Paraneoplastic Syndromes Associated with Laryngeal Cancer.

OBJECTIVES: Paraneoplastic syndromes occur rarely in association with laryngeal cancer. When present, the syndrome may be the first sign of the malignancy. The aim of the present study was to review and report on all published cases in the international literature.
METHODS: A search of PubMed was conducted for "paraneoplastic syndromes in laryngeal cancer" without any restrictions on language or publication year. The full texts of all relevant articles were reviewed and all cases of paraneoplastic syndromes associated with any type of laryngeal cancer were extracted and analyzed.
RESULTS: We identified 59 cases of paraneoplastic syndromes related to laryngeal cancer in the literature published from 1963 until recently. There were 46 squamous cell carcinomas and 10 neuroendocrine carcinomas. Twenty-two of the paraneoplastic syndromes involved the endocrine system, 21 were dermatologic or cutaneous, 8 neurologic, 5 osteoarticular or rheumatologic, 1 ocular, 1 muscular, and 1 hematologic. Treatment strategies included surgery, radiotherapy, chemotherapy, and often multimodal therapy, depending on the histology and stage of the laryngeal cancer.
CONCLUSIONS: Because of their rarity, paraneoplastic syndromes associated with laryngeal cancer are difficult to diagnose. By presenting and systematically reviewing all published cases in the international literature, the present review may help clinicians to recognize them and to suspect the diagnosis of laryngeal cancer at an earlier stage than otherwise might be possible.

Key Summary Points

Introduction

The symptoms and signs of various cancers are caused by the effects of the neoplasm locally, regionally, or distantly. In a few patients, these signs and symptoms are not directly produced by the primary tumor or its metastases, appearing rather to be produced by other, perhaps humoral, but often not fully understood mechanisms. These conditions are called “paraneoplastic syndromes” and their location does not coincide with the site of tumor [1-3]. Paraneoplastic syndromes are rare clinical syndromes due to the systemic effects of tumors; they are unrelated to tumor size, invasiveness, or metastases [4]. A paraneoplastic syndrome may be the first indication of an underlying cancer (initial, persistent or recurrent tumor, or asymptomatic metastasis). It is not due to direct organ invasion but is caused by substances elaborated by the distant neoplasm. These syndromes may precede the presentation of a cancer by many months, occasionally by several years. Whatever hormones and/or antibodies produce these syndromes, they share the property of acting far from their site of synthesis [5].

Other terminology for paraneoplastic syndromes includes paraneoplastic conditions, paraneoplastic effects, paraneoplastic events, non-metastatic syndromes, paraneoplastic phenomena, paraneoplastic disturbances, or remote effects. Paraneoplastic syndromes are more often recognized at the present time than previously, because of improving diagnostic methods and greater current knowledge about them among clinicians [6-9].

Small cell lung cancer is the tumor most frequently associated with these syndromes, although they can occur in almost any type of malignant tumor [10].

Laryngeal cancers, regardless of histology, have rarely been associated with paraneoplastic syndromes [1, 2, 11–13]. In this manuscript we will group these syndromes into seven headings: (1) dermatologic or cutaneous, (2) endocrine, (3) hematologic, (4) neurologic, (5) osteoarticular or rheumatologic, (6) ocular, and (7) muscular.

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Methods

In order to identify all published cases of paraneoplastic syndromes associated with laryngeal cancer, we performed a review of the more relevant articles that cover this issue. For this purpose, the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) method was used to conduct a systematic review of the current literature [14]. A PubMed internet search updated to March 3, 2019 was performed for publications using the following search terms in the title or abstract: “paraneoplastic syndrome” coupled with “head and neck cancer” or “larynx cancer”. The search results were reviewed for potentially eligible studies. When the abstract indicated that the article included a report of a paraneoplastic syndrome, the full-text article was searched and reviewed in order to know if the tumor was located in the larynx, excluding primary tumors at any other sites (e.g., hypopharynx). All articles were checked in full text for cross-references. References from full-text articles were cross-checked to ensure inclusion of all relevant publications in this review. Selected studies met the following inclusion criteria: (1) patients diagnosed with a paraneoplastic syndrome, (2) location of the tumor specified in the text within the larynx. Studies in which the location of the primary tumor was not specified clearly, or which were referred to as located in the larynx but were located in the pyriform sinus were excluded.

Results

Selection of Included Studies

The initial search identified 174 original articles, 42 of which were excluded on the basis of the aforementioned search criteria. Full texts of the remaining 132 studies were assessed. Of these, 85 articles were excluded as they did not include cases of laryngeal cancer with paraneoplastic syndromes, or the primary site was not specifically defined. This selection process resulted in the final inclusion of 47 articles (Fig. 1).

Fig. 1

Flow chart showing the process of the study selection for the systematic review

Description of Included Cases

In the selected articles, we identified in total 59 cases of paraneoplastic syndromes related to laryngeal cancer in the published literature from 1963 until recently. The average age of the patients was 61.55 years (median 61.5 years, range 45–78 years); age was unknown in 19 cases. There were 36 men and 7 women (16 gender not stated). In 18 cases the primary tumor was supraglottic, 12 cases glottis, and 1 subglottic (28 not stated). Histology was not mentioned in 3 cases. Most of the identified laryngeal cancers were squamous cell carcinoma (n = 46) (46/56: 82.1%) followed by neuroendocrine carcinoma (n = 10) (10/56: 17.9%). Endocrine (n = 22) and dermatologic or cutaneous (n = 21) paraneoplastic syndromes were the most prevalent, followed by neurologic (n = 8), osteoarticular or rheumatologic (n = 5), ocular (n = 1), muscular (n = 1), and hematologic (n = 1) syndromes. Applied treatment strategies included surgery, radiotherapy, chemotherapy, and often multimodal therapy, according to the site and stage of the tumors. Twenty-eight patients underwent surgery for the treatment of the primary tumor that caused the paraneoplastic syndrome, 23 received radiotherapy, 11 patients were treated with chemotherapy, and 20 patients underwent different multimodal treatment for their condition. Survival outcome differed highly among the published cases; 19 patients were alive, and 23 patients had died of disease at the times of publication. However, the value of these survival data is questionable as follow-up data are very often not included in the original articles or the follow-up time is very short.

Literature Review with Discussion

Paraneoplastic Dermatologic or Cutaneous Syndromes

Several paraneoplastic dermatologic or cutaneous syndromes have been reported [15]. Acanthosis nigricans, Bazex syndrome, bullous pemphigoid, dermatomyositis, yellow nail syndrome, tylosis, pityriasis rubra pilaris, and Leser–Trélat sign were observed in various patients with laryngeal cancer.

Acanthosis Nigricans

Acanthosis nigricans is a cutaneous condition characterized by hyperpigmented papillomatous plaques that usually affects flexor areas symmetrically, but it can be seen in any part of the body. When related to a malignant tumor, the condition appears abruptly, with rapid and extensive progression. The most frequently experienced association is with abdominal adenocarcinoma (60% are stomach cancer), but there have been cases associated with laryngeal tumors [16].

Bazex Syndrome

Bazex syndrome (also named Bazex’s acrokeratosis paraneoplastica, acrokeratosis paraneoplastica, acrokeratosis Bazex) is clinically characterized by erythematous squamous eruptions that spread centripetally from the fingertips and toes, ears, nose, and other sites.

Occasionally, vesicles, bullae, and crusts have been described. Symmetrical distribution is the norm. This syndrome has most often been associated with malignant tumors located above the diaphragm, and is most commonly associated with head and neck cancers (oral cavity, pharynx, larynx, and others) with nodal involvement [17, 18]. It has also been associated with cancers from other locations (including bronchus, thymus, prostate, uterus) and with different histologic types (myeloma, adenocarcinoma, anaplastic carcinoma, and others) [19].

Bazex’s acrokeratosis is the most frequent paraneoplastic syndrome associated with tumors located in the larynx [17, 19–30]. Occasionally, other cutaneous paraneoplastic syndromes (Bazex syndrome, hyperpigmentation, and acquired ichthyosis) have been reported in patients with larynx cancer [21].

In some cases, laryngeal cancer had been diagnosed because of the appearance of a cutaneous paraneoplastic syndrome [31, 32].

Bullous Pemphigoid

Bullous pemphigoid is a common autoimmune blistering disorder of the skin and has been observed in patients with various malignant tumors, although the significance of this association is controversial [33]. Some studies show an obvious association between malignancies and bullous pemphigoid, but other studies have failed to demonstrate a higher risk of malignancies among patients with bullous pemphigoid. The question remains whether in these cases bullous pemphigoid is a paraneoplasia or a coincidental association. Currently, it is suggested that the term “paraneoplastic pemphigoid” be avoided. “Pemphigoid associated with malignancies” is preferred [34].

Dermatomyositis

Dermatomyositis is an idiopathic inflammatory disease that can produce degenerative and inflammatory damage to muscle and skin in a symmetrical and progressive way. Despite its unknown cause, it has been associated with different tumors (lung, larynx, breast, and others) [35, 36].

Yellow Nail Syndrome

Yellow nail syndrome has been reported in patients affected by larynx cancer. The syndrome always regressed after treatment of the tumor [37]. The syndrome is characterized by nail discoloration and is associated with lymphedema (considered secondary to anomalies of lymphatic drainage), and also with bronchiectasis and sinusitis.

Tylosis

Tylosis, or hyperkeratosis, occurs on the palms of the hands (palmarum) or the plantar region of the foot (plantarum). Esophageal and, less commonly, laryngeal cancer may occur in association [38]. This disorder is considered paraneoplastic.

Pityriasis Rubra Pilaris

Pityriasis rubra pilaris constitutes a cluster of papulosquamous dermatoses often confused with various skin disorders (psoriasis in particular). This disease possibly results from dysregulation of the immune system as well as unusual response to certain antigens associated with rheumatological diseases, trauma and infections (human immunodeficiency virus), hypothyroidism, and solid and hematological malignancies. The syndrome has occurred in cases of laryngeal cancer [39].

Leser–Trélat

The Leser–Trélat sign, characterized by the sudden occurrence of multiple seborrheic keratoses, often with associated pruritus, is considered a marker of internal malignancy. Acanthosis nigricans can occur in 20% of such cases. The most frequently reported malignancies associated with the Leser–Trélat sign are stomach cancer, lymphoma, and gastrointestinal adenocarcinoma. There are also reports of occurrence in cases of laryngeal cancer [40].

Paraneoplastic Endocrine Syndromes

Production of polypeptide hormones is the causative factor in paraneoplastic endocrine syndromes related to lung, breast, carcinoids, and thyroid medullary cancer.

Carcinoid Syndrome

Carcinoid syndrome (carcinoidosis or argentaffinosis) most often is associated with metastatic neuroendocrine neoplasms (lung, gastrointestinal tract, ovary, etc.) [41-43]. The four major components of this syndrome are episodic diarrhea, skin flushing, affecting the face and the upper trunk, carcinoid heart disease, and bronchospasm. Dermatitis and depression occur less commonly. Some patients can manifest all of the above symptoms.

Most neuroendocrine malignancies of the larynx reported in the literature were nonfunctional and, therefore, without clinical syndromes [1, 12, 44, 45]. Five cases of laryngeal neuroendocrine carcinomas (one well differentiated, one large cell, and three moderately differentiated) with a carcinoid syndrome were reported [46-50]. The case described by Overholt et al. [48] as moderately differentiated neuroendocrine carcinoma has recently been considered to have been a large cell neuroendocrine carcinoma (Leon Barnes and James S. Lewis Jr., personal communication, 2019).

Nine of the ten patients affected by a paraneoplastic syndrome [carcinoid syndrome, Schwartz–Bartter syndrome, Eaton–Lambert syndrome, adrenocorticotropic hormone (ACTH) syndrome] died. Only one patient was alive with disease after 42 months of follow-up [13].

Ectopic ACTH Syndrome

Ectopic ACTH syndrome was reported in association with a larynx cancer by Imura et al. [51]. Bishop et al. [52] reported on the first case of small cell neuroendocrine carcinoma of the larynx associated with ectopic ACTH syndrome. The cell cytoplasm was immunoreactive for ACTH, gastrin-releasing polypeptide, neuron-specific enolase, β-endorphin, calcitonin, and keratin, by indirect immunoperoxidase techniques.

Schwartz–Bartter Syndrome

Schwartz–Bartter syndrome (syndrome of inappropriate secretion of antidiuretic hormone, SIADH) was first described by Schwartz et al. [53] in two patients with bronchogenic carcinoma. The syndrome is characterized by ectopic synthesis and excretion of vasopressin by cancer cells that leads to impaired excretion of free water, water intoxication, and hyponatremia. The reduced sodium level is due both to an enlarged amount of extracellular fluid and to its higher urinary excretion.

In the head and neck, SIADH is a well-known form of paraneoplastic syndrome. In a review by Ferlito et al. [11], 70 cases of this syndrome were found to be associated with head and neck cancers. Oral cavity was the commonest location of the primary tumor (29 cases). Thirteen cases involved the larynx. Squamous cell carcinoma was the predominant histology [54-58]. Three cases were small cell neuroendocrine carcinoma [59-61]. SIADH may precede the diagnosis of the cancer by several months.

Patients may present with initial headache, confusion and temporo-spatial disorientation, hyperreflexia, reduced levels of sodium, chlorine and osmolarity, decreased hematocrit, negative free-water clearance, and elevation of antidiuretic hormone. These tumors appear to have a very poor prognosis, as all these patients died despite adequate therapy.

Hypercalcemia

Hypercalcemia, which is the most frequently occurring metabolic complication of malignancy [62], often occurs during the late stages of malignancy. Hypercalcemia is a complication of many advanced tumors including carcinomas of the ovary, kidney, esophagus, and the head and neck, hematopoietic malignancies, and solid sarcomas [63, 64]. An uncommon cause is bone metastasis [65]. Many tumors cause hypercalcemia due to inappropriate hormonal regulation. Patients with laryngeal cancer often have hypercalcemia in the absence of metastasis [65]. Parathyroid hormone-related protein (PTHrP) is not confined to malignancy-associated hypercalcemia, and sufficient evidence now also supports its role in skeletal metastasis (through its modulation of bone turnover), as well as in tumor progression and metastasis [66]. Clinical signs of mild hypercalcemia include anorexia, constipation, abdominal pain, nausea and vomiting, thirst with polyuria, myalgias, weakness, fatigue, headaches, depression, and confusion. Hypercalcemia is a medical emergency [67]. Hypercalcemia associated with advanced malignancy portends a dismal prognosis. Hypercalcemia is managed by treatment of the cancer responsible for it [67].

Paraneoplastic Hematologic Syndromes

Paraneoplastic hematologic syndromes are more commonly associated with other malignancies than cancer of the larynx.

Trousseau Syndrome

Trousseau syndrome (disseminated intravascular coagulation or thromboembolism) was first reported by Armand Trousseau [68]. Trousseau described thrombotic events related to gastric cancer. Trousseau syndrome has been related to cancer of the pancreas, and occurred with ovarian, lung, colon, and breast cancer [69]. This syndrome is rare (less than 1% [70]) in head and neck cancers, although it has occurred in patients with laryngeal cancer [71]. It is diagnosed by the findings of thrombocytosis and elevated fibrin levels. Thrombosis of unknown cause may be the first manifestation of cancer [72, 73].

Paraneoplastic Neurologic Syndromes

Paraneoplastic neurologic syndromes frequently occur in cancer patients, but they are uncommon when the primary site is the larynx.

Cerebellar Degeneration

Cerebellar degeneration, or cerebellar cortex degeneration, may be associated with lung, ovary, and breast cancer [2], and occasionally with larynx cancer [74, 75]. It is primarily characterized by a wide-legged, unsteady, lurching walk accompanied by a back and forth tremor in the trunk and the body. Slow, unsteady, and jerky movement of the arms or legs, slowed and allured speech, and nystagmus may also be observed. The cause may be immunologic cross-reactions, and antineural antibodies, that are found in about 50% of the patients [6, 76]. The better known paraneoplastic neurologic syndromes are those with specific antibodies associated, and the clinical signs of these syndromes can precede clinical signs of the cancer [77].

Ataxia

Ataxia as a manifestation of cerebellar involvement is infrequent among the neurological manifestations of paraneoplastic syndromes and histologically usually corresponds to a diffuse massive loss of Purkinje cells, with little alteration of the white substance and frequent inflammatory signs. Clinically, it is manifested by a nonspecific cerebellar pattern with instability and dissymmetry that sometimes incorporates vestibular signs (spontaneous nystagmus). Garcia et al. [78] published a case of paraneoplastic ataxia due to a supraglottic larynx cancer. After surgery, ataxia was resolved within 3 weeks.

Eaton–Lambert Myasthenic Syndrome

Eaton–Lambert myasthenic syndrome was reported by Lambert et al. [79]. The complete syndrome was further delineated by Eaton and Lambert [57, 80]. The same disease had previously been described by Gray and Halton [81]. It is usually associated with small cell lung cancer [82], but also with larynx cancer [83-86]. As with cerebellar degeneration, the detection of serum and cerebrospinal fluid autoantibodies can be helpful for diagnosis.

Encephalomyelitis

Encephalomyelitis has been considered as a paraneoplastic syndrome associated with small cell lung cancer [7, 87]. There is abundant evidence in the literature that the anti-Hu antibody is a marker of encephalomyelitis [7]. Two cases of laryngeal cancer have been associated with this syndrome [88, 89].

Paraneoplastic Osteoarticular or Rheumatologic Syndromes

Paraneoplastic osteoarticular or rheumatologic syndromes occur rarely in laryngeal cancer and small cell lung carcinomas.

Polyarthritis

Polyarthritis has been associated with different cancers, both solid and hematological, and may be the earliest presentation of the malignancy. A neoplastic cause must be ruled out in any case of recently appearing polyarthritis [90]. Eggelmeijer and Macfarlane [91] reported an instance of larynx cancer associated with polyarthritis.

Pseudo-Still Disease

Cabane et al. [92] reported on an instance of aryepiglottic fold carcinoma in association with pseudo-Still disease, which is an inflammatory type of arthritis distinguished by pain, swelling, and tenderness in one or more joints along with splenic enlargement and lymphadenopathy.

Hypertrophic Osteoarthropathy

The syndrome of hypertrophic osteoarthropathy is distinguished by “clubbing” of the digits of the hand and/or foot, periosteal reaction, and arthralgia or arthritis which is the same syndrome associated with cyanotic congenital heart disease and chronic pulmonary infections. It may also occur in patients with carcinoma of the lung (particularly squamous cell carcinoma). Mackenzie and Scherbel [36] and Cohen [93] described three instances of this syndrome in patients with cancer of the larynx.

Paraneoplastic Ocular Syndromes

Paraneoplastic ocular syndromes are distinguished by progressive functional loss of photoreceptors and subsequent painless loss of vision, light-induced glare, night blindness, photosensitivity, and peripheral ring-like scotomas. Fundoscopic examination may be normal or might reveal arteriolar narrowing. The electroretinogram reveals abnormal cone and rod-mediated signals [94].

Cancer-Associated Retinopathy (CAR) and Melanoma-Associated Retinopathy (MAR)

The most frequently occurring paraneoplastic ocular syndromes are cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). Parc et al. [95] reported on CAR syndrome in a patient who complained of photophobia and bilateral visual loss who had a laryngeal cancer extirpated 18 months previously.

Paraneoplastic Muscular Syndromes

Paraneoplastic muscular syndromes like polymyositis are idiopathic inflammatory myopathies linked with cancer, but less frequent than dermatomyositis. Both conditions, polymyositis and dermatomyositis, present with proximal, symmetric muscle weakness. Clinical features along with raised creatine phosphokinase (CPK) and positive muscle biopsy are required for diagnosis. According to Hill et al. [96] about 30% of dermatomyositis and 15% of polymyositis patients were found to have associated cancer, with approximately 60% of the malignancies diagnosed after the onset of myopathy. Most were detected within 1 year of presentation of myositis and the type of cancer most often associated was adenocarcinoma. Associated carcinomas observed in previous studies were ovarian, lung, cervical, pancreatic, stomach, colorectal, and non-Hodgkin’s lymphoma.

Sahu et al. [97] reported a case of a laryngeal cancer associated with polymyositis. With the treatment of the laryngeal cancer, the patient achieved almost normal muscle strength with normalization of CPK level after 6 months.

Table 1 summarizes paraneoplastic syndromes reported to have occurred in patients with cancer of the larynx [16, 17, 23, 26, 27, 30, 33, 35–40, 46–52, 55–61, 65, 71, 75, 78, 83–86, 88, 89, 91–93, 95, 97–102].

Table 1

Paraneoplastic syndromes in patients with cancer of the larynx

Paraneoplastic syndrome type	Paraneoplastic syndrome name	Author (Refs.)	Year	Age (years)	Sex	Site	Type of tumor	Treatment	Follow-up
Dermatologic or cutaneous	Acanthosis nigricans	Oppolzer et al. [16]	1986	76	M	G	SCC	S + RT	Alive
	Bazex syndrome	Colomb et al. [23]	1981	68	M	SG	SCC	RT	Alive
		Rubisz-Brzezinska et al. [98]	1983	78	M	G	SCC	None	DOD
		Mounsey and Brown [27]	1992	66	M	G	SCC	RT + S	DOD
		Miquel et al. [26]	1997	64	M	SG	SCC	S + RT	Alive
		Khachemoune et al. [17]	2004	70	M	NA	SCC	S + C	NA
		Aksu and Karadeniz [30]	2006	62	M	G	SCC	RT	Alive
		Ehmann et al. [99]	2012	49	F	NA	SCC	RT + C + S	Alive
	Bullous pemphigoid	Hodge et al. [33]	1981	NA	NA	NA	SCC	NA	NA
	Dermatomyositis	Mackenzie and Scherbel [36]	1963	66	M	G	SCC	S	NA
		Tsvetkov [100]	1977	61	M	SG	SCC	RT	Alive
		Bonnetblanc et al. [35]	1990	NA	NA	NA	SCC	NA	Alive
		Zhang et al. [101]	2009	NA	NA	NA	NA	NA	NA
				NA	NA	NA	NA	NA	NA
				NA	NA	NA	NA	NA	NA
	Yellow nail syndrome	Guin and Elleman [37]	1979	61	M	NA	SCC	S	Alive
	Tylosis	Haines [38]	1967	66	M	G	SCC	RT	DOD
	Pityriasis rubra pilaris	Batinac et al. [39]	2009	46	M	G	SCC in situ	S	Alive
	Leser–Trélat sign	Rubisz-Brzezinska et al. [98]	1983	78	M	G	SCC	None	DOD
		Nyati et al. [40]	2016	NA	M	SG	SCC	RT + C + RT	Alive
				NA	F	G	SCC	RT	Alive
Endocrine	Carcinoid syndrome	Baugh et al. [46]	1987	50	F	SG	MDNC	S	DOD
		Wenig and Gnepp [49]	1989	NA	M	SG	WDNC	S + C	Alive
		Overholt et al. [48]	1995	57	M	SG	LCNCa	S + RT + S	DOD
		Kumai et al. [47]	1996	74	M	SG	MDNC	S	DOD
		Yamanaka et al. [50]	1997	NA	NA	NA	MDNC	NA	DOD
	Ectopic ACTH syndrome	Imura et al. [51]	1975	66	M	NA	SCC	S	DOD
		Bishop et al. [52]	1985	60	F	SG	SCNC	RT	DOD
	Schwartz–Bartter syndrome (SIADH)	Moses et al. [55]	1976	NA	NA	NA	SCC	NA	NA
				NA	NA	NA	SCC	NA	NA
		Trotoux et al. [59]	1979	61	M	SuG	SCNC	S + RT	DOD
		Takeuchi et al. [60]	1989	53	M	SG	SCNC	S	DOD
		Zohar et al. [58]	1991	62	M	SG	SCC	S + C	DOD
				65	M	NA	SCC	S + RT + C	DOD
				63	M	NA	SCC	None	DOD
		Talmi et al. [57]	1992	NA	NA	NA	SCC	NA	NA
				NA	NA	NA	SCC	NA	NA
				NA	NA	NA	SCC	NA	NA
				NA	NA	NA	SCC	NA	NA
		Roth et al. [56]	1994	76	M	NA	SCC	S + RT	DOD
		Myers and Kessimian [61]	1995	58	M	SG	SCNC	C	DOD
		Maxwell and Witterick [102]	2004	52	M	SG	SCC	RT + S + C	DOD
	Hypercalcemia	Angel et al. [65]	1982	52	F	NA	SCC	S + RT	DOD
Hematologic	Trousseau syndrome	Nikšic and Balogh [71]	1976	NA	NA	NA	SCC	NA	NA
Neurologic	Cerebellar degeneration	Müller et al. [75]	1969	NA	NA	NA	SCC	NA	NA
	Ataxia	Garcia et al. [78]	1998	66	M	SG	SCC	S	Alive
	Eaton–Lambert myasthenic syndrome	Fontanel et al. [83]	1973	58	M	G	SCC	S	Alive
		Medina et al. [84]	1984	64	F	SG	SCNC	C + RT	DOD
		Ferroir et al. [85]	1989	58	M	G	SCC	C + RT	DOD
		Shipley et al. [86]	2008	64	M	G	SCC	S	NA
	Encephalomyelitis	Baijens and Manni [88]	2006	74	M	SG	SCC	None	DOD
		Erro Aguirre et al. [89]	2016	53	M	NA	SCC	S + RT	Alive
Osteoarticular or rheumatologic	Polyarthritis	Eggelmeijer and Macfarlane [91]	1992	50	M	SG	SCC	S + RT	Alive
	Pseudo-Still disease	Cabane et al. [92]	1988	45	M	SG	SCC	C + S + RT	Alive
	Hypertrophic osteoarthropathy	Mackenzie and Scherbel [36]	1963	NA	NA	NA	SCC	NA	NA
				NA	NA	NA	SCC	NA	NA
		Cohen [93]	1993	66	M	NA	SCC	S	DOD
Ocular	Cone dysfunction	Parc et al. [95]	2006	50	F	NA	SCC	NA	Alive
Muscular	Polymyositis	Sahu et al. [97]	2016	54	M	NA	SCC	S + RT	Alive

SCC squamous cell carcinoma, WDNC well-differentiated neuroendocrine carcinoma, MDNC moderately differentiated neuroendocrine carcinoma, LCNC large cell neuroendocrine carcinoma, SCNC small cell neuroendocrine carcinoma, M male, F female, G glottic, SG supraglottic, SuG subglottic, DOD dead of disease, S surgery, C chemotherapy, RT radiotherapy, NA not available

aLeon Barnes and James S. Lewis Jr., personal communication, 2019

Conclusions

Paraneoplastic syndromes in laryngeal cancer occur infrequently and therefore are difficult to diagnose. The histology most frequently associated with paraneoplastic syndromes was squamous cell carcinoma and the most frequent location was supraglottic. By presenting and systematically reviewing all published cases in the international literature, the present review may help clinicians to recognize them.

Paraneoplastic syndromes occur rarely in association with laryngeal cancer.

When present, the syndrome may be the first sign of the malignancy.

A search of PubMed was conducted for “paraneoplastic syndromes in laryngeal cancer”.

Paraneoplastic syndromes associated with laryngeal cancer are difficult to diagnose.

Recognizing a paraneoplastic syndrome helps in suspecting a laryngeal cancer.