caucasian patients, a variety of malignancies are associated with DM, but NPC is sporadically found. In a review of the literature encompassing 590 Western patients with DM, 92 (16%) had associated malignancy. Cancer of the lung and stomach were most frequent among men in this group, whereas women were most likely to have breast or ovarian cancer [22,23]. There are several ways in which mechanistic factors may link paraneoplastic dermatologic syndromes with NPC. They may result from immune disregulation, leading to aberrant recognition of normal tissues after viral-mediated transformation and tumor formation. One potential pathway for a linkage may be the production of a tumor-related antigen that induces an autoimmune response because of the homologous sequence with some normal antigen (‘‘molecular mimicry’’). EBV is widely accepted as an etiologic agent in NPC tumorigenesis. Activation of an immune response to a ‘‘cryptic’’ epitope, not produced or exposed before viral infection, may result from the matching of a viral epitope to a mutated or endogenous antigen. The unmasking of cryptic immune epitopes in the setting of EBV infection may enable the activation and expansion of autoreactive immune response, perhaps through the dysfunction of suppressor T cells, leading to clinical connective tissue manifestations (antibodyantigen complex deposition, complement fixation, and tissue damage) [13]. In a woman with a primary NPC associated with hypertrophic osteoarthropathy (HOA) and cutaneous vasculitis, the serum contained antibodies to EBV and U1 Ribonucleic Protein (RNP) antigens. Cryoproteins isolated from her serum contained antibodies to U1 RNP and a protein with a molecular weight of 32 kD, which reacted specifically with antibodies to U1 RNP. HLA typing revealed HLA-B7 and DR1, and these have been reported to be increased in Japanese patients with rheumatic diseases who have autoantibodies to U1 RNP. These findings indicated that some features of the PNS in this patient might have been caused by immune complexes, part of which were formed by specific autoantibodies produced under genetically controlled conditions of immune responsiveness [24]. Stone [25] proposed multiple trigger mechanisms caused by malignancy to account for the onset of DM. He cited the changes in extracellular membrane around tumors with entry into the circulation of altered glycosaminoglycans. The secretion of biologically active molecules by the transformed NPC cells may be another factor, resulting in a paraneoplastic phenomenon inducing connective tissue diseases. In most reported cases, the course of the PNS precedes the diagnosis of NPC [26], and then runs parallel to
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the cancer, with improvement of the DM after chemotherapy and radiation therapy of the tumor [27]. Several researchers have suggested that patients with DM be screened for the possible presence of NPC [28]. An unfavourable prognosis is suggested when DM is associated with NPC [18].
4. Paraneoplastic endocrine syndromes Patients affected by NPC usually consult the endocrinologist when they develop hypopituitarism as a consequence of radiotherapy. The majority of patients present with local symptoms due to the tumor and it is rare for patients with occult NPC to present initially with endocrine manifestations. Paraneoplastic endocrine syndromes result from aberrant production of protein hormones, hormone precursors, or hormone-like substances by tumors. Ectopic or inappropriate hormone secretion causing clinically manifest syndromes is uncommon in patients with cancer of the head and neck [29]. The most important of these is the syndrome of inappropriate secretion of arginine vasopressin, known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or as Schwartz–Bartter syndrome. SIADH was first described in association with bronchogenic carcinoma [30]. The condition also has been reported to occur in various other types of malignant neoplasms, in central nervous system disorders, with numerous cardiopulmonary diseases, and in drug-related iatrogenic cases. Of particular interest is the SIADH associated with ectopic secretion of vasopressin by tumor cells. However, this condition has been associated only rarely with tumors of the head and neck. Only in 1981, 24 years after the first description of SIADH, was it found in association with a sarcoma of the epipharynx [31]. Hayes et al. [32] proposed that SIADH observed after induction chemotherapy for squamous cell carcinoma of the head and neck might be produced by the rapid lysis of cancer cells by cytotoxic agents, thus releasing vasopressin or some other substance capable of producing SIADH. An entirely different pathophysiologic explanation was offered by Wenig and Heller [33], who analyzed six cases of SIADH after radical neck dissection for cervical metastases; five of the six patients also received radiation therapy. It was suggested that impaired venous return led to increased intracranial pressure, indirectly causing SIADH. The oral cavity is the most common primary tumor site of the head and neck in paraneoplastic SIADH, and squamous cell carcinoma is the most common histological type in these cases. Kavanagh et al. [34] observed a patient with undifferentiated NPC whose clinical presentation, results of laboratory studies, and clinical response to water deprivation suggested the presence of SIADH. This was the first report of pathologic confirmation of the syndrome with the use of
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both molecular and immunologic probes. Histologic examination of the nasopharyngeal mass with the use of in situ hybridization and immunohistochemical techniques confirmed expression of the messenger RNA for the vasopressin precursor, propressophysin, and its translated peptide products in the biopsy sample. Talmi et al. [35] reported a retrospective review of 1436 patients with head and neck malignancy. In 43 of these patients (3%), SIADH was found to be associated with the cancer of the head and neck, and six of these primary tumor were detected in the nasopharynx. Antidiuretic hormone (ADH) or its biologically active form in human, i.e., arginine vasopressin, is normally synthesized in the hypothalamus and then transported through the hypothalamic-neurohypophyseal stalk to the posterior pituitary, where it is stored and finally released. ADH physiologically participates in maintaining a constant serum osmolarity and intravascular volume, acting on the renal tubular apparatus by retaining water and concentrating urine. The SIADH is characterized by excessive blood levels or actions of vasopressin associated with hyponatremia without edema. The inability to excrete a diluted urine implies a subsequent retention of ingested fluids, with expansion of the extracellular fluid volume. Hyponatremia is due to higher urinary excretion caused by decreased reabsorption of sodium—both factors contribute to the syndrome. Diagnostic criteria for SIADH are: hyponatremia (<135 mEq/L), serum hypo-osmolarity (<280 mOsm/kg), urine concentration or specific gravity greater than expected for serum osmolarity (continued urinary excretion of sodium, urine osmolarity of >500 mOsm/kg or >300 mmol/Kg, urinary concentration of sodium of >20 mEq/L), no edema, orthostatic hypotension, or features of dehydratation, no evidence of volume depletion, normal renal, adrenal, and thyroid function, elevated plasma concentration of vasopressin, hypouricemia due to increased renal clearance, hypocreatininemia and hypoalbuminemia [29]. The syndrome may precede the presentation of the cancer by a few weeks or months. Identification of endocrine syndromes is important because they cause symptoms which are frequently treatable. In SIADH, appropriate treatment consists on the treatment of the primary tumor and restriction of fluid intake. In severe cases this syndrome should be treated with hypertonic saline solution (3% saline) and furosemide. The treatment of choice in tumor relapse and recurrent SIADH is demeclocycline (600–1200 mg/d in divided doses) [36]. The prognosis depends on the underlying malignancy and its treatment. Tan et al. [37] reported the first case of occult NPC initially presented with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) production. Cushing’s syndrome, accompanied by high plasma levels of ACTH, hypokaliemia and increased serum and urine cortisol concentrations, is a common example of a paraneoplastic
endocrine disorder linked to a malignancy. Ectopic ACTH syndrome is most commonly associated with small cell carcinoma of the lung or various carcinoid tumors; particularly bronchial and thymic. Other well documented causes include medullary carcinoma of the thyroid, pheocromocytoma, medullary paraganglioma, pancreatic islet cell tumors, and tumors of the colon, prostate, and ovary. 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 been shown that normal non-pituitary cells from various organs and tissues, express the proopiomelanocortin gene from which ACTH is derived [38]. Immunoreactive proopiomelanocortin peptides have been demonstrated in these tissues. The ubiquitous nature of proopiomelanocortin gene expression most likely accounts for the wide variety of tumors responsible for the ectopic ACTH syndrome. The basic mechanism involved in the ectopic production of ACTH by tumors is poorly understood and the dysdifferentiation hypothesis proposed by Baylin and Mendelsohn [39] 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.
5. Paraneoplastic hematologic syndromes Tumor fever and leukemoid reaction are associated with NPC as PNS. They are usually observed in patients with metastatic disease. Tumor fever is frequently associated with other PNS, of which leukemoid reaction is the most common. These remote effects are not produced as a direct effect of the tumor or its metastasis. A single case of hematologic syndrome was reported in 1985 by Maalej et al. [9]. In 1993, Cvitkovic et al. [40] reported a cohort of 255 patients affected by undifferentiated NPC. Forty-seven of the 255 patients had paraneoplastic hematologic syndromes. Fever of unknown origin was found in 23 patients, and in 17 patients it was associated with leukemoid reaction. Leukemoid reaction was observed in 41 cases. Isolated leukemoid reaction was observed in 17 patients. Liaw et al. [41] reported on 67 patients with NPC proven to have developed paraneoplastic tumor fever. All 67 patients had metastases when tumor fever occurred. The most common metastatic sites were bone and liver. The time between the first febrile episode and the confirmation of tumor fever ranged from 1 week to 3 months. Fever in cancer patient is often the result of infection. However, paraneoplastic fever may be caused by malignant disease, in the absence of infection. Standard antipyretic drugs and antibiotics are usually ineffective. The evaluation of fever in cancer patients, should include a careful clinical history, complete physical examination,
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complete blood count, blood culture, chest X-ray, urine, and other relevant material examination. The criteria for tumor fever include all of the following: (1) temperature exceeding 38 8C at least once; (2) fever duration of at least 1 week; (3) negative clinical and radiological examination for infectious disease; (4) negative blood cultures and urine examination; (5) persistent fever despite adequate antibiotic treatment [41]. Leukemoid reaction is characterized by the elevation of peripheral count to more than 20,000/ml without infection or leukemia. In some cases, symptoms result from neutrophilic leukemoid reactions, which are characterized by the presence of immature white blood cells in the blood-stream, and may be accompanied by hypereosinophilia and itching. These reactions typically are observed in patient with lymphomas; however, they have also been reported in association with NPC. Cvitkovic et al. [40] also observed a 16% rate of leukemoid reaction in undifferentiated NPC. The paraneoplastic origin of these phenomena suggested taking into account the absence of infection and/or tumor necrosis. In addition, the lack of relationship between the leukemoid reaction and the tumoral mass also favored the hypothesis of a dysregulation of the immune response. Granulocytemacrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNFa) and interleukin-1 alpha (IL1a) are involved in the generation of the inflammatory response and the synthesis and the differentiation of neutrophilic leukocytes. IL-1a is an essential mediator of the immune response and IL-1a, directly produced by tumoral cells of a thyroid squamous cell carcinoma, has been reported to be responsible for paraneoplastic fever and hyperleucocytosis [42]. In undifferentiated NPC, different immunoregulatory molecules produced and released by the malignant cells could attract and locally stimulate T cells to produce cytokines. Conversely, in a case of paraneoplastic leukemoid reaction associated with an undifferentiated NPC reported by Saussez et al. [43] serum IL-1a and TNFa, remained undetectable suggesting that these factors were not involved in the occurrence of the paraneoplastic leukemoid syndrome. In paraneoplastic fever standard antipyretic drugs and antibiotics are usually ineffective. Naproxene, indometacin, and systemic chemotherapy all are effective in ameliorating tumor fever. Successful treatment of local or metastatic disease consistently reverses both the fever and peripheralblood profile, although they can reappear with tumor relapse. Systemic metastases should be suspected in patient with NPC who have fever of unknown origin. Paraneoplastic hematologic syndromes could be important both in the diagnosis and follow-up of patients with NPC. They could also simulate or evoke metastatic dissemination and could occasionally prevent patients from having potentially curative therapy. The hematologic leukemoid syndrome must be clearly distinct from leukoerythroblastosis, secondary to bone
517
marrow invasion, which occurs in the late evolution of various malignancies.
6. Paraneoplastic osteoarticular or rheumatologic syndromes The real incidence of paraneoplastic osteoarticular syndromes is difficult to determine, because NPC can be associated with finger clubbing as a part of a paraneoplastic condition or as an external manifestation of occult pulmonary metastases [44]. Many ‘‘false-paraneoplastic’’ osteoarticular syndromes are reported in the head and neck literature, in which symptoms were related to direct disruption of the normal function of the lungs by distant metastases. Indeed, the most common site of distant metastases associated with finger clubbing is pulmonary. At present, primary carcinoma of the lung is the entity most frequently associated with this condition. HOA without pulmonary metastases in NPC is unusual. In 1977, Zornoza et al. [45] reported two cases of NPC associated with HOA, one without pulmonary metastases. Isolated HOA with NPC without digital clubbing was also reported [46]. HOA in malignancy is very rare in children, but most of the reported HOA associated with NPC involve young patients [47,48]. Digital clubbing is a clinical sign resulting from the overgrowth of fibroblasts and neovasculature at the pulp of the nail bed. HOA may be associated with soft tissue swelling of the extremities and clubbing of the fingers and toes. HOA is characterized by periosteal reactions of long bones. It is usually associated with pulmonary, cardiac or hepatic disease. HOA has three characteristic features: (1) clubbing of the fingers and toes; (2) pain and swelling at the distal ends of the limbs; and (3) periosteal proliferation, mainly involving the distal ends of the bones of the extremities. These characteristics commonly are symmetrical. According to accepted pathophysiology, in finger clubbing there may be an increase in blood flow to the nail bed resulting from increased circulation, rather than to neovascularization. In HOA, the periosteal new bone is smooth at first and is undulating and rough later. It may be deposited most conspicuously on the concavity of long bones. The mechanism by which pulmonary metastases results in clubbing might be due to anoxia. The histopathological features include an inflammatory cell reaction with round cell infiltration and, later, periosteal new bone formation. Recently, vascular endothelial growth factor and plateletderived growth factor were suggested for their role in the pathogenesis of digital clubbing which is a condition frequently associated with HOA [49]. Differential diagnosis between HOA and coexisting bone metastasis must be made with caution. Bone scintigraphy seems to be the most sensitive tool to distinguish between these two diseases. Intense symmetrical uptake of radio-
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isotope along the cortex of long bones, the so-called ‘‘parallel tract sign’’, is typical. Plain radiographs demonstrating prominent periosteal reaction are also effective for this [50]. HOA may develop even before there is radiographic evidence of lung metastases, and it may precede pulmonary symptoms by several months. These features may persist for quite some time or may resolve spontaneously. However, a striking feature is the reversibility of these signs after successful treatment of the primary cancer [51,52]. The treatment of paraneoplastic osteoarticular or rheumatic syndromes consists of therapy for the underlying malignancy and symptomatic treatment with non-steroidal anti-inflammatory drugs or corticosteroids. Development of finger clubbing during or after treatment for NPC heralds imminent pulmonary metastasis. The development of finger clubbing in NPC is rapid and the progression halts after the suppression or elimination of the malignant process.
The most common paraneoplastic ocular syndromes in head and neck cancer are cancer-associated retinopathy and melanoma-associated retinopathy [56]. These have been occasionally reported in association with cancer of the larynx and hypopharynx. NPC is commonly manifest as a neck mass, nasal obstruction, nasal bleeding, and occasionally hearing loss. NPC typically presents to ophthalmologists with one or more cranial nerve palsies. The fifth and sixth nerves are the most commonly affected. These are primarily due to tumor invasion of the cavernous sinus and/or skull base. However, early invasion of the optic nerve is very rare. Three cases of optic neuritis as paraneoplastic ocular syndromes associated with NPC are reported [57,58] with no evidence of a tumor mass around the optic nerve or any histological evidence of tumor infiltration. A possible remote effect of NPC was postulated.
7. Paraneoplastic neurologic syndromes
9. Conclusions
Paraneoplastic neurologic syndromes are believed to be autoimmune and due to activation of the immune system to destroy distant tumors. The neural tissues are damaged by immune-mediated inflammation as they express onconeural proteins coexpressed by tumors [53]. Both the central and peripheral nervous systems can be affected. Sensory neuropathy is a classical paraneoplastic neurologic syndrome affecting the peripheral nervous systems associated with solid tumors, mostly common small cell lung carcinoma seropositive for anti-Hu antibody (antineuronal nuclear antibody type 1 [ANNA-1]) [54]. Paraneoplastic, predominantly motor, acute inflammatory demyelinating polyradiculoneuropathy compatible with Guillain–Barre´ syndrome, and chronic inflammatory demyelinating polyneuropathy have been reported associated with certain lymphomas, B-cell acute lymphoblastic leukemia and renal clear cell carcinoma. These syndromes have been occasionally described in association with head and neck cancer, although only two cases are available in the literature. Baijens and Manni [26] reported a case that presented with a neurologic syndrome before the diagnosis of NPC; the patient manifested progressive weakness in the upper extremities and episodes of mental confusion. A poliomyelitis-like clinical manifestation with neuronal loss in the anterior and posterior horns was diagnosed, with deterioration of the sensibility of both feet. Serum anti-Hu antibodies were positive. Chan et al. [55] reported a case with simultaneous paraneoplastic predominantly motor polyneuropathy/polyradiculoneuropathy and inflammatory myopathy upon relapse of a NPC. The paraneoplastic anti-neural autoantibodies can more specifically lead to the diagnosis of the underlying primary malignancy or recurrent tumor.
PNS may precede the clinical manifestation of a persistent or recurrent tumor or of asymptomatic metastases [59]. In the literature PNS are mostly described in case reports or review articles. Excluding false-paraneoplastic cases, more than 260 NPC have been reported with PNS (Table 1). The exact incidence of PNS in association with head and neck cancer is not known, but it is surely underestimated, because many cases are not reported in the literature or they are not well recognized. The incidence does not appear related to the age of the patients. The majority of patients present with local symptoms due to the tumor, but it is not rare for patients with occult NPC to initially present with systemic manifestations. PNS often represents the only signal of a silent neoplasm and sometimes it precedes the tumor itself. The predominant histological type of NPC associated with PNS is squamous cell carcinoma. Because of their protean manifestation, they should be evaluated by a coordinated multidisciplinary team, including medical oncologists, surgeons, radiation oncologists, endocrinologists, hematologists, neurologists, dermatologists, and ophthalmologists. In addition to their association with EBV, NPC display a series of immunologic and humoral characteristics that have no equivalent among other head and neck carcinomas. An awareness of the association of these diseases in the West is of particular importance to head and neck surgeons, who are responsible for early cancer diagnosis and implementation of appropriate therapy. These syndromes can follow the clinical course of the tumor and thus be useful for monitoring its evolution.
8. Paraneoplastic ocular syndromes
C. Toro et al. / Auris Nasus Larynx 36 (2009) 513–520 Table 1 Paraneoplastic syndromes occurring in patients with nasopharyngeal carcinoma. Source
Patients no.
Cutaneous or dermatologic syndromes Wong [14] Miyachi et al. [24] Teo et al. [18] Peng et al. [16] Hu et al. [28] Leow and Goh [19] Boussen et al. [27] Ang et al. [17] Ferris and Koch [13] Botsios et al. [11] Wang et al. [20] Martini et al. [21] Baijens and Manni [26]
9 1 10 17 61 5 3 6 2 1 1 1 1
Endocrine syndromes Yokokawa et al. [31] Kavanagh et al. [34] Talmi et al. [35] Tan et al. [37] Baijens and Manni [26] Hematologic syndromes Maalej et al. [9] Cvitkovic et al. [40] Saussez et al. [43] Liaw at al. [41]
1 1 6 1 1 1 47 1 67
Osteoarticular or rheumatologic syndromes Zornoza et al. [45] Wollner et al. [51] Vera Sempere et al. [47] Tan et al. [37] Wang et al. [50] Varan et al. [46] Biswal et al. [44] Sohn et al. [48] Ulusakarya et al. [52] Baijens and Manni [26]
2 1 1 1 2 1 2 1 1 1
Neurologic syndromes Baijens and Manni [26] Chan et al. [55]
1 1
Ocular syndromes Hoh et al. [57] Tsai et al. [58]
1 2
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