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

HEAD AND NECK ONCO L OGY

L. W. J. Baijens Æ J. J. Manni

Paraneoplastic syndromes in patients with primary malignancies 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 patients with head and neck cancer. Four patients with different histological types of head and neck cancer are presented in which the primary malignancy was preceded and/or accompanied by a paraneoplastic syndrome. In the first patient erythrodermia preceded the diagnosis of a nasopharyngeal carcinoma. The second patient presented with a B cell lymphoma of the nasopharynx in association with the syndrome of inappropriate secretion of arginine vasopressine (SchwartzBartter syndrome). In the third patient paraneoplastic polyarthritis had been diagnosed 5 months before a hypopharyngeal carcinoma was diagnosed. In the last patient the paraneoplastic anti-Hu positive encephalomyelitis was associated with a primary malignancy in the larynx with neck metastases. Diagnostic procedures, treatment and follow-up of these patients are reported and accompanied by a review of the literature. Keywords Paraneoplastic syndromes Æ Head and neck cancer Æ Squamous cell carcinoma Æ Anti-Hu autoantibodies Æ Mucocutaneous lesions

Introduction A paraneoplastic syndrome describes an association of symptoms and signs not directly related to the site or local manifestations of a malignant tumour or its metastases and occurring in a minority of cancer

L. W. J. Baijens (&) Æ J. J. Manni Department of Otorhinolaryngology Head and Neck Surgery, Maastricht University Hospital, PO Box 5800, 6202 AZ Maastricht, The Netherlands E-mail: [email protected] Tel.: +31-433877580 Fax: +31-3875580

patients [5, 13]. Often the paraneoplastic syndrome presents before the initial symptoms or diagnosis of the primary malignancy or the recurrent tumour is made [5]. Paraneoplastic syndromes occur in 1 to 7.4% of all cancer patients [7, 21]. The mechanisms of most paraneoplastic syndromes are not well known. Ectopic hormone production is probably the most common mechanism [12]. Immunologic interactions in particular autoimmune responses play an important role in neurological paraneoplastic syndromes [1, 7, 10, 17]. In the literature, paraneoplastic syndromes in association with head and neck cancer have occasionally been reported. Squamous cell carcinoma is the most common histopathology of the primary malignancy of the head and neck associated with paraneoplastic syndromes [12]. Also other histological types such as thyroid carcinoma, lymphoma, thymoma, melanoma and paraganglioma of the head and neck have been reported in association with paraneoplastic syndromes [12]. Ferlito et al. divided paraneoplastic syndromes associated with head and neck cancer in four groups: paraneoplastic dermatological, 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 described as paraneoplastic syndromes, also in head and neck cancer patients. Bazex syndrome is a frequently reported paraneoplastic dermatological syndrome [5]. Head and neck cancer has only occasionally been reported in association with haematological and neurological syndromes [5]. In the literature cerebellar degeneration and the Eaton-Lambert myasthenia syndrome are the most reported paraneoplastic neurological syndromes. They are seldom associated with laryngeal cancers. These neurological syndromes are usually associated with small cell lung cancer [16, 17]. Serum and cerebrospinal fluid autoantibodies have recently been identified for several neurological paraneoplastic syndromes [5, 16]. In this paper we report four different paraneoplastic syndromes associated with different primary tumours of the head and neck.

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Case report Case 1 A 60-year-old woman was referred to the dermatological department of our university hospital in November 2002 because of a therapy-resistant generalized erythematous cutaneous eruption that had developed 2 months previously. At first the skin of the trunk was affected, followed by progression towards the extremities, face and neck (Fig. 1). At the dermatological department, she was treated with a diversity of topical medication and systemic antihistaminics without any effect. Several skin biopsies showed a non-specific chronic dermatitis. Skin culture showed normal results. To exclude a paraneoplastic syndrome the patient was referred to the departments of internal medicine and gynaecology for extensive examination for a primary malignancy. Clinical examinations and imaging techniques showed normal results. From that moment she was treated for late onset constitutional eczema with cyclosporin and imipramine. Despite the medication the erythema persisted. In April 2003 she was referred to our department of otorhinolaryngology and head and neck surgery because

of recurrent epistaxis and neck nodes. During the ear, nose and throat examination, a glue ear on the left side was observed. Nasendoscopy revealed a nasopharyngeal tumour. Neck nodes were palpated in region II-III on the left side. Gradually she developed an abducens paralysis on the left side. On CT scan the paralysis could be explained by tumour invasion of the sinus cavernosus. Biopsy of the nasopharynx tumour revealed a carcinoma. Fine-needle aspiration cytology (FNAC) of the neck nodes showed a squamous cell carcinoma. The diagnosis of nasopharyngeal carcinoma with neck metastasis and a dermatological paraneoplastic syndrome was made. The tumour was classified as cT4N2M0. Radiotherapy was started in July 2003. In 6 weeks a total dose of 70.2 Gy was given. During radiotherapy the skin rash and abducens paralysis disappeared. Six months after radiotherapy the patient is still in remission. Case 2 A 71-year-old man visited our out-patient department in July 2003 because of bilateral hearing loss since several weeks without other complaints. He had never experienced 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-Hodgkin lymphoma was made. CT scan showed an isolated nasopharyngeal lesion without intracerebral extension. The patient was referred to the department of internal medicine for chemotherapy. Before the therapy was started, he developed a syndrome of inappropriate secretion of antidiuretic hormone (SIADH or Schwartz-Bartter syndrome) with weakness and lethargy and excessive blood levels of vasopressin in combination with hyponatremia, which was interpreted as a paraneoplastic syndrome. For the SIADH he was treated with restriction of fluid intake. Chemotherapy (cyclophosphamide, doxorubicin, vincristine, 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

Fig. 1 Report number one: patient with a paraneoplastic dermatological syndrome. Erythrodermia: generalized erythematous and elevated cutaneous eruption with scaling and pruritus

A 48-year-old man was referred to the department of rheumatology in November 1991 because of acute onset pain in several joints. The left knee, shoulders and the first metatarsophalangeal joint on the left side were involved, soon followed by an inflammatory swelling of

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the left knee. There were no rheumatoid nodules. Family history of rheumatoid arthritis was negative. Blood tests were negative for the Waaler-Rose test, complement factors III and IV and anti-nuclear factor. Skin and muscle biopsies showed normal tissue. CT scans of the thorax and abdomen and skeletal X-rays were normal. The diagnosis of an unclassified collagen disease or vasculitis was made. The patient showed a very good response on treatment with a high dose of prednisone. Five months later he developed dysphagia and dysphonia. He was referred to our department. A cT4N2cM0 hypopharynxcarcinoma was diagnosed. A diagnosis of a paraneoplastic syndrome preceding a head and neck cancer was made. A laryngopharyngectomy with radical neck dissection on the right side and modified (functional) neck dissection on the left side was performed. During postoperative radiotherapy he developed multiple bone metastases. The patient died several weeks later.

Case 4 A 74-year-old man was hospitalised at the university neurological department in August 2003 for evaluation of progressive weakness in the upper extremities and episodes of mental confusion. He developed a progressive unsteady walking pattern over a 6-month period. Also a deterioration of the sensibility of both feet was reported. No other neurological symptoms were observed. The neurological status deteriorated and a progressive paresis of the upper and lower extremities was observed. A poliomyelitis-like clinical manifestation with neuronal loss in the anterior and posterior horns was diagnosed. Electromyography showed signs of denervation of the muscles of the extremities. Also a moderate polyneuropathy was observed. Magnetic resonance imaging of the brain and spinal cord showed a stenosis of the cervical canal. There was no evidence of intracranial infarction, haemorrhage or tumour. A lumbar puncture showed only a reactive lymphocytosis. The possibility of a paraneoplastic neurological syndrome was considered. Serum anti-Hu antibodies were positive. CT scan of the thorax was normal. The patient was referred to our department for evaluation of a neck node at the left side. FNAC of this node showed atypical malignant cells. During panendoscopy a biopsy was taken of a small ulcer at the right arytenoid. Histopathological examination revealed squamous cell carcinoma. The supraglottic carcinoma was staged cT1N1M0. A paraneoplastic anti-Hu positive encephalomyelitis in combination with a laryngeal cancer was diagnosed in this patient. The patient’s extreme weak condition did not allow radio- and/or chemotherapy. Immunosuppressive medication was started to treat the paraneoplastic syndrome. A high dose of prednisone in association with sandimmun neoral and azathioprine was started. The patient died several weeks later in

October 2003 before radiotherapy of the supraglottic malignancy was started.

Discussion The exact incidence of paraneoplastic syndromes in association with head and neck cancer is not known. In the literature paraneoplastic syndromes in association with head and neck cancer are mostly described in case reports or review articles. In Table 1 the localisation and histological types of the paraneoplastic syndromes most commonly associated with head and neck cancer are presented. Generally paraneoplastic syndromes are classified in four major groups as mentioned in the introduction. Three of the four patients fit in this classification. The fourth one fits in the group of rheumatological paraneoplastic syndromes. Many of the mucocutaneous lesions have been described as paraneoplastic dermatological syndromes also associated with head and neck cancer. The great diversity of these mucocutaneous lesions makes a uniform aetiology unlikely [9]. In some mucocutaneous lesions, the presence of immunoglobulins and complement in the basement membrane assume a tumour-mediated immune response [5, 9]. In dermatological paraneoplastic syndromes the mucocutaneous lesions often improve significantly after treatment of the underlying malignancy [5]. In case 1 the skin rash also disappeared during radiotherapy. The cutaneous lesions are often resistant to topical medication as in our case. SIADH is classified under endocrine paraneoplastic syndromes. Hoffman et al. reported a higher incidence (3%) of SIADH in patients with head and neck cancer than previously was assumed [8, 12, 19]. SIADH can cause neurological symptoms like hyperreflexia, mental confusion and even coma [5]. The diagnosis of SIADH can be confirmed by detection of serum hyponatremia and hypo-osmolarity [5, 15, 19]. In case 2 excessive blood levels of vasopressin with hyponatremia were detected and were interpreted in combination with the neurological symptoms as a paraneoplastic syndrome. The oral cavity is the most common primary tumour site of the head and neck in paraneoplastic syndrome of SIADH [5, 8]. Squamous cell carcinoma is the most common histological type in SIADH in head and neck cancer [8, 15]. Hoffman et al. have suggested several pathologic mechanisms for SIADH. Ectopic secretion of arginine vasopressin [15] or an arginine vasopressin-like substance or secretion of releasing factor for arginine vasopressin are the most likely mechanisms [5]. The treatment of the primary tumour and restriction of fluid intake form the treatment of SIADH [12, 15]. The third patient developed an asymmetrical paraneoplastic polyarthritis. In the literature asymmetric polyarthritis with an explosive onset in association with malignancies has been described [14]. Paraneoplastic polyarthritis in association with head and neck cancer is reported extremely rarely. Joint symptoms develop very suddenly

35 Table 1 Localization and histology of the primary malignancy in patients with head and neck cancer associated with paraneoplastic syndromes [1, 3, 4, 5, 8, 9, 10, 11, 17, 18]. SSC squamous cell carcinoma, NPC nasopharyngeal carcinoma, ADC adenocarcinoma, SCNC small cell neuroendocrine carcinoma

Paraneoplastic syndrome

Localization neoplasm

Histology neoplasm

Paraneoplastic symptoms and findings

Cushing syndrome

Nasopharynx Pharynx Larynx Thyroid Oral cavity Pharynx Hypopharynx Larynx

SCCADCNPCSCNC

Schwartz-Bartter syndrome

Oral cavity Larynx Hypopharynx

NPC, SCNCSCC, ADC

Polyarthritis

Larynx

SCC

Lambert-Eaton syndrome

Larynx

SCNCSCC

Moon face Facial redness Muscular atrophy Skin pigmentation Predilection extremities Psoriasiform aspect Symmetric manifestations Erythematous squamous plaques Nail dystrophy Headache, mental confusion, Hyperreflexia Serum hyponatremia, Hypochloremia, hypo-osmolarity High antiduretic hormone Explosive asymmetrical joint pain Predilection lower extremities Absence rheumatoid nodules Absence rheumatoid factor Negative family history Proximal motor neuron weakness Decreased/absent reflexes Dry mouth, diplopiaSerum antineuronal autoantibodies

Bazex syndrome

and with predominant involvement of the lower extremities. The small joints of the hands and wrists are usually spared. Rheumatoid nodules are absent. Also blood tests for rheumatoid arthritis are negative. The natural history regarding the family is negative for rheumatoid arthritis. The pathologic mechanism for paraneoplastic polyarthritis is not known. Autoimmune cross reactivity of synovial and tumour antigens has been suggested [3]. An extensive search for occult malignancy in rheumatic syndromes is not recommended unless accompanied by specific findings suggestive of malignancy [14]. The treatment of paraneoplastic rheumatic syndromes consists of therapy for the underlying malignancy [18] and symptomatic treatment with non-steroidal anti-inflammatory drugs or corticosteroids [4]. The fourth patient suffered from a seropositive anti-Hu paraneoplastic syndrome. Occasionally paraneoplastic neurological syndromes in association with head and neck cancer have been reported. Of the anti-Hu positive syndromes, 70 to 90% are associated with small cell lung cancer [1, 20]. In two thirds of the patients the paraneoplastic neurological syndrome usually occurs before the primary malignancy has been diagnosed [1]. Antineuronal autoantibodies have been identified for a number of paraneoplastic neurological syndromes [5, 16]. The hypothesis of paraneoplastic neurological syndromes is based on expression of tumoral antigens [16]. Normally these antigens only occur in neurons. These onconeuronal antigens because of the tumoral location outside the blood-brain barrier are activating the immune system. The pathogenesis is based on auto-immunity against these tumour antigens that lead to severe neurological damage [1, 10]. On the other hand the antineuronal autoantibodies can cause a decrease of tumour

ADCSCC

growth and even tumour regression [2, 10, 16]. Median survival of patients with anti-Hu positive serum is significantly longer than in anti-Hu negative patients despite the stage of the primary tumour [6]. The paraneoplastic anti-neuronal autoantibodies can more specifically lead to the diagnosis of the underlying primary malignancy or recurrent tumour [1, 10]. Early detection of these specific autoantibodies probably can prevent irreversible neuronal damage by starting immunotherapy and treatment of the underlying malignancy in an early stage [17]. Knowledge of paraneoplastic syndromes associated with head and neck cancer is important. Dermatological and rheumatologic paraneoplastic syndromes present very suddenly, but in some cases they can improve during treatment of the primary tumour as in the two described cases. Early detection of a paraneoplastic syndrome can prevent severe life-threatening neurological or endocrine (SIADH) manifestations. In general the results of treatment of the paraneoplastic syndromes and even treatment of the associated primary tumour are disappointing [16]. The effect of the paraneoplastic syndrome on the survival rate depends on the type of paraneoplastic syndrome [15].

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