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Paraneoplastic Syndromes in Patients with Primary Malignancies of the Head and Neck

Paraneoplastic Syndromes in Patients with Primary Malignancies of the Head and Neck

Eur Arch Otorhinolaryngol (2006) 263: 32–36 DOI 10.1007/s00405-005-0942-1

HEAD AND NECK

L. W. J. Baijens Æ J. J. Manni Paraneoplastic in patients with primary of the head and neck. Four cases and a review of the literature

Received: 8 December 2004 / Accepted: 31 January 2005 / Published online: 29 June 2005 Ó Springer-Verlag 2005

Abstract Paraneoplastic syndromes rarely affect pa- patients [5, 13]. Often the paraneoplastic tients with head and neck . Four patients with presents before the initial symptoms or diagnosis of the different histological types of are primary or the recurrent tumour is made [5]. presented in which the primary malignancy was pre- Paraneoplastic syndromes occur in 1 to 7.4% of all ceded and/or accompanied by a paraneoplastic syn- cancer patients [7, 21]. The mechanisms of most para- drome. In the first patient erythrodermia preceded the neoplastic syndromes are not well known. Ectopic hor- diagnosis of a nasopharyngeal . The second mone production is probably the most common patient presented with a B cell of the mechanism [12]. Immunologic interactions in particular nasopharynx in association with the syndrome of inap- autoimmune responses play an important role in neu- propriate secretion of arginine vasopressine (Schwartz- rological paraneoplastic syndromes [1, 7, 10, 17]. In the Bartter syndrome). In the third patient paraneoplastic literature, paraneoplastic syndromes in association with polyarthritis had been diagnosed 5 months before a head and neck cancer have occasionally been reported. hypopharyngeal carcinoma was diagnosed. In the last is the most common histopa- patient the paraneoplastic anti-Hu positive encephalo- thology of the primary malignancy of the head and neck was associated with a primary malignancy in the associated with paraneoplastic syndromes [12]. Also with neck metastases. Diagnostic procedures, other histological types such as thyroid carcinoma, treatment and follow-up of these patients are reported lymphoma, , and paraganglioma of and accompanied by a review of the literature. the head and neck have been reported in association with paraneoplastic syndromes [12]. Ferlito et al. divided Keywords Paraneoplastic syndromes Æ Head and neck paraneoplastic syndromes associated with head and cancer Æ Squamous cell carcinoma Æ Anti-Hu neck cancer in four groups: paraneoplastic dermato- Æ Mucocutaneous lesions logical, endocrine, haematological and neurological syndromes [5]. In the literature more groups are reported such as rheumatological paraneoplastic syndromes [3, 4, 14, 18]. Many dermatological conditions have been de- Introduction scribed as paraneoplastic syndromes, also in head and neck cancer patients. Bazex syndrome is a frequently A describes an association of reported paraneoplastic dermatological syndrome [5]. symptoms and signs not directly related to the site or Head and neck cancer has only occasionally been re- local manifestations of a malignant tumour or its ported in association with haematological and neuro- metastases and occurring in a minority of cancer logical syndromes [5]. In the literature cerebellar degeneration and the Eaton-Lambert myasthenia syn- drome are the most reported paraneoplastic neurologi- cal syndromes. They are seldom associated with laryngeal . These neurological syndromes are L. W. J. Baijens (&) Æ J. J. Manni usually associated with small cell [16, 17]. Department of Otorhinolaryngology Head and Neck , Serum and cerebrospinal fluid autoantibodies have re- Maastricht University Hospital, PO Box 5800, cently been identified for several neurological paraneo- 6202 AZ Maastricht, The Netherlands plastic syndromes [5, 16]. In this paper we report four E-mail: [email protected] different paraneoplastic syndromes associated with dif- Tel.: +31-433877580 Fax: +31-3875580 ferent primary tumours of the head and neck. 33

of recurrent epistaxis and neck nodes. During the ear, Case report nose and throat examination, a glue ear on the left side was observed. Nasendoscopy revealed a nasopharyngeal Case 1 tumour. Neck nodes were palpated in region II-III on the left side. Gradually she developed an abducens A 60-year-old woman was referred to the dermatological paralysis on the left side. On CT scan the paralysis could department of our university hospital in November 2002 be explained by tumour of the sinus caverno- because of a therapy-resistant generalized erythematous sus. of the nasopharynx tumour revealed a car- cutaneous eruption that had developed 2 months pre- cinoma. Fine-needle aspiration cytology (FNAC) of the viously. At first the skin of the trunk was affected, fol- neck nodes showed a squamous cell carcinoma. The lowed by progression towards the extremities, face and diagnosis of with neck neck (Fig. 1). At the dermatological department, she and a dermatological paraneoplastic syn- was treated with a diversity of topical medication and drome was made. The tumour was classified as systemic antihistaminics without any effect. Several skin cT4N2M0. Radiotherapy was started in July 2003. In showed a non-specific chronic dermatitis. Skin 6 weeks a total dose of 70.2 Gy was given. During culture showed normal results. To exclude a paraneo- radiotherapy the skin rash and abducens paralysis dis- plastic syndrome the patient was referred to the appeared. Six months after radiotherapy the patient is departments of internal medicine and for still in remission. extensive examination for a primary malignancy. Clini- cal examinations and imaging techniques showed nor- mal results. From that moment she was treated for late Case 2 onset constitutional eczema with cyclosporin and imip- ramine. Despite the medication the persisted. A 71-year-old man visited our out-patient department in In April 2003 she was referred to our department of July 2003 because of bilateral since several otorhinolaryngology and head and neck surgery because weeks without other complaints. He had never experi- enced otological problems in the past. He suffered from diabetes mellitus type II, which was treated with oral anti-diabetic medication. During routine ear, nose and throat examination glue ears were found bilaterally. The audiogram showed a bilateral mixed hearing loss with Fletcher index of 45 dB. The mean air bone gap was 25 dB. Endoscopy revealed a suspect lesion in the nasopharynx. Transtympanic ventilation tubes were placed, and nasopharyngeal biopsy was obtained. The diagnosis of a B cell non- was made. CT scan showed an isolated nasopharyngeal lesion without intracerebral extension. The patient was re- ferred to the department of internal medicine for che- motherapy. Before the therapy was started, he developed a syndrome of inappropriate secretion of antidiuretic (SIADH or Schwartz-Bartter syndrome) with weakness and lethargy and excessive blood levels of in combination with hyponatremia, which was interpreted as a paraneoplastic syndrome. For the SIADH he was treated with restriction of fluid intake. (cyclophosphamide, doxorubicin, vin- cristine, prednisolone: CHOP) was started in September 2003. The symptoms of SIADH as well as the primary tumour disappeared after chemotherapy. Five months after the initial treatment the patient is still in remission.

Case 3

A 48-year-old man was referred to the department of in November 1991 because of acute onset Fig. 1 Report number one: patient with a paraneoplastic derma- pain in several joints. The left knee, shoulders and the tological syndrome. Erythrodermia: generalized erythematous and first metatarsophalangeal joint on the left side were in- elevated cutaneous eruption with scaling and pruritus volved, soon followed by an inflammatory swelling of 34 the left knee. There were no rheumatoid nodules. Family October 2003 before radiotherapy of the supraglottic history of rheumatoid arthritis was negative. Blood tests malignancy was started. were negative for the Waaler-Rose test, complement factors III and IV and anti-nuclear factor. Skin and muscle biopsies showed normal tissue. CT Discussion scans of the thorax and abdomen and skeletal X-rays were normal. The diagnosis of an unclassified collagen The exact incidence of paraneoplastic syndromes in disease or vasculitis was made. The patient showed a association with head and neck cancer is not known. In very good response on treatment with a high dose of the literature paraneoplastic syndromes in association prednisone. Five months later he developed dysphagia with head and neck cancer are mostly described in case and dysphonia. He was referred to our department. A reports or review articles. In Table 1 the localisation and cT4N2cM0 hypopharynxcarcinoma was diagnosed. histological types of the paraneoplastic syndromes most A diagnosis of a paraneoplastic syndrome preceding a commonly associated with head and neck cancer are head and neck cancer was made. A laryngopharyngec- presented. Generally paraneoplastic syndromes are tomy with radical neck dissection on the right side and classified in four major groups as mentioned in the modified (functional) neck dissection on the left side was introduction. Three of the four patients fit in this classi- performed. During postoperative radiotherapy he fication. The fourth one fits in the group of rheumato- developed multiple bone metastases. The patient died logical paraneoplastic syndromes. Many of the several weeks later. mucocutaneous lesions have been described as paraneo- plastic dermatological syndromes also associated with head and neck cancer. The great diversity of these Case 4 mucocutaneous lesions makes a uniform aetiology un- likely [9]. In some mucocutaneous lesions, the presence of A 74-year-old man was hospitalised at the university immunoglobulins and complement in the basement neurological department in August 2003 for evaluation membrane assume a tumour-mediated of progressive weakness in the upper extremities and [5, 9]. In dermatological paraneoplastic syndromes the episodes of mental confusion. He developed a progres- mucocutaneous lesions often improve significantly after sive unsteady walking pattern over a 6-month period. treatment of the underlying malignancy [5]. In case 1 the Also a deterioration of the sensibility of both feet was skin rash also disappeared during radiotherapy. The reported. No other neurological symptoms were ob- cutaneous lesions are often resistant to topical medica- served. The neurological status deteriorated and a pro- tion as in our case. SIADH is classified under endocrine gressive paresis of the upper and lower extremities was paraneoplastic syndromes. Hoffman et al. reported a observed. A poliomyelitis-like clinical manifestation higher incidence (3%) of SIADH in patients with head with neuronal loss in the anterior and posterior horns and neck cancer than previously was assumed [8, 12, 19]. was diagnosed. Electromyography showed signs of SIADH can cause neurological symptoms like hyper- denervation of the muscles of the extremities. Also a reflexia, mental confusion and even coma [5]. The diag- moderate polyneuropathy was observed. Magnetic res- nosis of SIADH can be confirmed by detection of serum onance imaging of the brain and spinal cord showed a hyponatremia and hypo-osmolarity [5, 15, 19]. In case 2 stenosis of the cervical canal. There was no evidence of excessive blood levels of vasopressin with hyponatremia intracranial infarction, haemorrhage or tumour. A were detected and were interpreted in combination with lumbar puncture showed only a reactive lymphocytosis. the neurological symptoms as a paraneoplastic syn- The possibility of a paraneoplastic neurological syn- drome. The oral cavity is the most common primary drome was considered. Serum anti-Hu were tumour site of the head and neck in paraneoplastic syn- positive. CT scan of the thorax was normal. The patient drome of SIADH [5, 8]. Squamous cell carcinoma is the was referred to our department for evaluation of a neck most common histological type in SIADH in head and node at the left side. FNAC of this node showed atypical neck cancer [8, 15]. Hoffman et al. have suggested several malignant cells. During panendoscopy a biopsy was ta- pathologic mechanisms for SIADH. Ectopic secretion of ken of a small ulcer at the right arytenoid. Histopatho- arginine vasopressin [15] or an arginine vasopressin-like logical examination revealed squamous cell carcinoma. substance or secretion of releasing factor for arginine The supraglottic carcinoma was staged cT1N1M0. A vasopressin are the most likely mechanisms [5]. The paraneoplastic anti-Hu positive in treatment of the primary tumour and restriction of fluid combination with a was diagnosed in intake form the treatment of SIADH [12, 15]. The third this patient. The patient’s extreme weak condition did patient developed an asymmetrical paraneoplastic pol- not allow radio- and/or chemotherapy. Immunosup- yarthritis. In the literature asymmetric polyarthritis with pressive medication was started to treat the paraneo- an explosive onset in association with malignancies has plastic syndrome. A high dose of prednisone in been described [14]. Paraneoplastic polyarthritis in association with sandimmun neoral and azathioprine association with head and neck cancer is reported ex- was started. The patient died several weeks later in tremely rarely. Joint symptoms develop very suddenly 35

Table 1 Localization and histology of the primary Paraneoplastic Localization Histology Paraneoplastic symptoms malignancy in patients with syndrome neoplasm and findings head and neck cancer associated with paraneoplastic Cushing syndrome Nasopharynx SCCADCNPCSCNC Moon face syndromes [1, 3, 4, 5, 8, 9, 10, Facial redness 11, 17, 18]. SSC squamous cell Larynx Muscular atrophy carcinoma, NPC Thyroid Skin pigmentation nasopharyngeal carcinoma, Bazex syndrome Oral cavity Predilection extremities ADC , SCNC Pharynx ADCSCC Psoriasiform aspect small cell neuroendocrine Hypopharynx Symmetric manifestations carcinoma Larynx Erythematous squamous plaques Nail dystrophy Schwartz-Bartter Oral cavity NPC, SCNCSCC, Headache, mental confusion, syndrome Larynx ADC Hyperreflexia Hypopharynx Serum hyponatremia, Hypochloremia, hypo-osmolarity High antiduretic hormone Polyarthritis Larynx SCC Explosive asymmetrical joint pain Predilection lower extremities Absence rheumatoid nodules Absence rheumatoid factor Negative family history Lambert-Eaton Larynx SCNCSCC Proximal motor neuron weakness syndrome Decreased/absent reflexes Dry mouth, diplopiaSerum antineuronal autoantibodies

and with predominant involvement of the lower growth and even tumour regression [2, 10, 16]. Median extremities. The small joints of the hands and wrists are survival of patients with anti-Hu positive serum is sig- usually spared. Rheumatoid nodules are absent. Also nificantly longer than in anti-Hu negative patients de- blood tests for rheumatoid arthritis are negative. The spite the stage of the primary tumour [6]. The natural history regarding the family is negative for paraneoplastic anti-neuronal autoantibodies can more rheumatoid arthritis. The pathologic mechanism for specifically lead to the diagnosis of the underlying pri- paraneoplastic polyarthritis is not known. Autoimmune mary malignancy or recurrent tumour [1, 10]. Early cross reactivity of synovial and tumour antigens has been detection of these specific autoantibodies probably can suggested [3]. An extensive search for occult malignancy prevent irreversible neuronal damage by starting immu- in rheumatic syndromes is not recommended unless notherapy and treatment of the underlying malignancy in accompanied by specific findings suggestive of malig- an early stage [17]. Knowledge of paraneoplastic syn- nancy [14]. The treatment of paraneoplastic rheumatic dromes associated with head and neck cancer is impor- syndromes consists of therapy for the underlying malig- tant. Dermatological and rheumatologic paraneoplastic nancy [18] and symptomatic treatment with non-steroi- syndromes present very suddenly, but in some cases they dal anti-inflammatory drugs or corticosteroids [4]. The can improve during treatment of the primary tumour as fourth patient suffered from a seropositive anti-Hu in the two described cases. Early detection of a para- paraneoplastic syndrome. Occasionally paraneoplastic neoplastic syndrome can prevent severe life-threatening neurological syndromes in association with head and neurological or endocrine (SIADH) manifestations. In neck cancer have been reported. Of the anti-Hu positive general the results of treatment of the paraneoplastic syndromes, 70 to 90% are associated with small cell lung syndromes and even treatment of the associated primary cancer [1, 20]. In two thirds of the patients the para- tumour are disappointing [16]. The effect of the para- neoplastic neurological syndrome usually occurs before neoplastic syndrome on the survival rate depends on the the primary malignancy has been diagnosed [1]. Anti- type of paraneoplastic syndrome [15]. neuronal autoantibodies have been identified for a number of paraneoplastic neurological syndromes [5, 16]. The hypothesis of paraneoplastic neurological syn- References dromes is based on expression of tumoral antigens [16]. Normally these antigens only occur in neurons. These 1. Dalmau J, Posner B (1999) Paraneoplastic syndromes. Arch onconeuronal antigens because of the tumoral location Neurol 56:405–408 outside the blood-brain barrier are activating the im- 2. Darnell RB, DeAngelis LM (1993) Regression of small-cell mune system. The pathogenesis is based on auto-immu- lung carcinoma in patients with paraneoplastic neuronal anti- nity against these tumour antigens that lead to severe bodies. Lancet 341:21–22 3. Eggelmeijer F, Macfarlane JD (1992) Polyarthritis as the pre- neurological damage [1, 10]. On the other hand the anti- senting symptom of the occurrence and recurrence of a lar- neuronal autoantibodies can cause a decrease of tumour yngeal carcinoma. Ann Rheum Dis 51:556–557 36

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