Paraneoplastic syndromes refer to manifestations that present distantly from the primary site or metastatic site of a tumour. They represent disorders that result due to the systemic effects rather than the local effect of the tumour. A handful of cases of nasopharyngeal carcinoma have been reported to present with these remote effects. The underlying mechanisms that give rise to these indirect manifestations have been attributed to humoral factors or immune response. Cross reactivity between normal tissues and host antitumour antibody also plays a critical role. There are six main categories of paraneoplastic syndromes; dermatologic or cutaneous, endocrine, hematologic, osteoarticular/rheumatologic, neurological and ocular. Dermatologic manifestations represent the most common paraneoplastic effect of NPC. These indirect effects usually antedate the diagnosis of NPC in about 80 % of cases whereas in some other they may also occur after the cancer is diagnosed. Although these phenomena are relatively rarely associated with NPC compared to other cancers such as lung cancers where they occur more frequently, the possibility of a nasopharyngeal carcinoma should also be considered by clinicians. This may provide an opportunity to detect cancer at an earlier stage or even help to detect occult malignancy. In most cases the signs and symptoms resolve following treatment of the underlying cancers while in certain cases directed therapy may be required. Reappearance of paraneoplasia usually occurs with case recurrences. Thereby their presence following remission may also help to identify relapses at an early stage. This contribution provides an overview of the paraneoplastic manifestations of NPC which is one the most frequently encountered malignancy in mainland China with emphasis on those which are more commonly associated with NPC.
Paraneoplastic syndromes occur in up to 10% cancer cases. The most common cancers associated with these phenomena are: lung (SCLC, NSCLC), pancreatic, lymphoma (Hodgkin and non-Hodgkin), prostate, ovary. However, till date several cases of paraneoplasia have been reported in association with nasopharyngeal carcinoma. According to Toro C, Rinaldo A, Silver C et al. more than 260 cases of NPC have been reported to present with paraneoplastic syndrome in literature. NPC accounts for about 18% of malignancy in China. In contrast to America and other regions where the cancer occur rarely, NPC is responsible for a huge burden of disease in China. Despite recent advances, many challenges are yet to be overcome in this aspect of oncology. As such a thorough understanding of the presentations of NPC is of utmost value for the timely diagnosis of the malignancy. Clinicians are very well acquainted with the typical signs and symptoms of NPC which include cervical lymphadenopathy in 75% of cases, nasal obstruction, epistaxis, recurrent otitis media, sore throat, hearing loss, facial numbness due to cranial nerve dysfunctions (mainly II-VI, IX-XII). However, when it comes to the paraneoplastic manifestations, they are often underdiagnosed and misinterpreted for other benign conditions that mimic them. Therefore, the aim of this review is to provide a proper understanding of the current status on the paraneoplastic effects of NPC for the timely detection of cases and improving outcome and survival of patients.
CLASSIFICATION OF PARANEOPLASTIC SYNDROME ASSOCIATED WITH NPC
In 1940, cancers were first reported to present with distant signs and symptoms which were not due to local mass effects. These effects were then termed as paraneoplastic syndromes which are also known as non-metastatic effects, remote effects, indirect effects, distant effects. They were proposed to result due to secretion of peptides from the tumour. These substances may mimic normal hormones, interfere with normal metabolic pathway or trigger an immune response. In some cases, the cause maybe idiopathic. Different organ and tissues may be the target of these phenomena and therefore they have been divided into six main groups according to the organ or system they influence.
Paraneoplastic cutaneous or dermatologie syndromes Acanthosis nigricans Bazex’s syndrome (paraneoplastic acrokeratosis) Bowen’s disease Bullous pemphigoid Dermatomyositis Sweet’s syndrome Tripe palms Yellow nail syndrome Paraneoplastic endocrine syndromes Calcitonin Carcinoid syndrome Cushing’s syndrome or ectopic adrenocorticotrophic hormone syndrome Nonmetastatic hypercalcemia Schwartz-Bartter syndrome or syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Paraneoplastic hématologie syndromes Thrombophlebitis migrans or migratory thrombophlebitis or Trousseau’s syndrome Consumption coagulopathies Leukocytosis Paraneoplastic neurologic syndromes Eaton-Lambert myasthénie syndrome Paraneoplastic osteoarticular syndromes Hypertrophie osteoarthropathy
It is the most common paraneoplastic syndrome associated with NPC. The link between NPC and dermatomyositis was first reported in 1969.Dermatomyositis comprises signs and symptoms that target the skin and muscles. The skin very often reflects changes happening internally. The occurrence of dermatomyositis should always point towards a high index of suspicion for an underlying malignant process which is present in about 10-40 % of cases of dermatomyositis. Cancers that have been cited in literature to be associated with dermatomyositis are: ovarian cancer, lung cancer, pancreatic cancer, breast cancer, non-Hodgkin lymphoma, testicular cancer. However, the most frequent cancer that manifests with dermatomyositis is NPC with an incidence of 1/1000 cases. In a review of 2439 patients with DM by Nobuhiro Kanaji et al., 21% of cases has been associated with dermatomyosistis. In Guadong province, where the disease is endemic, a large number of cases have been reported. Histologically, the type II and Type III NPC are mostly associated with cutaneous manifestations. The clinical skin and muscle changes may present before the tumour present itself, at the same time as the tumour or upto 5 years following appearance of the lesion.
The diagnostic work up should include a full history and physical examinations. Rigid nasoendoscopies, biopsies, serum EBV viral capsid Ig A antibody and imaging studies should also be performed.
The pathophysiplogy of dematological syndrome is still poorly understood. Several theories have been proposed which include:
Autoimmune response due to tumour antigen which trigger an immune response.
Secretion of active metabolites by transferred NPC cells.
Kaji et al. recently identified an autoreactive antibody with 155/140 kPa nuclear protein.
This may serve as a serological marker. Its level rises with increasing severity and decreases following successful treatment.
Treatment usually is directed towards the malignancy. Removal of the tumour decreases the level of tumour autoantibody. In most cases the signs and symptoms resolve following successful treatment. Glucocorticoid therapy and immunosuppression also form an integral part of the management strategies. Glucocorticoid in dose range of 0.5-1.0mg/kg are often used to provide relief. Azathioprine, methotrexate and cyclophosphamide can be employed as adjuvant therapy. However, cases unresponsive to steroids have also been reported. In such situation, second line treatment with IVIG is a choice.
NEOPLASTIC FEVER AS A REMOTE EFFECT OF NPC
The term neoplastic fever is also well known as tumour fever. It is a challenge for most clinicians and therefore proper understanding of the topic is mandatory for timely diagnosis and treatment of the condition. Tumour fever is defined as an elevated body temperature more than 37.8 degree Celsius which is caused exceptionally by the malignancy. 15- 20% of cases of fever of unknown origin is due to neoplastic fever. According to Liaw et al., 67 patients of NPC presented with this condition from 1982 to 1996.This phenomenon occurs most frequently in the metastatic state of NPC.
POSSIBLE UNDERLYING THEORIES
The mechanisms giving rise to tumour fever are believed to be cytotoxin mediated. The chemicals responsible are TNF, IL-6, interferon mainly. Tumour necrosis and bone marrow necrosis may account for the release of the mediators
56346811683042005609590603885Stimulate production of prostaglandins
020000Stimulate production of prostaglandins
Bone marrow necrosis
Bone marrow necrosis
53916612975Change in body temperature
4000020000Change in body temperature
2957384997120417205332025 Act on hypothalamus
4000020000 Act on hypothalamus
DIAGNOSING NEOPLASTIC FEVER
Establishing the diagnosis of neoplastic fever is a troublesome task. Thorough investigations are of vital importance to rule out the other causes of fever. Neoplastic fever is then diagnosed by excluding other possible etiologies. The diagnostic work up should include: complete history and physical examination, laboratory investigations; full blood count, ESR, CRP, biochemical profile, blood, urine, sputum culture and analysis, CT scan and MRI.
Characteristics features of neoplastic fever
Temperature ; 37.8 C at least once a day
Duration of fever more than 2 weeks
No infective etiology
No history of drug allergy, transfusion reaction, radiation
No response to antibiotics
Less response to acetaminophen
Fever lysis by naproxen within 24 hours. Sustained normal temperature while on naproxen
The treatment options include:
Cancer directed therapy: In a handful number of cases, fever may subsides following chemotherapy for the tumour.
Steroids also may help in palliating the symptoms.
NSAIDS: Naproxen, Indomethacin, Ibuprofen, diclofenac
Naproxen has a special place in the treatment of tumour fever. Several studies have proved its superiority over other NSAIDS in tumour fever. It causes lysis of fever in 24 hours following administration and the response is well sustained as long as the patients are on naproxen. This provides a diagnostic difference. However due to its side effects such gastritis and gastrointestinal bleeding, caution is warranted in some patients especially those with thrombocytopenia.
Managing neoplastic fever is still complex. In the near future, cytokine antagonist may play a role hopefully.
Leukemoid reaction or leukocytosis is defined as an elevated number of white blood cells usually more than 50 000/ul in the absence of infection, leukemia or tumour necrosis. The reaction occurs outside the bone marrow. The incidence rate of leukemoid reaction in NPC patients has been reported to be 16% according to Cvikovic et al. Tumour fever forms an intergral part of leukemoid reaction. In 2014, a first case of pediatric NPC with leukemoid reaction has been documented in literature. The underlying mechanism is due to secretion of cytokines mainly granulocyte –colony stimulating factor G-CSF, granulocyte macrophage colony stimulating factor GM-CSF and interleukin 1 and 6. Diagnostic work up should aim at excluding CML and CNL. Marked left shift, raised mature neutrophils on peripheral blood count, raised leucocyte alkaline phosphatase and high level of hematopoietic growth factors assist in diagnosing the condition. Patients presenting with leukemoid reaction usually have a poor prognosis as they often fail chemo radiation after leucocyte level more than 100 000/ul. Specific treatment to normalize the leucocyte count is still unclear. Antineoplastic therapy targeting the tumour remain the choice till date.
The occurrence of immune thrombocytopenia in patients with NPC has been scarcely reported in literature. The phenomenon is more routinely associated with lymphoproliferative disorder and chronic myelogenous leukemia. The incidence is 2-10% in chronic lymphocytic leukemia, 1% in Hodgkin lymphoma and 0.76 % in non-Hodgkin lymphoma. Thrombocytopenia can occur as a result of decreased platelet production, increased platelet destruction or increased sequestration. Platelet sequestration is the cause for immune thrombocytopenia. The underlying mechanism is believed to be immunologic in origin. In 2010, Kunyu Yang et al. reported 2 cases of grade 3 immune thrombocytopenia in China. The origin was deduced to be immunologic as indicated by the laboratory investigations carried out. However, EBV virus has also been known to trigger immune thrombocytopenia but the mechanism is still obscure. In a study conducted in 2008,32.4% of children with active EBV infection were found to have thrombocytopenia by C.CHSIAO et al. A platelet counts of zero has been documented with EBV infection in 2017 by Patrick Twohis et al. Given the high prevalence of EBV infection in NPC patients, whether the immune thrombocytopenia is due as a result of paraneoplastic syndrome or contributed also by EBV virus, is a matter of debate.
Thrombocytopenia is diagnosed when platelet count is less than 100 000 per microliter of circulating blood. Active medical interventions are warranted when the count is less than 30 000/ ul. Prednisolone 1 mg/kg for 21 days followed by tapering is the initial choice of treatment. Iv immunoglobulin 1g/kg as a single dose or 1-2g/kg in divided dose over 2-5 days may be prescribed. Transfusion can be carried out as indicated to keep the platelet count at least 50 000/ul. Aminocaproic acid (1-2g 6 hourly), tranexemic acid 1g three times daily can be of help in case of oral bleeding. NSAIDS, aspirin, warfarin, anticoagulant should be discontinued. Vitamin K can be injected as indicated. Rituximab have a killing effect on B clones and this allows it as a therapeutic option. For patients who failed the above lines of treatment, splenectomy can be of value. Recently, romiplostim and eitrombopag have been introduced as treatment modalities.
ENDOCRINOPATHIES IN NPC
The condition arises due to overproduction of cortisol by the adrenal glands. The resulting effect appear in the form of truncal obesity, thin extremities, moon face, fragile skin and hypertension among several other signs. Ectopic ACTH secretion by tumours cause the paraneoplastic effect. It is more frequently associated with 50% of lung cancers and 36% to 46% of carcinoid tumour. Even though nasopharynx does not contain neuroendocrine tissue, ACTH production from the nasopharynx in cases of NPC has been reported. KCB Tan et al. reported two such cases of NPC. First one presented with Cushing syndrome and immunostaining for ACTH was positive. Second one presented with Paget’s disease and high level of ACTH. This may be explained by the fact that normal non pituitary cells from organ and tissues express proopiomelanocortin gene from which ACTH is derived. The later theory which can explained the paraneoplastic effect in NPC was proposed by Sylin and Mandelson. As such, an underling nasopharynx cancer should also be considered in patients with Cushing syndrome.
SIADH OR SCHWARTZ BARTTER SYNDROME:
First discovered in 1957 by Schwartz et al., this is a common disturbance affecting patients with head and neck malignancies and appears because of inappropriate secretion of arginine vasopressin. In 1997, Ferlito et al., conducted a study to know the incidence of SIADH in head and neck malignancies. Among 1436 patients, the incidence of SIADH was 3%. NPC accounted for 9 cases which represented a percentage of 12.86%. Patients with serum sodium concentration in the range of 130-135 mEq/l are usually asymptomatic or present with nausea, vomiting, lethargy. Clinically overt signs may also occur including orthostatic hypotension, dehydration, seizures, coma and death in severe cases. Diagnosis is based on the following g features: hyponatremia< 135 mEq/l, urine osmolality>300mEq/l, urine specific gravity>1.015, serum osmolality <280 mOsm/kg, urine sodium concentration> 20mEq/l. Fluid restriction, hypertonic saline, demeclocycline in relapse cases and cancer directed therapy form part of the management strategies.
PARANEOPLASTIC OSTEOARTICULAR OR RHEUMATOLOGIC SYNDROME
Hypertrophic osteoarthropathy –HOA, was first described by Hippocrates in 1985.It is a condition whereby there is abnormal proliferation of periosteal tissues leading to periostosis, arthritis, digital clubbing and joint pain. There are two main types; primary also called as pachydermoperiostosis and secondary which is sub grouped into pulmonary and non-pulmonary. The condition is mainly associated with thoracic malignancies. In NPC patients, a handful of cases of HOA have been reported. The incidence is higher in pulmonary metastasis and pediatric patients. Ennouri et al., reported 32 cases of NPC with paraneoplastic syndromes. Out of these patients 17 had HOA and 13 had clubbing of fingers.24 patients had lung metastasis. The pulmonary metastases are held responsible for the HOA and clubbing. Since hypertrophic osteoarthropathy is mainly associated with pulmonary condition, the term hypertrophic pulmonary osteoarthropathy is often used(HPOA). HOA can nevertheless appear in absence of lung involvement as described by Srinivas et al. who reported a 20-year-old patient of NPC with HOA in 2010.The pediatric group involvement is further convinced by Hyuk Chan et al. who elaborated 31 cases of HOA in childhood malignancy from 1890 – 2002 among which 13 had NPC.
The underlying theories responsible for rheumatologic effects are believed to be due to vagal stimulation as unilateral vagotomy improves the clinical features or because of non-activated platelet products which impair venous circulation. Megakaryocytes, platelet clumps are impacted into the circulation giving rise to the typical manifestations. Other factors that may contribute are elevated growth factors, VEGF and PDGF. Treatment include painkillers; NSAIDS, morphine for severe pain, steroids and treatment of underlying tumour. Radiation may alleviate bone pain as indicated by Yeo et al. The prognosis of NPC with HOA is poor. HOA represents an adverse feature as it is a disabling condition affecting survival.
PARANEOPLASTIC NEUROLOGIC PRESENTATIONS OF NPC
Diverse forms of neurologic responses result due to cross-reactions between onconeuronal antibodies and normal tissues leading an inflammatory process that targets the central and peripheral nervous system. They are termed as paraneoplastic neurologic manifestations and are sub-grouped into central, peripheral, neuromuscular junctional and muscular. PND occurs in the presence of an underlying malignancy and onconeuronal antibodies are usually a presenting feature. Nevertheless, the absence of the latter does not rule out a paraneoplastic neurologic disease. The cancers routinely associated with PND are lung cancers, testicular cancers, thymoma and ovarian cancer. However, in rare circumstances, PND can be associated with NPC. Barjen and Mami revealed such a case where the NPC patient demonstrated weakness and decreased sensation in bilateral feet. Loss of neurons in anterior and posterior horns with positive serum anti-Hu antibody was noted. PND may attack a single region of the nervous system or multiple regions as well. An NPC patient with peripheral neuropathy of lower limbs and bowel and urinary incontinence was described by Kong NH et al. in the absence of meningeal or leptomeningeal metastasis. The classical syndromes that are mostly encountered are Opsoclonus-myoclonus, Lambert-Eaton Myasthenic Syndrome (LEMS), sensory neuropathy and Myasthenia Gravis. The antibodies involved in PND are categorized into three groups; 1A which contain Hu or ANNA-1, Yo or PCA1, Ri or ANNA-2, CV2 CRMP5, amphiphysin, Ma2; 1B which comprise SOX and ZIC and 1C containing GAD. PND is diagnosed based on the exclusion of other possible causes such as infection, toxic and metabolic causes, metastases and adverse effects of therapies. Specific diagnostic tests include NCS, CSF examination, EMG, autoimmune antibodies testing. A muscle biopsy may be performed as indicated to rule out dermatomyositis or necrosing myopathy. Steroids, IV immunoglobulin, plasma exchange, azathioprine, cyclophosphamide form part of the treatment modalities. Chemoradiotherapy for NPC also helps to relieve the remote effects. In 2015, Taib et al. brought forward a case of Opsoclonus-myoclonus with in association with NPC. The patient exhibited otalgia, decreased hearing, dizziness and signs of cerebellar degeneration. The condition was improved after IVG, steroids and chemoradiotherapy. As such PND in association with NPC is a rare but probable condition that needs to be addressed judiciously.