paraneoplastic syndromes in patients with head and neck cancer

Paraneoplastic Syndromes in Patients With Head and Neck Cancer

AMERICO M. MINOTTI, MD, STILIANOS E. KOUNTAKIS, MD, AND CHARLES M. STIERNBERG, MD, FACS

Paraneoplastic syndromes may be defined as distinct physiological disorders of malignancy that occur remote from a tumor site-l This definition does not include the effects of endocrine activity that is inherently produced by endocrine tissue from which the tumor is derived. For example, a thyroid carcinoma producing thyroxine causing Grave’s disease would not be considered a paraneoplastic syndrome, but a thyroid carcinoma producing adrenocorticotropic hormone (ACTH) causing Cushing’s syndrome would.

Paraneoplastic syndromes in patients with head and neck cancers may be caused by ectopic hormone production, tumor mediated immunologic disorders, or disorders of metabolism. Ectopic hormone production is the most common mechanism accounting for these syndromes. These hormones may be identical or nearly identical in structure and function to their physiological counterparts.’ Paraneoplastic syndromes may manifest as neuropathies, central nervous system (CNS) disorders, dermatologic disorders, metabolic disorders, or hematologic disorders. Primary tumors of the head and neck most commonly associated with paraneoplastic syndromes include squamous cell carcinoma (SCC), lymphoma, thyroid carcinoma, thymoma, mela- noma, and paraganglioma. Oat cell carcinoma and SCC of the lung are the two most common metastatic tumors to the head and neck that cause these syndromes [Table 1).

From the Department of Otolaryngology-Head and Neck Surgery, University of Texas Medical School at Houston, Houston, TX.

Address reprint requests to Americo M. Minotti, MD, Department of Otolaryngology-Head and Neck Surgery, Universitv of Texas Medical School at Houston, 6431 Fannin, Suite 6.132, Houston, TX 77030.

Copyright 0 1994 by W.B. Saunders Company 0196-0709/94/l 505-0004$500/O

PRIMARY MALIGNANCIES OF THE HEAD AND NECK

Paraneoplastic Syndromes of SCC

SCC is the most common primary malignancy of the head and neck associated with paraneoplastic syndromes. Paraneoplastic syndromes in patients with SCC present as dermatologic disorders, hypercalcemia, leukocytosis, or hyponatremia. Three dermatologic disorders associated with SCC of the head and neck are Bazex’s syndrome (paraneoplastic acrokeratosis), acanthosis nigricans, and tripe palm.

Bazex’s syndrome is characterized by a scaly cutaneous eruption (often pigmented) favoring sites on the ears and extremities. In all known cases, this syndrome has been uniquely associated with an underlying malignancy.3s4 It more commonly occurs in men and is primarily observed in SCC of the head and neck and SCC metastatic to cervical lymph nodes.’ More than 60% of the patients with Bazex’s syndrome have a primary SCC of the head and neck and 80% to 90% have a primary SCC of the head and neck or SCC metastatic to cervical lymph nodes. This novel location-specific association has drawn inter- est from head and neck surgeons.6

Common sites of cutaneous involvement include the ears, nails, nose, and hands, with the ears being the most common site. Other less common sites include the feet, knees, and elbows.4-6 In a review of XI patients with Ba- zex’s syndrome by Bolognia et a1,4 63% of the patients manifested the syndrome, by an av- erage of 11 months, before the initial symptoms or diagnosis of malignancy. In 90% of these patients, either a noticeable improvement in the appearance of skin lesions after successful therapy was observed or a lack of improvement was found in cases of a persis-

336 American Journal of Otolaryngology, Vol 15, No 5 (September-October), 1994: pp 336-343

PARANEOPLASTIC SYNDROMES OF OTOLARYNGOLOGY 337

TABLE 1. Paraneoplastic Syndromes

Classification Ectopic hormone production

Immune mediated disorders Disorders of metabolism

Tumor types Primary tumors of the head and neck

see Lymphoma Thyroid carcinoma

Thymomas

Melanomas Glomus tumors

Metastatic tumors to the head and neck

SCC of the lung

Small cell carcinoma of the lung

tent tumor. In approximately 10% of these cases, the rediscovery of skin lesions fore- shadowed the recurrence of tumor or the de- velopment of metastatic disease.*

Histological findings in Bazex’s syndrome are hyperkeratosis, acanthosis, parakeratosis, dyskeratotic keratinocytes, pigmented macro- phages, and a mononuclear perivascular infil- trate. Although these histological features are nonspecific, they can be useful in eliminating alternative diagnoses, such as psoriasis, lu- pus, and mycosis. Bazex’s syndrome is thought to develop as a result of an immune reaction against a common antigen present on both the tumor and the involved skin or by a keratinocyte transforming growth factor that induces psoriaform skin lesions.*

The skin lesions of Bazex’s syndrome have been reported to be resistant to traditional dermatologic treatments, such as topical steroids, keratolytics, and ultraviolet radiation. Im- provement has been reported with the use of vitamin D, topical salicylic acid, and systemic steroids.*

Tripe palm syndrome is a palmar keratosis reported in association with internal malignancy, malignant acanthosis nigricans, and benign dermatosis. Associated malignancies include XC, oat cell carcinoma, gastric carcinoma, and adenocarcinoma of the lung. The syndrome is characterized by a scaly rugose- like appearance resembling intestinal villi (tripe) on the palms of the hand. The lack of extending eruptions and localization to the palms distinguish it from Bazex’s syndrome. This syndrome is not as clearly defined as Ba-

zex’s syndrome because of the scarcity of cases reported and its association with benign skin lesions7

Malignant acanthosis nigricans is a palmar keratoderma characterized by hyperpigmented and thickened skin on the axilla and neck. It can be seen in patients with SCC but is more often observed in patients with gastric carcinoma.87g

Hypercalcemia and leukocytosis are the most common paraneoplastic syndromes found in patients with SCC of the head and neck; they frequently occur together. Hyper- calcemia occurs in approximately 10% of patients with cancer. The incidence of hypercalcemia reported in patients with SCC of the head and neck ranges between 2.9% and 25Oh.l’ In the majority of patients with primary SCC of the head and neck, hypercalcemia has been attributed to tumor production of parathyroid hormone-related protein (PHRP). This highly conserved peptide has been shown to have a similar structure and function as parathyroid hormone.“-l3 Yoneda et al found that approximately 5% of patients with oral malignancies had hypercalcemia, whereas 5% had leukocytosis. Of these patients, 2.5% had both leukocytosis and hypercalcemia, suggesting a strong association between the two.‘4*‘5

Elevated interleukin-1 (IL-1)-a, PHRP, and granulocyte colony stimulating factor (GCSF) levels have been observed in patients with both hypercalcemia and leukocytosis. IL-lo and GCSF work in concert to increase granulocyte production. This is thought to account for the leukocytosis in these patients.11*16

The incidence of hypercalcemia increases with tumor stage. In a large retrospective study conducted by Tachimori et al with esophageal carcinoma, there was a 1.3% incidence of hypercalcemia at time of primary detection and a 38% incidence of hypercalcemia in patients with recurrent or unresectable disease.17 The diagnosis, management, and treatment of hypercalcemia of malignancy is discussed later.

Paraneoplastic Syndromes of Lymphomas

Recognized paraneoplastic syndromes of lymphomas are diverse and include hypercal-

338 MINOTTI, KOUNTAKIS, AND STIERNBERG

cemia, fevers, dermatologic disorders, autoimmune mediated cerebellar degeneration,l* glomerulonephritis,” autoimmune hemolytic anemia,” and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).‘l Hypercalcemia has been reported to occur in 5% of patients with lymphoma.” Paraneo- plastic hypercalcemia may occur by different mechanisms in lymphomas than in SCC. It may be mediated by a PHRP-like substance or by extra renal synthesis of vitamin D.2911923 Hypercalcemia in Hodgkin’s disease is not associated with PHKP production but with a mechanism involving elevated vitamin D levels. IL-l and tumor necrosis factor (TNF) play a role in humoral hypercalcemia as we11.24

Fever in lymphomas is a fairly well- recognized phenomenon. It is produced via cytosine production, primarily IL-l.” Sweet’s syndrome is an acute febrile neutrophilic dermatosis that is most commonly observed in patients with lymphomas, leukemias, and sometimes myelomas. Features of Sweet’s syndrome include fever, neutrophilia, and the presence of painful red cutaneous plaques and nodules measuring 0.5 to 12 cm in dimen- sion. These lesions are located primarily over the upper extremities and the head and neck. Approximately l/5 of patients with Sweet’s syndrome have an underlying malignancy. Two-thirds of the time, patients will present with these symptoms before a diagnosis of the causative underlying disease. Sweet’s syndrome is also associated with anemia, throm- bocytopenia, and glomerulonephritis. The dermatosis is self-limited, usually resolving in 1 to 3 months without treatment. Quicker responses may be obtained with corticosteroid therapyaz5

Eosinophilic fascitis is a painful diffuse fascitis that presents with hypergammaglobine- mia and peripheral eosinophilia. The cutaneous lesions appear as edematous plaques located over the extremities and the trunk. This paraneoplastic syndrome, observed in patients with lymphomas and leukemias, is his- tologically defined by a lymphocytic inflam- mation in the superficial muscular fascia and dermis. Deposition of immune products are observed in the dermis and muscular fascia. Eosinophilic fascitis may also occur in patients with benign disorders, such as aplastic

anemia, idiopathic thrombocytopenic pur- pura, and pancytopenia. Treatment is accom- plished by controlling the underlying malignancy. Steroids have been shown to be inef- fective.26

Paraneoplastic glomerulonephritis occa- sionally occurs in non-Hodgkin’s lymphoma. The clinical course of this glomerulonephritis typically resolves when remission by antitu- mor therapy occurs.1g

Paraneoplastic Syndromes of Thymomas

Thymomas are found in the anterior supe- rior mediastinum and may present in the su- praclavicular area.” Paraneoplastic syndromes associated with these tumors are primarily produced by mechanisms involving the action of tumor-mediated autoantibodies. These autoantibodies may exert inhibitory or stimulatory effects on organ systems. Myas- thenia gravis occurs in approximately 50% of patients with thymomas.27-2g Of patients with myasthenia gravis, 80% to 90% have been reported to have autoantibodies against ele- ments of striated muscle.30 Other syndromes less commonly associated with thymomas that have been reported are agammaglobuline- mia, pure red blood cell aplasia, Cushing’s syndrome,27 pemphigus31 sensorimotor my- eloradiculopathy,32 and SIADH.” Treatment is by surgical excision. Malignant thymomas are usually responsive to radiotherapy.27

Paraneoplastic Syndromes of Thyroid and Parathyroid Cancer

Paraneoplastic syndromes of thyroid carcinoma have been commonly reported to occur in papillary, medullary, and primary SCC of the thyroid. Papillary carcinoma has been reported in association with acanthosis nigricans [a dermatologic condition characterized by hyperpigmented, soft verrucous lesions symmetrically distributed in body folds) and insulin resistance.* Cushing’s syndrome and black thyroid carcinoma (caused by ectopic production of melanin) have been described in patients with medullary carcinoma.33-37 Hypercorticism in patients with paraneoplastic Cushing’s syndrome occurs secondary to ectopic ACTH or corticotropin releasing factor


(CRF) production. Normally, the pituitary adrenal axis relies on negative feedback control mechanisms to maintain endocrine ho- meostasis. Ectopic hormone production from an underlying malignancy evades this control system, thus producing unregulated hyperadrenalism (Fig 1).27v33

Primary XC of the thyroid accounts for only approximately 1% of thyroid malignancies. However, a significant number of these patients have been reported to have hypercalcemia, leucocytosis, or both. Mechanisms of hypercalcemia and leukocytosis are thought to be similar to those of other primary SCC of the head and necks3’

Several reports have been made of parathyroid carcinoma associated with polycythemia Vera. Postoperatively, these patients went into remission from their blood dyscrasias. It has been suggested that this could be because of tumor-induced production of a growth factor.3g

Paraneoplastic Syndromes of Glomus Tumors

Approximately 1% to 3% of all glomus tumors are said to be functional tumors produc-

cs

RHM

Fig 1. Mechanisms of hyperadrenalism in paraneoplastic Cushing’s syndrome. H, hypothalamus; AP, anterior pituitary; T, tumor; AC, adrenal cortex; CS, cotticosteroids; CRF, corticotropin releasing factor; ACTH, sdrenocotticotropic hormone.

ing pheochromocytoma-like or carcinoid-like clinical symptoms. Pheochromocytoma-like symptoms include headache, hypertension, and tachycardia, whereas carcinoid-like symptoms may include diarrhea, headaches, and cutaneous flushing. These symptoms are attributed to tumor production of vasoactive amines. Because of the potential increased morbidity associated with these functional tumors, 24 hour urine assays for metanephrines, catacholamines, and 5-hydroxyindoleacetic acid should be performed to determine tumor endocrine activity.40-42 Carcinoid tumors ca- pable of producing vasoactive amines have been reported in the middle ear and larynx as well. However, elevated levels of vasogenic amines produced by these tumors have not been reported to be clinically significant.43-45

Recently, a new paraneoplastic syndrome of glomus tumors has been described. In this study, postoperative ileus was more common in patients with cholecystokinin (CCKJ- producing glomus tumors when compared with nonglomus tumors in similar locations. Because CCK normally increases gall bladder contraction, pancreatic secretion, and gastric emptying, it stands to reason that removal of a CCK-producing tumor could produce postoperative ileus. It has been suggested that these patients have prolonged parenteral nutrition in the early postoperative period.4”

Neuroblastomas

Certain types of neuroblastoma can secrete vasoactive amines. Assays of vanillylmandelic acid (VMA), dopamine, and homovanil- lit acid (HVA) have been shown to be elevated in children with neuroblastoma.47 These levels have not been found to be clinically significant. However, assays for these catechol- amine metabolites may be valuable as diag- nostic and/or prognostic indicators.48-4g

METASTATIC TUMORS TO THE HEAD AND NECK

Both small cell carcinoma and SCC of the lung may metastasize to the head and neck. These tumors have been reported to produce a variety of paraneoplastic syndromes. Parane- oplastic syndromes of oat cell carcinoma in-


elude SIADH,*’ Crushing’s syndrome, addiso- nian hyperpigmentation,27 Trousseaus’s syndrome [migratory thrombophlebitis),50 and cerebellar degeneration.51 SIADH is the most common cause of hyponatremia in patients with small cell carcinoma of the lung. Atria1 natriuretic hormone is another hormone ectopically produced by SCC of the lung.‘l It produces hyponatremia by increasing sodium excretion. ACTH may also be ectopically produced by this tumor. This may lead to Cush- ing’s syndrome via stimulation of the adrenal cortex or hyperpigmentation by the production of melanocyte-stimulating hormone (MSH), a break-down product of ACTH-like parent proteinsz7

Signs of hyperestrogenism,” aplastic anemia,53 or cerebellar degeneration51 may be the initial manifestations of occult SCC of the lung. Hyperestrogenism is the most common of these. Signs and clinical findings include gynecomastia, vascular spiders, and hyper- trophic osteoarthropathy. The mechanism for this is not well understood.”

HYPONATREMIA OF MALIGNANCY

SIADH is more commonly associated with cancer of the head and neck than previously thought. A few small series have been reported. A recent retrospective review of more than 1,400 patients determined that 3% of patients with head and neck cancer had SIADH in association with their malignancy. SCC, neuroblastoma, and adenoid cystic carcinoma are some primary malignancies accounting for this. Laboratory values compatible with the diagnosis of SIADH are low serum sodium, blood urea nitrogen (BUN), uric acid, creati- nine, and albumin levels, whereas serum hy- posmolarity is accompanied by an inappropriate urine hyperosmolarity. Antidiuretic hormone (ADH) serum levels may or may not be elevated.54 SIADH is more common in advanced tumor stage and in patients with recurrent tumor.15954 Clinical manifestations of hyponatremia include mental status changes, such as restlessness, irritability, and confusion. Seizures and coma may develop in con- ditions of severe hyponatremia (Table 2). Patients are rarely symptomatic with sodium serum levels greater than 125 mEq/L.55 Hy-

TABLE 2. Clinical Manifestations of Hyponatremia

Sodium Serum Levels

cl20 mEq/L ~110 mEq/L

Clinical Restlessness Seizures manifestations Irritability Coma

Confusion

Data from reference 55.

ponatremia of SIADH nearly always resolves by treatment with fluid restriction. Occasion- ally, symptomatic nonresponsive patients may require treatment with a high salt and high protein diet or with ADH-antagonizing agents such as demeclocycline or lithium.‘5,55

HYPERCALCEMIA OF MALIGNANCY

Hypercalcemia is the most common metabolic complication of malignancy.ll It is the most common paraneoplastic syndrome in patients with cancer of the head and neck and occurs in approximately 10% of all advanced ma1ignancies.l’ Humoral hypercalcemia of malignancy accounts for nearly 80% of these cases. Osteolytic hypercalcemia occurs far less frequently. SCC and lymphoma are the most common primary tumors of the head and neck producing hypercalcemia.‘0*5” Humoral mechanisms for these tumors have already been discussed.

Clinical signs of mild hypercalcemia include dehydration, anorexia, nausea, consti- pation, ileus, fatigue, and confusion. Severe hypercalcemia is considered a medical emergency. Complications of severe hypercalcemia include arrhythmia, seizure, coma, and cardiac arrest (Table 3).27

Treatment of hypercalcemia of malignancy is primarily directed toward controlling the underlying malignancy. 5fluorouracil and cisplatinum are often temporarily effective in controlling hypercalcemia in patients with scc.‘” However, initial emergency management in symptomatic patients should include intravenous hydration with isotonic saline and diuresis with furosemide. Mithramycin, steroids, calcitonin, and indomethacin have also been used with some success in selected patients.55 Recently, gallium nitrate has also


TABLE 3. Clinical Signs of Hypercalcemia

Mild (11-13 mg/dL) Anorexia Fatigue

Nausea Depression

Moderate (13-l 5 mg/dL) Confusion Renal insufficiency

Calcification of organs

Severe (>15 mg/dL) ECG changes

Coma Cardiac arrest

Data from references 27 and 55.

been used successfully to treat hypercalcemia of malignancy.56

DISORDERS OF METABOLISM

General metabolic abnormalities observed in patients with head and neck cancer are increased protein breakdown, increased glucose production, increased glucose tolerance, increased lipolysis, and insulin resistance. These changes in metabolism may eventually lead to cachexia.57-58 Cachexia is a major cause of death in the patient with head and neck cancer.5g Although the mechanisms of cachexia are not fully understood, the dispar- ity between tumor size and metabolic demand in patients with cachexia have led investiga- tors to believe that cachexia of malignancy may be humorally mediated.60*61 Humoral factors thought to serve as agents of paraneoplastic cachexia include TNF, IL-l, and IL-6 TNF, formally known as cachectin, is a cyto- tine found to induce catabolic responses, which may contribute to cachexia found in chronic diseases such as malignancy. TNF causes anorexia and wasting when adminis- tered to animal subjects.“‘.“’ Some effects of TNF on various mammalian cells are anorexia, fever, increased sympathetic activity, mesenteric ischemia, and delayed gastric emptying.63 In the future, it is hoped that monoclonal antibodies will be developed to selectively inhibit TNF/cachectin action.“l In the mean time, therapy is directed toward op- timizing nutritional support.64

SUMMARY

Paraneoplastic syndromes are distinct physiological disorders of malignancy that occur remote from a tumor site. A review of a number of paraneoplastic syndromes occur- ring in patients with head and neck cancer has been discussed. These syndromes can produce life-threatening sequelae in the patient with cancer. Understanding these syndromes may provide important clinical information to assist in the early detection of occult malignancy and in reducing the occurrence of tumor-associated morbidity.

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paraneoplastic syndromes in patients with head and neck cancer

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