Paraneoplastic syndromes in patients with nasopharyngeal cancer

doi:10.1016/j.anl.2008.10.006

Auris Nasus Larynx

Volume 36, Issue 5, October 2009, Pages 513-520

https://doi.org/10.1016/j.anl.2008.10.006 Get rights and content

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.

Section snippets

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is relatively uncommon in Western countries, but is 10–50 times more common 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

Paraneoplastic syndromes

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 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

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

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.

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

Paraneoplastic neurologic syndromes

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

Paraneoplastic ocular syndromes

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

Conclusions

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

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Citation Excerpt :
A similar case was reported by Beckam et al., in 2010 which states that the extent of the tumor on MRI fails to indicate why the third cranial nerve was the only affected cranial nerve.12 More than 260 cases of NPCs associated with paraneoplastic syndrome (PNS) affecting various organ systems have been reported.13 PNS occurs due to immune cross-reactivity between tumor cells and normal tissue.
Neuro-ophthalmic manifestations may be the first and sole presenting feature of a nasopharyngeal carcinoma. Peri-neural spread is an emerging phenomenon that explains the distant spread of tumour cells well beyond the local extent of invasion. This under recognized route of tumour spread often results in delayed diagnosis and reduced life expectancy. The authors report a case of an isolated third nerve palsy as the only initial manifestation of nasopharyngeal carcinoma and emphasize the need for a high index of suspicion.
The patient presented with left painful pupil involving complete third nerve palsy. Contrast enhanced imaging was initially deferred due to renal impairment. Plain MRI with MRA brain was normal. Hematology was suggestive of giant cell arteritis which is a rare but well documented cause of painful nerve palsies in the elderly. Unresponsiveness to steroids prompted contrast imaging with a reduced gadolinium dosing and hemodialysis backup which finally revealed a nasopharyngeal carcinoma.
This report is the journey of a third nerve palsy from a clinical diagnosis of an aneurysm (pupil involving palsy) to a probable diagnosis of giant cell arteritis (based on hematology) and to a final diagnosis of nasopharyngeal carcinoma (based on contrast imaging and immunohistochemistry)
Nasopharyngeal carcinoma can be successfully cured if detected early. This report highlights the various manifestations of nasopharyngeal carcinoma and challenges faced in diagnosing this elusive tumor.
Nasopharyngeal cancers, an overview
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Les cancers du cavum ont une incidence d’environ 0,5 cas par an et par 100 000 habitants pour les hommes en France, mais sont endémiques dans des régions comme l’Asie du Sud-Est. La prise en charge thérapeutique par radiothérapie exclusive, qui a longtemps été le standard, permet d’obtenir des taux de contrôle local pour les stades T3-T4 de l’ordre de 50 à 75 % des cas. Les techniques d’irradiation en modulation d’intensité permettent une excellente couverture dosimétrique avec une meilleure protection des organes à risque et doivent être privilégiées. L’apport d’une chimiothérapie concomitante à l’IMRT améliore significativement les taux de survie globale qui sont supérieurs ou égaux à 75 % à cinq ans dans les stades avancés. Dans la pratique courante, une radiochimiothérapie concomitante à base de sels de platine est réalisée mais la place des cures néoadjuvantes et/ou adjuvantes est discutée dans le but principal de diminuer les rechutes à distance, des études sont en cours. Enfin, la surveillance doit être axée sur la détection précoce de rechutes locales potentiellement curables et sur la prise en charge des séquelles thérapeutiques à long terme.
Cancer of the nasopharynx is an uncommon malignancy in France (incidence = 0.5/year/100,000 men) but is endemic in areas like in South-East Asia. Exclusive radiation therapy used to be the standard and results in local control rates for T3-T4 tumors around 50-75 %. Intensity-modulated radiotherapy (IMRT) improves tumor coverage with a sparing of organs at risk and has to be privileged. Concurrent chemotherapy with IMRT achieved significant survival benefice with 5-year overall survival above 75 %. Concurrent radiochemotherapy with platinium is the most frequent scheme but induction and adjuvant chemotherapies are discussed to reduce distant failure: studies are currently ongoing. Follow-up aims to detect early local failures with a chance of cure and to manage long-term toxicities.
Cutaneous alerts in systemic malignancy: Part 1
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Citation Excerpt :
The former is usually hereditary and progresses slowly, while the latter—the paraneoplastic form—is associated with cardiopulmonary disorders. In 80% of cases, the paraneoplastic presentation is associated with lung cancer, metastases to the lung, nasopharyngeal carcinoma, and other less common cancers.19,25,29,66,67 Vascular skin manifestations in patients with underlying malignancies are quite nonspecific.5
The aim of this review is to familiarize dermatologists and clinicians in general with cutaneous signs and symptoms that can help lead to an early diagnosis of an underlying malignancy. Because the skin is one of the most accessible organs, it should never be overlooked in systemic disease. Examination of the skin has the advantage of revealing important information about the patient's condition without requiring the use of invasive techniques.
In the literature, most discussions of cutaneous manifestations of internal malignancy refer to classic paraneoplastic syndromes, but a wide variety of skin conditions, while not strictly paraneoplastic, can, in certain contexts, indicate the presence of malignancy or an increased risk of developing cancer later in life.
In this review, various skin conditions that can signal malignancy or increased cancer risk are presented in randomly ordered groups based on clinical morphology.
Conditions with multiple signs and symptoms have been classified on the basis of their most characteristic feature.
El objetivo de esta revisión es alertar al dermatólogo y a los clínicos en general de los signos y síntomas cutáneos que pueden contribuir al diagnóstico precoz de una neoplasia subyacente. Puesto que la piel es uno de los órganos más accesible, nunca debe ser ignorada en las enfermedades sistémicas. Posee la ventaja de que su exploración no requiere técnicas agresivas y nos revela datos importantes de la situación del paciente.
Habitualmente se abordan los síndromes paraneoplásicos clásicos, pero hay una gran variedad de procesos cutáneos no estrictamente paraneoplásicos, que en un determinado contexto sugieren la presencia de una malignidad o bien tienen más riesgo de desarrollarla a lo largo de la vida.
Se ha optado por enumerar las distintas dermatosis agrupándolas por su morfología clínica, siguiendo un orden aleatorio.
Varios de los procesos comparten signos y síntomas múltiples por lo que se ha recurrido al más notorio para incluirlo en un determinado grupo.
Nasopharyngeal carcinoma in dermatomyositis patients: A 10-year retrospective review in Hospital Selayang, Malaysia
2012, Reports of Practical Oncology and Radiotherapy
Citation Excerpt :
Dermatomyositis is defined as an idiopathic inflammatory myopathy with clinically distinctive cutaneous manifestations.1 However, when the symptoms are associated with malignancies, the condition is known as paraneoplastic syndrome which represents the clinical manifestation of the remote and indirect effects produced by tumor metabolites or other products.2 Dermatomyositis is highly associated with various types of malignancies, namely carcinoma of nasopharynx, breast, lung, colorectal, uterus and non-Hodgkin lymphoma.3
The objective of our review is to investigate the association between dermatomyositis patients and nasopharyngeal carcinoma (NPC) together with the clinical presentation of the patients and their management in otorhinolaryngology.
NPC is a malignant disease with good prognosis on early diagnosis. However, the relationship between the dermatomyositis and NPC and its management is not well defined.
A 10-year retrospective review of case records of 21 dermatomyositis patients seen in Otorhinolaryngology Department of Hospital Selayang from January 2000 to November 2010.
These patients ranged from 19 to 74 years old and a total of 8 (38%) out of 21 adults with dermatomyositis were detected to have malignancy. Five out of 8 patients had NPC (62.5%). The mean age of patients with NPC and dermatomyositis was 48 years. NPC is diagnosed in 4 out of 5 patients (80%) in the first year of diagnosis of dermatomyositis. The clinical findings of the examination of nasopharynx ranged from hyperemia to exophytic nasopharyngeal mass. Histologically, it is only related to NPC of WHO types II and III.
There is a strong relationship between dermatomyositis and malignancy, especially NPC. Clinicians should have a high index of suspicion for malignancy in all dermatomyositis patients. Rigid nasoendoscopies and biopsies, serum Epstein–Barr viral capsid IgA antibody and imaging studies are helpful in detecting NPC in dermatomyositis patients.
Paraneoplastic dermatomyositis and nasopharyngeal carcinoma: Diagnosis, treatment and prognosis
2011, Annales Francaises d'Oto-Rhino-Laryngologie et de Pathologie Cervico-Faciale
La dermatomyosite (DM) est une pathologie inflammatoire multi-organe dont les manifestations cutanées et musculaires sont au premier plan. La physiopathologie est encore très mal comprise, mais il s’agit d’un dérèglement de l’immunité humorale et cellulaire. Le diagnostic de DM est basé sur cinq critères : une faiblesse des muscles proximaux des membres, une élévation des enzymes musculaires sériques, des anomalies musculaires histopathologiques visibles sur la biopsie musculaire, des anomalies électromyographiques, et des manifestations cliniques inflammatoires dermatologiques (éruption héliotrope, poïkilodermie et lésions inflammatoires au niveau des mains et en regard des articulations). La DM s’observe fréquemment au cours de certains cancers, et peut apparaître avant le cancer, en même temps que le cancer ou après le diagnostic de cancer. L’incidence de DM associée avec les carcinomes nasopharyngés est de l’ordre d’un pour 1000 cas de cancer nasopharyngé. Le traitement est fondé sur les immunosuppresseurs non sélectifs même en cas de cancer, et en particulier sur les corticoïdes par voie générale à long cours. Cependant, le développement de thérapies ciblées pourra modifier cette approche thérapeutique dans un avenir proche. Malgré l’immunosuppression iatrogène, le pronostic des cancers nasopharyngés associés à la DM paranéoplasique n’est pas modifié. Notre rapport a pour objectif de rapporter un cas à titre d’illustration d’une évolution paranéoplasique (évoluant en même temps que le cancer) et de faire une mise au point des connaissances actuelles concernant la DM paranéoplasique dans ces cancers.
Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: Diagnosis, treatment and prognosis
2011, European Annals of Otorhinolaryngology, Head and Neck Diseases
Citation Excerpt :
NPC accounts for less than 1% of all malignancies and affects approximately one person in 100,000 in North America and Western Europe, but is more frequent in Asia and North Africa, affecting five to nine per 100,000 of the population [4]. It is particularly frequent in southern China, totaling almost one-third of all malignancies treated, according to Hu et al. [2] It is characterized by the frequency of an undifferentiated pathological subtype, its relationship to Epstein-Barr virus with viral DNA detectable in tumor cells, a high metastatic potential and frequent association with paraneoplastic syndromes such as fever, clubbing osteoarthropathy and leukemoid reactions [5]. DM is an idiopathic inflammatory myopathy with prominent and often characteristic cutaneous manifestations.
Dermatomyositis (DM) is a multisystem inflammatory disorder primarily affecting the skin and muscles. Its pathophysiology is still very poorly understood, but humoral and cellular immune dysregulation is apparent. Diagnosis of DM is based on five criteria: proximal limb muscle weakness, serum muscle enzyme elevation, histopathologic muscle abnormalities on muscle biopsy, electromyographic abnormalities, and clinical inflammatory dermatological manifestations (heliotrope rash, poikiloderma, and inflammatory lesions on the hands and facing joints). DM is frequently associated with certain cancers, and may appear before, concurrent with, or after diagnosis of cancer. DM has been reported to be associated with approximately one per 1000 cases of nasopharyngeal carcinoma. Treatment is based on long-course nonselective immunosuppression, particularly corticosteroids, by general route, even when malignancy is present, but new-targeted therapies may modify the treatment strategy in the near future. Despite iatrogenic immunosuppression, the prognosis of nasopharyngeal cancer is not worse in patients with paraneoplastic DM. We report one case as an illustration of this paraneoplastic course (evolving in parallel with the cancer), and to make an update on the state of knowledge on paraneoplastic DM in such cancers.

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Paraneoplastic syndromes in patients with nasopharyngeal cancer

Abstract

Section snippets

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

Ann Oncol

Am J Med

Int J Radiat Oncol Biol Phys

Lancet

Med Hypotheses

Am J Med

Lancet Neurol

Nasopharyngeal carcinoma: an overview

J Hong Kong Med Assoc

Über lymphoepitheliale Geschwülste

Beitr Pathol Anat

Sur un cas d’épithélioma épidermoïde développé dans le massif maxillaire supérieur étendu aux ligaments de la face, aux cavités buccale, nasale et orbitaire ainsi qu’aux ganglions du cou guéri par la radiothérapie

Rev Laryngol

Paraneoplastic syndromes in patients with primary head and neck cancer

Eur Arch Otorhinolaryngol

Early paraneoplastic syndrome in medical oncology: clinicopathological analysis of 1694 patients treated over 20 years

Neoplasma

Paraneoplastic syndromes in patients with laryngeal and hypopharyngeal cancers

Ann Otol Rhinol Laryngol

The paraneoplastic syndrome in nasopharynx cancer. 32 cases

Presse Med

Rhinopharyngeal carcinoma and dermatomyositis: description of a clinical case

Reumatismo

Dermatomyositis and malignancy of the pharynx in Caucasian patients: report of two observations

Rheumatol Int

Polymyositis

Berl Klin Wochenschr

Connective tissue disease coincident with nasopharyngeal carcinoma. Two sporadic cases in a Western population

Arch Otolaryngol Head Neck Surg

Dermatomyositis: a clinical investigation of twenty-three cases in Hong Kong

Br J Dermatol

Clinical and pathological characteristics of nasopharyngeal carcinoma

Asian J Surg

Nasopharyngeal carcinoma with dermatomyositis. Analysis of 12 cases

Arch Otolaryngol Head Neck Surg

Classical and amyopathic dermatomyositis seen at the National Skin Centre of Singapore: a 3-year retrospective review of their clinical characteristics and association with malignancy

Ann Acad Med Singapore

Malignancy in adult dermatomyositis

Int J Dermatol

Urticarial vasculitis and dermatomyositis in a patient with nasopharyngeal carcinoma

Cutis

A child with dermatomyositis and a suspicious lymphadenopathy

J Rheumatol

Dermatomyositis and malignancy: a review of the literature

Ann Intern Med

Hypertrophic osteoarthropathy, cutaneous vasculitis, and mixed-type cryoglobulinemia in a patient with nasopharyngeal carcinoma

Arthritis Rheum

Paraneoplastic syndromes in patients with primary malignancies of the head and neck. Four cases and a review of the literature

Eur Arch Otorhinolaryngol

Dermatomyosite et cancer du cavum: 3 observations

Ann Dermatol Venereol