Paraneoplastic syndromes associated with gynecological cancers: A systematic review

Gynecologic Oncology 146 (2017) 661–671

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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Review Article

Paraneoplastic syndromes associated with gynecological cancers: A systematic review Mathieu Viau a, Marie-Claude Renaud b, Jean Grégoire b, Alexandra Sebastianelli b, Marie Plante b,⁎ a b

Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire de Québec, Université Laval 2705 boulevard Laurier, Québec City, Québec G1V 4G2, Canada Gynecologic Oncology Division, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Université Laval 11 côte du Palais, Québec City, Québec G1R 2J6, Canada

H I G H L I G H T S • • • •

A variety of paraneoplastic syndromes can be associated with gynecological cancers. These syndromes can affect all systems, and may lead to severe complications. A systematic literature search identified those related to gynecologic oncology. This article provides a summary and up-to-date information about each syndrome.

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Article history: Received 6 May 2017 Received in revised form 19 June 2017 Accepted 19 June 2017 Available online 24 June 2017 Keywords: Paraneoplastic syndromes Paraneoplastic neurological syndromes Paraneoplastic dermatoses

a b s t r a c t A number of paraneoplastic syndromes have been described with gynecological cancers. These syndromes are induced by substances secreted by the tumor or by an immune response triggered by the cancer. Each system of the human body can be affected by different syndromes. Indeed, paraneoplastic syndromes occurring from tumors of the gynecologic tract were found to involve the nervous, ophthalmologic, dermatologic, rheumatologic, endocrine, hematologic and renal systems. These syndromes can manifest before, at the time, or after the diagnosis of cancer. They can also occur at the time of a recurrence. Knowledge about these syndromes is important for physicians caring for patients with cancers, as they can result in severe morbidity and must be treated appropriately. Literature regarding paraneoplastic syndromes associated with tumors of the female genital tract is scattered and the subject has not been reviewed recently. A systematic literature search was thus conducted to identify paraneoplastic syndromes associated with gynecologic cancers. This review focuses on the cancers involved with each paraneoplastic syndrome, and on their pathophysiology, clinical manifestations, possible complications, outcomes, and treatments. As the mainstay of treatment in these conditions is often to address the underlying tumor, it is of upmost importance that physicians be aware of these rare cancer manifestations. © 2017 Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Subacute cerebellar degeneration/cerebellar ataxia . . . . . . . . . . . . . . . . . 3.1.2. Limbic encephalitis and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis 3.1.3. Opsoclonus-Myoclonus syndrome (OMS) . . . . . . . . . . . . . . . . . . . . . 3.1.4. Paraneoplastic subacute sensory neuropathy . . . . . . . . . . . . . . . . . . . . 3.1.5. Sensorimotor neuropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. E-mail addresses: [email protected] (M. Viau), [email protected] (J. Grégoire), [email protected] (M. Plante).

http://dx.doi.org/10.1016/j.ygyno.2017.06.025 0090-8258/© 2017 Elsevier Inc. All rights reserved.

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3.1.6. Lambert-Eaton myasthenic syndrome (LEMS) . . . . . . . . . . . 3.1.7. Myasthenia gravis (MG) . . . . . . . . . . . . . . . . . . . . 3.2. Ophthalmology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Cancer-associated retinopathy (CAR) . . . . . . . . . . . . . . . 3.2.2. Bilateral diffuse uveal melanocytic proliferation (BDUMP) . . . . . 3.2.3. Paraneoplastic optic neuropathy and neuromyelitis optica . . . . . 3.3. Dermatology and rheumatology . . . . . . . . . . . . . . . . . . . . . 3.3.1. Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Palmar fasciitis and polyarthritis syndrome (PFPAS) . . . . . . . . 3.3.3. Digital ischemia . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4. Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.5. Malignant acanthosis nigricans (MAN) . . . . . . . . . . . . . . 3.3.6. Tripe palms . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.7. Leser-Trélat sign . . . . . . . . . . . . . . . . . . . . . . . . 3.3.8. Erythema gyratum repens (EGR). . . . . . . . . . . . . . . . . 3.3.9. Hypertrichosis lanuginosa acquisita . . . . . . . . . . . . . . . 3.3.10. Multicentric reticulohistiocytosis . . . . . . . . . . . . . . . . 3.3.11. Sweet syndrome . . . . . . . . . . . . . . . . . . . . . . . 3.3.12. Pemphigoid gestationis . . . . . . . . . . . . . . . . . . . . 3.3.13. Paraneoplastic pemphigus (PNP) . . . . . . . . . . . . . . . . 3.4. Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Hypercalcemia . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Osteomalacia . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.5. Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.6. Cushing's syndrome . . . . . . . . . . . . . . . . . . . . . . 3.4.7. Carcinoid syndrome . . . . . . . . . . . . . . . . . . . . . . 3.4.8. Syndrome of inappropriate antidiuretic hormone secretion (SIADH). 3.4.9. Zollinger-Ellison syndrome . . . . . . . . . . . . . . . . . . . 3.5. Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Trousseau's syndrome . . . . . . . . . . . . . . . . . . . . . 3.5.2. Antiphospholipid syndrome (APS) . . . . . . . . . . . . . . . . 3.5.3. Thrombocytosis . . . . . . . . . . . . . . . . . . . . . . . . 3.5.4. Neutrophilia . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.5. Erythrocytosis . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.6. Autoimmune hemolytic anemia . . . . . . . . . . . . . . . . . 3.5.7. Thrombocytopenia . . . . . . . . . . . . . . . . . . . . . . . 3.5.8. Pancytopenia . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Nephrology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6.1. Paraneoplastic glomerulopathy . . . . . . . . . . . . . . . . . 3.6.2. Hyperaldosteronism . . . . . . . . . . . . . . . . . . . . . . 3.7. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7.1. Demons-Meigs' syndrome. . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Paraneoplastic syndromes are clinical manifestations of a malignancy not directly caused by the primary tumor, metastasis, or their treatment with chemotherapy or radiotherapy [1]. These manifestations are induced by biological substances such as hormones, cytokines, and growth factors secreted by malignant neoplasm, or by cancer-associated immune reactions. Hormone hypersecretion from a hormone-secreting tissue is not considered a paraneoplastic syndrome [1]. They can affect all systems, and may lead to severe and life-threatening complications. These syndromes can appear before or concomitantly with the cancer, but can also develop after the diagnosis or at the time of recurrence. It is of the upmost importance for clinicians to be aware of the various existing paraneoplastic syndromes, because these syndromes can be the first clinical presentation of an otherwise clinically silent malignancy. Their association with occult malignancy mandates an appropriate diagnostic workout. Moreover, treatment cornerstone of these conditions is usually to address the associated neoplastic process.

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A review article by Ashour et al. in 1997 thoroughly described the paraneoplastic syndromes associated with gynecologic malignancies [1]. Since the publication of this landmark article, a substantial amount of additional knowledge has become available. The present article summarizes and provides an up-to-date literature review of the different paraneoplastic syndromes that can be related with cancers of the female genital tract. 2. Methods A systematic literature search was conducted through PubMed, Embase and Cochrane Library in October 2016. A search was done for the references containing in their title or abstract the terms vulva, vulvar, vagina, vaginal, cervix, cervical, uterus, uterine, endometrial, endometrium, tube*, tubal, ovary, ovaries, or ovarian and cancer* or neoplasm* with any of these expressions: paraneoplastic syndrome(s), paraneoplastic disease(s), or paraneoplastic manifestation(s). In PubMed, MeSH terms “Genital Neoplasms, Female” and “Paraneoplastic Syndromes” were also used.

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Similarly, in Embase, the Emtree vocabulary “female genital tract tumor” and “paraneoplastic syndrome” were added to expand the search. The Cochrane Library database was explored by topic and using the keyword “paraneoplastic”. Only articles written in English or French were included. All article types were considered, with no restriction of publication date. After removal of duplicates from the different searches, 985 articles remained. Titles and abstracts were screened to determine those relevant for the review. Copies of the full texts were obtained, when available. The references of retrieved articles were cross-checked for additional papers. The list of all syndromes identified in this literature review is found in Table 1.

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neurotoxicity resulting from chemotherapy or radiotherapy. They can also be caused by paraneoplastic syndromes. Paraneoplastic neurologic disorders are triggered by an antitumor immune response producing antibodies that react with both the tumor and the nervous system [2], thus leading to functional or structural damages. A variety of antibodies have been described, associated with different clinical syndromes and cancers [2]. As the aetiology of these neurologic disorders can be paraneoplastic or non-paraneoplastic, diagnostic criteria have been proposed to suspect a paraneoplastic origin in a given patient. These criteria rely on a combination of the type of neurologic syndrome, the presence of cancer, neurologic improvement in response to tumor treatment, and the type of onconeuronal antibodies [3].

3. Review 3.1. Neurology Neurologic manifestations in patients with cancer can be caused by metastases, metabolic disorders, infections, vascular insults or by the

Table 1 Paraneoplastic syndromes associated with gynecological cancers. Neurology Subacute cerebellar degeneration/cerebellar ataxiaa Limbic encephalitis Anti-NMDAR encephalitisa Opsoclonus-Myoclonus syndrome Subacute sensory neuropathy Sensorimotor neuropathy Lambert-Eaton myasthenic syndrome Myasthenia gravis Ophthalmology Cancer-associated retinopathya Bilateral diffuse uveal melanocytic proliferation Paraneoplastic optic neuropathy and neuromyelitis optica Dermatology and Rheumatology Dermatomyositisa Palmar fasciitis and polyarthritis syndrome Digital ischemia Amyloidosis Malignant acanthosis nigricans Tripe palms Leser-Trélat sign Erythema gyratum repens Hypertrichosis lanuginosa acquisita Multicentric reticulohistiocytosis Sweet syndrome Pemphigoid gestationis Paraneoplastic pemphigus Endocrinology Hypercalcemiaa Osteomalacia Hyperthyroidisma Hypo/hyperglycemia Cushing's syndrome Carcinoid syndrome yndrome of Inappropriate Antidiuretic Hormone Secretiona Zollinger-Ellison syndrome Hematology Trousseau's syndromea Antiphospholipid syndrome Thrombocytosisa Neutrophilia Erythrocytosis Autoimmune hemolytic anemia Thrombocytopenia Pancytopenia Nephrology Paraneoplastic glomerulopathy Hyperaldosteronism Miscellaneous Demons-Meigs' syndromea a Paraneoplastic syndrome(s) most commonly found in each system.

3.1.1. Subacute cerebellar degeneration/cerebellar ataxia Paraneoplastic cerebellar degeneration (PCD) is the most frequent paraneoplastic neurological syndrome in patients with breast or gynecologic tumors [4]. PCD usually has an aggressive course [5] and manifests as a cerebellar dysfunction, provoking gait and truncal ataxia, dysarthria, and nystagmus. Diplopia and vertigo are also common. Symptoms of PCD are due to a widespread loss of cerebellar Purkinje cells [2], caused by a cellular immune response related to antineuronal antibodies. The antibody most commonly associated with PCD is antiYo, found with cancer of the ovary, breast, or other gynecological malignancies [4]. Other related cancers include small-cell lung cancer (antiHu, anti-CRMP5) and Hodgkin's disease (anti-Tr, anti-mGluR1) [2]. Patients with PCD and positive anti-Yo antibodies almost always have an underlying cancer [2,5], thus an abdominal exploratory surgery should be considered for patients with cerebellar degeneration and positive anti-Yo with no evidence of cancer despite an extensive investigation, because PCD can be induced even by a small tumor [5]. Neurologic outcomes of patients with PCD are poor, and most patients remain disabled despite effective cancer treatment and immunotherapy [5]. 3.1.2. Limbic encephalitis and anti-N-methyl-D-aspartate receptor (antiNMDAR) encephalitis Limbic encephalitis consists of rapid development of neuropsychiatric symptoms including irritability, depression, seizures, hallucinations, and short-term memory loss [3]. Various antibodies that react with neuronal cell intracellular antigens can cause limbic encephalitis. The antibodies more frequently associated with this disorder are anti-Hu, which can be found in ovarian tumors [4], anti-Ma2, and anti-CRMP [3]. Anti-NMDAR encephalitis is an immune-mediated encephalitis usually affecting young female of reproductive age and associated with ovarian teratoma [6]. This syndrome can be preceded by a viral prodrome of hyperthermia or headache [6]. Anti-NMDAR encephalitis presents with the neuropsychiatric and behavioural symptoms, accompanied by decreased level of consciousness, central hypoventilation, autonomic instability, and dyskinesias. It is potentially fatal [6]. Almost 200 patients with this syndrome have been reported [6], and better awareness of its existence is likely to increase the number of known cases. Most published cases demonstrated the presence of mature teratomas [4], however immature teratomas account for about 20% of cases [6]. Anti-NMDAR antibodies are produced by an immune response to neural tissues contained in teratomas [6]. Diagnosis of anti-NMDAR encephalitis can be established by detection of these antibodies in the serum or cerebrospinal fluid (CFS), although they may sometimes only be detected in CSF [6]. Intensive care and ventilator support may be required for a prolonged period of time. Tumor resection is the cornerstone of treatment [6]. Corticosteroids, plasmapheresis, immunoglobulins and anticonvulsants can help alleviate the symptoms. Recovery may take months or years, and some patients experience permanent sequelae [6]. However, as anti-NMDAR encephalitis results from reversible

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surface antibody-mediated neuronal dysfunction, most patients will improve or fully recover with treatment [6]. 3.1.3. Opsoclonus-Myoclonus syndrome (OMS) Patients with OMS present with opsoclonus, a disorder of eye movement characterized by involuntary conjugated saccades of large amplitude, and myoclonus, defined as myoclonic jerks mostly involving the trunk and limbs. They can also develop cerebellar symptoms such as nystagmus, ataxia, and dysarthria [7]. This syndrome can be idiopathic, metabolic, parainfectious, or paraneoplastic [7]. The tumors more frequently involved in adults are small cell lung cancer (SCLC), breast and gynecological cancers [3]. An investigation for cancer, with high resolution CT of the chest and abdomen, mammography and gynecological examination should be performed [8]. Currently recognized onconeuronal antibodies are usually not found in paraneoplastic OMS, except anti-Ri when related to breast cancer [7]. Treatment of OMS includes corticosteroids, immunotherapy, and treatment of the underlying cancer [2,3,7]. 3.1.4. Paraneoplastic subacute sensory neuropathy This paraneoplastic syndrome is most commonly associated with SCLC, but may be associated with other cancers such as cervical [4] and ovarian carcinomas, and with uterine sarcoma [4,9]. For example, in patients with stage I epithelial ovarian cancer, the incidence of subclinical sensory neuropathy is as high as 33.3%, and it becomes more clinically obvious in advanced-stage cancer where up to 71.1% of patients show neurophysiological abnormalities [10]. Anti-Hu, amphyphisin [4], and anti-CV2 antibodies are sometimes implicated, but frequently no onconeural antibody is identified [9]. Clinical manifestations initially include asymmetric numbness and pain of the limbs, and proprioception may also be affected [3,9]. It can occur simultaneously with other paraneoplastic neurologic syndromes such as encephalomyelitis [3]. 3.1.5. Sensorimotor neuropathy The cornerstone of sensorimotor neuropathy is predominant motor impairment [4], usually of subacute onset [11]. This paraneoplastic syndrome is frequently not associated with an identifiable onconeural antibody [9]. Clinically apparent sensorimotor neuropathy is rarely associated with gynecologic tumors [4], however patients with advanced stage epithelial ovarian cancer often present electrophysiological evidence of both sensory and motor involvement [10]. It has also seldom been reported with squamous cell carcinoma of the cervix and uterine adenocarcinoma [11]. Motor manifestations can be associated with central nervous system (CNS) involvement, mostly encephalomyelitis, and autonomic dysfunction, leading to heterogeneous disorders. Electrophysiological studies show abnormalities in sensory conduction values. 3.1.6. Lambert-Eaton myasthenic syndrome (LEMS) This autoimmune neuromuscular junction disease is frequently associated with cancer in more than half of patients, mostly SCLC [12, 13]. This condition is uncommon in gynecologic oncology, but has already been described with small-cell carcinoma of the cervix [13], and with uterine leiomyosarcoma [12]. A diagnosis of LEMS mandates investigations to detect an underlying neoplasm. Clinically, patients present proximal muscle weakness, mostly affecting lower limbs, prominent fatigability, diminished deep tendon reflexes, ptosis and anticholinergic symptoms such as dry mouth, dry eyes, postural hypotension and constipation [12]. LEMS is caused by antibodies directed against presynaptic P/Q type voltage-gated calcium channels at the neuromuscular junction, leading to impaired neuromuscular transmission. These antibodies are specific for LEMS and are detected in over 90% of cases [12], but don't predict the presence of cancer. Treatment cornerstone is directed against the

underlying malignancy, as successful tumor treatment can be associated with improvement of LEMS [2,13]. Options for symptomatic relief consist in pharmacologic modulation of acetylcholine and immunomodulation [2,13]. 3.1.7. Myasthenia gravis (MG) Myasthenia gravis is the most common neuromuscular transmission disorder [12]. It is caused by antibodies directed against the postsynaptic nicotinic acetylcholine receptors, blocking the action of acetylcholine and resulting in muscle weakness [12]. Weakness in MG usually involves the face, neck, shoulders and arms. Characteristically, extraocular muscles are affected, leading to diplopia and ptosis. Also, respiratory muscles weakness can precipitate acute primary respiratory failure [12]. Elevated titer of serum binding antibodies to acetylcholine receptors confirms a clinical diagnosis of MG [12]. Treatment of MG includes anticholinesterase medication [12], immunoglobulin therapy, and plasma exchanges [2]. This condition is usually associated with thymic hyperplasia and thymoma, but has also been rarely described with tumors of the female genital tract. Treatment of the underlying malignancy contributes to clinical improvement. 3.2. Ophthalmology 3.2.1. Cancer-associated retinopathy (CAR) This rare phenomenon is characterized by retinal degeneration caused by loss of photoreceptors. It usually presents with subacute decreased visual acuity, loss of color vision, narrowed visual fields, and photopsia. Fundus examination may reveal alteration of the retinal pigment epithelium and attenuation of the retinal vessels [14]. Fluorescein angiogram can disclose perivascular leakage secondary to vasculitis, and electroretinography classically demonstrates profoundly decreased or absent response [14]. CAR is mostly associated with SCLC, followed by gynecologic malignancies [15]. It is caused by autoantibodies against retinal proteins leading to degeneration of the retina [14]. Numerous antibodies have been described. Antibody to recoverin, a protein found in the photoreceptor cells of the eyes, is the most frequent antibody present in the serum of patients with CAR [2]. These antibodies can cross-react with retinal cells and trigger retinal cell death through an apoptotic mechanism [14]. Aberrant recoverin expression in the tumors may be responsible for the abnormal immune response [14]. Treatment of the underlying malignancy does not improve vision [14,15]. Therapeutic options include steroids, immunosuppressive agents, plasmapheresis, and intravenous immunoglobulins [14,15]. Because CAR is caused by irreversible degeneration of photoreceptor cells, treatment may prevent progression, but rarely improves visual acuity [14]. 3.2.2. Bilateral diffuse uveal melanocytic proliferation (BDUMP) This extremely rare ophthalmic condition presents with subacute bilateral visual loss, and is most often related to gynecological malignancies [16]. BDUMP is caused by rapid proliferation of uveal melanocytes, leading to diffuse thickening of the uveal tract [16]. The aetiology of melanocytes proliferation is unclear, but this process may be responsible for the toxic or hypoxic injuries to adjacent structures [16]. These damages can result in serous retinal detachments, degeneration of the retinal pigment epithelium, rapidly developing cataracts, and glaucoma [16]. In women, the most frequent tumors associated with BDUMP are ovarian and uterine carcinomas, usually poorly differentiated [16]. It has also been described with cervical carcinoma, and with Bartholin gland carcinoma. Treatment options are limited. Treatment of the underlying tumor may improve visual symptoms. Other therapeutic

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options include corticosteroids, plasmapheresis, and ocular surgery or irradiation, but outcomes are usually poor [15]. 3.2.3. Paraneoplastic optic neuropathy and neuromyelitis optica Paraneoplastic optic neuropathy is anecdotic in gynecologic oncology [15]. Immunologic response directed against the neuronal antigen CRMP-5 can cause damage to the optic nerve, resulting in progressive bilateral vision loss and diminished visual fields [15]. This condition is almost always associated with neurologic manifestations of central and peripheral nervous system dysfunction [15]. Another cause of damage to the optic nerve is neuromyelitis optica (NMO), an inflammatory demyelinating disorder affecting the optic nerves and spinal cord [17]. It is usually associated with antibodies against aquaporin-4 [17]. NMO is mostly non-paraneoplastic, but there is a subgroup of patients with paraneoplastic NMO [18]. Although breast carcinoma is the most common tumor associated with paraneoplastic NMO, it has seldom been described with gynecologic tumors such as cervical carcinoma and ovarian teratoma [17]. 3.3. Dermatology and rheumatology 3.3.1. Dermatomyositis There are two forms of dermatomyositis; juvenile and adult dermatomyositis. Juvenile dermatomyositis is not considered a paraneoplastic disease [19], however, adult dermatomyositis is associated with a malignancy in approximately 25% of cases [19]. The most common cancers in women with dermatomyositis are ovarian and breast cancers [19,20]. Patients with dermatomyositis have a 12-fold increased risk of cervical cancer, and 10-fold risk of ovarian cancer [21]. Dermatomyositis usually precedes the diagnosis of ovarian cancer [20,22]. The highest risk of cancer is in the first year after diagnosis of dermatomyositis [20]. When adult dermatomyositis is diagnosed in a patient with no identified cancer, appropriate investigations must be performed to rule out any underlying malignancy. These investigations must include CA125, mammography, and imaging such as CT of the thorax, abdomen and pelvis or PET-CT [19]. If no cancer is detected, gynecologic surveillance with transvaginal ultrasonography and serum CA125 every 6 months for two years after the diagnosis of dermatomyositis is advised [19]. The clinical hallmarks of dermatomyositis are classic skin manifestations with muscle weakness, although achalasia and interstitial lung disease can also be present [19,22]. The characteristic skin findings in dermatomyositis include an erythematous-violaceous rash involving sun-exposed areas, but usually sparing the interscapular area, and a facial heliotrope rash (Fig. 1A) with some degree of facial edema. Moreover, Gottron's papules over the knuckles (Fig. 1B), cuticular dystrophia, and periungual erythema can be found. Cutaneous vesicles are a risk factor for the presence of malignancy, especially of gynecological origin [22]. Dermatomyositis usually presents with symmetrical proximal muscle weakness [19], however amyopathic dermatomyositis, a condition

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with minimal or no muscle involvement, is possible [19,20]. Elevation of the serum creatine kinase can be found as a consequence of muscle damage [22]. On muscle biopsy, perivascular infiltrates of inflammatory cells, and destruction of muscle fibers with evidence of regeneration are seen [22]. Paraneoplastic dermatomyositis activity is closely related to the evolution of the underlying malignancy [20]. Systemic corticosteroids, intravenous immunoglobulin, and immunosuppressive therapy can also be beneficial [19,22]. 3.3.2. Palmar fasciitis and polyarthritis syndrome (PFPAS) This uncommon paraneoplastic syndrome is mostly related to ovarian cancer, but can also be found with other malignancies, such as breast and gastrointestinal carcinomas [23]. Cancers of the vulva, cervix, and uterus were also involved in this syndrome [23]. It is usually caused by an advanced stage cancer [23]. In addition, non-paraneoplastic conditions such as benign ovarian tumors and certain medications can precipitate PFPAS [23]. PFPAS presents with painful swelling of both hands with inflammation and fibrosis of palmar fascia leading to rapidly progressive induration and flexion contractures of the hands. Plantar fascia is also affected in 20% of cases [23]. PFPAS is associated with arthritis of small fingers and wrist joints, but also of larger joints, mostly the shoulders. Concomitant carpal tunnel syndrome has seldom been reported. Treatment of the underlying malignancy may bring reduction of inflammation, but flexor contractures usually persist [23]. 3.3.3. Digital ischemia This syndrome presents with pain, permanent digital cyanosis or pallor, and ulceration of the fingers [24]. Raynaud's phenomenon can precede clear manifestations of digital ischemia [24]. These manifestations can result from vasospasm, intimal proliferation, thrombosis, vasculitis, or drug toxicity. With regards to gynecologic oncology, this syndrome is mostly associated with ovarian carcinomas, but has also been reported with other gynecological malignancies [25]. 3.3.4. Amyloidosis Paraneoplastic amyloidosis is usually associated with hematological malignancies and is rare in solid tumors except in renal carcinomas [26]. However, systemic amyloidosis has been described once secondary to poorly differentiated ovarian carcinoma [26]. 3.3.5. Malignant acanthosis nigricans (MAN) Acanthosis nigricans can be of benign or malignant origin [27]. MAN is a rapidly progressive form of acanthosis nigricans, causing hyperpigmented, lichenified plaques with a velvety texture, especially in the skin folds of intertriginous zones, such as axillae, back of the neck, and groins [20]. Histopathological appearance of acanthosis nigricans at skin biopsy is noteworthy for hyperkeratosis, acanthosis, increased dermal

Fig. 1. Patient with dermatomyositis presenting with heliotrope rash (A) and Gottron's papules affecting the proximal and distal interphalangeal joints (B).

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pigmentation, and papillomatosis with mild inflammation [27]. Intense pruritus may be present. Involvement of the oral cavity and other mucosal surfaces is far less common, but is typical of malignant acanthosis nigricans [27]. It is hypothesized that tumor releases substances stimulating keratinocytes and dermal fibroblasts receptors. It is almost always associated with adenocarcinomas, mostly gastric adenocarcinomas. Cases arising with carcinoma of the cervix, endometrium, and ovary have been seldom reported [20,27,28]. Tumors associated with MAN are usually highly aggressive [27]. Severity of MAN correlates with the course of the tumor; however complete resolution may never occur [20,28]. Options for symptomatic treatment include retinoids, keratolytics, and corticosteroids [28]. 3.3.6. Tripe palms The expression “Tripe palms” comes from the thickened and velvety appearance affecting the palms and sometimes the soles, with hyperpigmentation and pronounced dermatoglyphics resembling the internal surface of bovine tripe [29,30]. It is often found in association with acanthosis nigricans. More than 90% of patients with Tripe palms have a malignancy, especially gastric and pulmonary carcinomas [29]. It is also reported in association with cervical, uterine, and ovarian cancers [30]. Treatment of the underlying tumor can improve or cure the lesions. 3.3.7. Leser-Trélat sign The Leser-Trélat sign is characterized by the sudden eruption and rapid increase of multiple seborrheic keratoses and skin tags, usually involving the back and chest, in association with an internal malignancy [29,31]. It can coexist with malignant acanthosis nigricans. This syndrome is predominantly found in gastrointestinal adenocarcinomas and lymphoproliferative disorders [29],but has been infrequently described, among others, with cervical, uterine and ovarian cancers [31,32]. It can also rarely be present with a benign neoplasm or during pregnancy [32]. 3.3.8. Erythema gyratum repens (EGR) Patients with EGR present pruritic scaling erythematous lesions forming concentric bands with a “wood-grain” pattern. This migrating dermatosis predominantly affects the trunk and proximal extremities [33]. Histopathological findings of EGR are nonspecific. Most patients have an underlying malignancy, usually of the bronchus, esophagus, or breast [29]. It has also been rarely reported in association with cervical and uterine cancers [20]. The eruptions tend to rapidly resolve after tumor treatment [20]. 3.3.9. Hypertrichosis lanuginosa acquisita Hypertrichosis lanuginosa acquisita is defined by a sudden growth of lanugo hair. This hair is distributed over the face, trunk, and extremities [20]. Besides a paraneoplastic aetiology, it can be caused by metabolic or endocrine disorders and by certain drugs [34]. The most frequent cancers involved in women with hypertrichosis lanuginosa acquisita are colorectal, lung, and breast cancer [20,34]. In gynecologic oncology, this syndrome has been described with carcinoma of the cervix, endometrial cancers, and with ovarian adenocarcinoma and sex cord stromal tumors [34]. Hypertrichosis lanuginosa acquisita is usually seen with patients with advanced disease, and symptoms will usually improve with the treatment of the underlying malignancy [20,34]. 3.3.10. Multicentric reticulohistiocytosis Multicentric reticulohistiocytosis is a rare disease. Only about one quarter of cases are triggered by malignancy [20,35]. This condition has been described with different tumors, including gynecologic cancers

such as cervical, endometrial and ovarian carcinoma [20,35]. It is caused by stimulation of histiocytes by cytokines [35]. This reactive process results in both rheumatologic and dermatologic manifestations. It causes inflammatory polyarticular arthritis, most commonly of the hands, wrists, shoulders, hips, and knees [20,35]. This severe erosive arthritis can lead to widespread destruction of the articulations. The cutaneous findings present as small, multiple reddish-brown nodules and papules occurring over the hands, arms, face, legs, and mucosal surfaces. Periungual papules arranged around the nail folds may give a classic “coral-bead” appearance [20,35]. Treatment modalities include glucocorticoids, methotrexate, alkylating agents, and disease-modifying antirheumatic drugs (DMARDs) [20,35]. 3.3.11. Sweet syndrome Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by painful erythematous nodules and plaques generally located on the upper extremities, trunk, head and neck [36]. The skin lesions can also be vesicular, bullous, or ulcerated [37]. Most patients present fever and neutrophilia, but these features can be absent in malignancy associated Sweet syndrome [37]. Extracutaneous manifestations, such as arthralgias, conjunctivitis, renal involvement, and anemia may be present [36,37]. Biopsy of the skin lesions is necessary for confirmation and reveals neutrophilic dermal infiltrate [37]. Pathogenesis of this syndrome is uncertain, but cytokines and granulocyte colony-stimulating factor (G-CSF) are probably involved [38]. This syndrome may be drug-induced or encountered in benign conditions including infections and autoimmune diseases [36]. About 20% of cases are malignancy-associated [20,38]. It is mostly associated with acute myelogenous leukemia, but can be present to a lesser extent with solid tumors [36], predominantly genitourinary tumors [20]. Skin lesions spontaneously disappear in a few weeks. Treatment with systemic corticosteroids usually results in a rapid improvement of cutaneous and extracutaneous manifestations [37]. 3.3.12. Pemphigoid gestationis Pemphigoid gestationis, originally named herpes gestationis, is a rare dermatologic condition usually arising during pregnancy or early postpartum. Clinically, patients experience very pruritic erythematous urticarial papules, plaques, vesicules, or bullous lesions distributed over the abdomen, trunk, and extremities [39]. These subepithelial lesions are caused by IgG and C3 deposition in the epithelial basement membrane zone [40]. Symptomatic treatment of this autoimmune disease usually involves topical or systemic corticosteroids [39]. Pemphigoid gestationis has been occasionally described in association with gestational trophoblastic disease, probably caused by the extremely high levels of human chorionic gonadotrophin (HCG) [39,40], but also with metastatic uterine carcinoma [40]. 3.3.13. Paraneoplastic pemphigus (PNP) This mucocutaneous disease is related with hematologic neoplasms in 84% of cases [41]. It has also been rarely reported with a variety of solid tumors, including rare cases of gynecologic tumors. The oral mucosa is involved in all cases, provoking diffuse painful erosions and ulcerations resistant to treatment [41]. Pharyngeal lesions can cause severe dysphagia. Conjunctivitis affects about two-thirds of patients [41]. Skin lesions, characteristically polymorphous then progressing to blisters, are found usually on the trunk and proximal extremities [41]. These eruptions are precipitated by antibodies provoking acantholysis and dyskeratosis [41]. The autoimmune reaction can result in a potentially lethal bronchiolitis obliterans [42]. Clinical improvement is possible after treatment of the underlying malignancy, but oral erosions tend to persist [41].

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3.4. Endocrinology 3.4.1. Hypercalcemia Hypercalcemia is a common paraneoplastic syndrome. It can result in mental alteration, gastrointestinal symptoms, cardiac arrhythmias, coma and death. Among other aetiologies, hypercalcemia related to malignancy can be caused by tumor secretion of parathyroid hormone-related protein (PTHrP), a protein similar to the parathyroid hormone. Like PTH, PTHrP prevents calcium renal excretion and activates bone resorption, leading to an increased calcium serum level. It also increases renal phosphate excretion. Hypercalcemia is frequent with small-cell carcinoma of the ovary, two thirds of the cases being associated with hypercalcemia [43], but can occasionally be associated with other ovarian and gynecological tract tumors, particularly clear cell carcinoma of the ovary. Treatment of hypercalcemia secondary to PTHrP includes treatment of the underlying cancer, aggressive intravenous hydration, bisphosphonates and calcitonin. In severe cases, dialysis may be required. 3.4.2. Osteomalacia This rare paraneoplastic syndrome is caused by secretion of phosphatonins, bioactive substances that lead to renal phosphate wasting and inhibiting of 1α-hydroxylation of vitamin D [44]. This results in hypophosphatemia and low bone mineral density, and can present as muscle weakness, bone pain and fractures. Tumor-induced osteomalacia has been infrequently described in gynecologic oncology, but has been reported in metastatic ovarian cancer [44]. 3.4.3. Hyperthyroidism Hyperthyroidism in gynecologic malignancies can be seen in two distinct situations; gestational trophoblastic disease (GTD) and ectopic functioning thyroid tissue such as struma ovarii. In GTD, hyperthyroidism is caused by the very high levels of HCG which stimulates TSH homologous α subunit. As patients with GTD are usually treated early, clinical hyperthyroidism is rare and will resolve with subsequent fall in serum HCG. Struma ovarii is an ovarian tumor composed of thyroid tissue and mature teratoma. Thyroglobulin can be shown by immunohistochemistry [45]. Hyperthyroidism secondary to this active tissue occurs in about 5 to 8% of cases [45,46], and thus there is a risk of perioperative thyroid storm with life-threatening consequences [45]. After surgery, thyroid function must be assessed, as hyperthyroidism or hypothyroidism can ensue [45]. Most struma ovarii are benign, but rare cases of papillary, follicular and insular thyroid-type carcinomas have been described in the literature [46]. Thyroid tissue can also be found in strumal carcinoid, which is composed of struma and distinct carcinoid tumor. Rare cases of thyroid carcinoma with metastasis to the ovary can also account for ectopic thyroid tissue in the genital tract [46]. 3.4.4. Hypoglycemia Cancer can result in hypoglycemia in many ways, including tumor metabolic burden, hepatic insufficiency, and secretion of insulin or insulin-like substances. Insulin production by extra-pancreatic non-islet-cell tumors is rare [47]. It has nevertheless been reported in several ovarian tumors, mostly carcinoid tumors [47]. In non-islet-cell tumors, big insulin-like growth factor II (IGF-II) may also be released and cause profound hypoglycemia [48]. In these situations, insulin secretion is suppressed. Secretion of IGF-II has been described with various gynecologic tumors. Another hormone, glucagon-like peptide 1 (GLP-1), which enhances insulin production in response to glucose, has been shown to be secreted in large amount by an ovarian strumal carcinoid, thus leading to severe postprandial hypoglycemia [49]. There is also one report of an ovarian teratoma [50] secreting somatostatin, in a patient suffering

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from periodic hypoglycemia, possibly because of glucagon inhibition by somatostatin. 3.4.5. Hyperglycemia Hyperglycemia as a consequence of gynecologic tumors has exceptionally been reported. Two case reports associate hyperglycemia with elevated somatostatin concentrations secreted by an ovarian strumal carcinoid [49] and ovarian teratoma [50], because somatostatin also inhibits insulin production. 3.4.6. Cushing's syndrome This syndrome results from chronic glucocorticoid excess. Hypercortisolism can result in proximal muscle wasting with central obesity, weight gain, menstrual irregularities, easy bruising, skin atrophy with purple striae, hypertension, hypokalemia, hyperglycemia and acanthosis nigricans [51]. Supraclavicular and dorsal fat pads (buffalo hump), facial plethora and round face (Cushingoid facies) are classical signs of Cushing's syndrome. Adrenocorticotropin (ACTH) secretion by a pituitary adenoma or an ectopic ACTH-secreting tumor is most commonly involved, even though adrenal tumors or hyperplasia and exogenous glucocorticoids are also possible aetiologies. In Cushing's syndrome, low-dose dexamethasone test fails to suppress cortisol production. When ACTH secretion by a pituitary adenoma is responsible, high-dose dexamethasone test will lower serum cortisol. Ectopic secretion of ACTH is mostly associated with carcinoma of the lung, thymic carcinoid, pheochromocytomas, or islet cell tumor of the pancreas [51,52]. Ectopic ACTH secretion has been infrequently reported in a variety of ovarian tumors [51]. Cortisol secretion by an ovarian carcinoma is also possible [52]. 3.4.7. Carcinoid syndrome The carcinoid syndrome has been described with both primary ovarian carcinoid tumors and carcinoid metastasis to the ovary. This syndrome occurs in approximately one third of patients with ovarian carcinoid tumors of insular histology, but rarely in strumal and trabecular carcinoid tumors [53]. It is caused by secretion of serotonin-like substances into the systemic circulation. In opposition with carcinoid tumors of the gastrointestinal tract, serotonin-like substances secreted by ovarian tumors are released directly into the systemic circulation through the ovarian veins, bypassing hepatic deactivation [53]. These bioactive peptides can cause flushing, diarrhea, bronchospasm, and right heart failure secondary to tricuspid insufficiency or pulmonary valve stenosis [53]. Patients will have elevated urine 5-HIAA and serum serotonin levels. In some patients, the ovarian carcinoid tumors were found to produce the gastrointestinal hormone peptide YY (PYY), which inhibits intestinal motility, and resulted in severe constipation [54]. 3.4.8. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) This syndrome has a variety of possible aetiologies, including infections, CNS disorders and can be precipitated in post-operative state. It is a paraneoplastic syndrome mostly associated with SCLC, but it has also been occasionally reported with gynecologic tumors [55]. High antidiuretic hormone (ADH) levels cause excessive renal water retention and hypoosmotic hyponatremia. Acute hyponatremia is more likely to be symptomatic, secondary to cerebral edema. Neurologic symptoms predominate, including headache, lethargy, nausea and vomiting. Severe hyponatremia can lead to decreased level of consciousness and death. In SIADH, urine sodium and osmolality are abnormally high in relation to serum low osmolality [55]. Mainstay of treatment is water restriction and treatment of the underlying disease. Rapid correction of hyponatremia can bring severe neurological complications such as central pontine myelinolysis.

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3.4.9. Zollinger-Ellison syndrome Zollinger-Ellison syndrome is caused by abnormal gastrin secretion, usually by gastrointestinal tumors. Supraphysiologic levels of gastrin result in gastric acid hypersecretion and severe duodenal or gastric peptic ulcers, easily demonstrated by endoscopy. They can cause epigastric pain, or bleed and present with melena. Most gastrin-secreting tumors arise in the gastrointestinal tract. Gynecologic tumors are rare aetiologies of Zollinger-Ellison syndrome [56], but this syndrome has been reported with mucinous ovarian cystadenoma, borderline tumors, and cystadenocarcinoma [56].

3.5. Hematology 3.5.1. Trousseau's syndrome Trousseau's syndrome, first described as a visceral cancer related migratory phlebitis, now encompasses a variety of paraneoplastic thromboembolic events, such as venous thromboembolism, pulmonary embolism, arterial thromboses and systemic arterial emboli caused by nonbacterial thrombotic endocarditis [57,58]. This syndrome is probably precipitated by overlapping mechanisms resulting in a prothrombotic condition [57]. These mechanisms include activation of clotting by vessel wall injury [58], increase of tissue factor levels and activity, procoagulant factors produced secondary to tumor hypoxia, venous stasis by mechanical compression, and, in some cancers, carcinoma secreted mucins [57]. In addition to cancer-related and host-related risk factors, therapeutic interventions such as surgery, chemotherapy [59], hormone therapy or granulocyte-monocyte colonystimulating factor [58] can contribute to the thrombotic activity. Paradoxically, this thrombotic activity can also precipitate a disseminated intravascular coagulopathy, leading to hemorrhagic manifestations [1]. In patients with cancer, the incidence of clinically significant thrombosis ranges from 1% to 10% [59]. Venous thromboembolism (VTE) is the most common thromboembolic event in patients with cancer. In women, gynecologic, pancreatic, and colorectal cancers are most frequently associated with VTE [59]. The risk of occult malignancy at the time of an idiopathic VTE is approximately 10% [59]. In ovarian cancer, about 5–15% of patients are diagnosed with a VTE within the first 2 years, patients with advanced-stage disease being at higher risk [60]. A more uncommon manifestation of Trousseau's syndrome is nonbacterial thrombotic endocarditis, a condition characterized by platelet and fibrin vegetations on cardiac valves, not related to an infection, and leading to systemic emboli and infarction of peripheral organs [61]. It is associated with a disseminated intravascular coagulation process, resulting in low fibrinogen and platelets [59]. The most frequently encountered carcinomas associated with nonbacterial thrombotic endocarditis are pulmonary, pancreatic and ovarian adenocarcinomas [61].

3.5.2. Antiphospholipid syndrome (APS) APS is an autoimmune disorder characterized by thrombotic events or pregnancy complications, along with laboratory findings of antiphospholipid antibodies. Of particular interest, an overlap in clinical presentation exists between APS and Trousseau's syndrome. APS can develop secondarily to autoimmune disorders, infections, traumas, malignancies or independently of any underlying disease. A wide variety of hematological neoplasms and solid tumors have been reported in patients with this syndrome, including cervical, uterine and ovarian carcinomas [62]. In solid tumors, it is postulated that antiphospholipid antibodies may be produced as an immune response to cancer, or that some tumors secrete anticardiolipin antibodies [62]. The paraneoplastic nature of some cases is supported by the fact that antiphospholipid antibodies can disappear after treatment of the underlying cancer, accompanied by clinical improvement [62]. Moreover, patients with malignancies are significantly more often anticardiolipin positive as compared with patients without cancer [63].

3.5.3. Thrombocytosis Paraneoplastic thrombocytosis is a well-recognized phenomenon in patients with a variety of solid tumors, including gynecologic cancers such as vulvar, cervical and endometrial carcinomas [64]. This phenomenon has been extensively studied in patients with epithelial ovarian cancer (EOC), where it is found in approximately one-third of cases [65]. In a recent study, Stone et al. [65] investigated the complex relationship between thrombocytosis and EOC. Their findings suggest that thrombocytosis is caused by the secretion of interleukin-6 (IL-6) that stimulates the hepatic synthesis of thrombopoietin, a factor promoting megakaryocyte proliferation in the bone marrow. In EOC, patients with thrombocytosis are significantly more likely to suffer from vascular thromboembolic complications than those with normal platelet counts. Even if thrombocytosis is associated with factors of poor prognostic, it was also found to be independently related to an increased risk of death [65]. This effect on prognostic suggests a role of platelets and their products on tumor cells and disease progression. First, platelets and their products increase angiogenesis and stabilize tumor vascularisation [65]. They also up-regulate anti-apoptotic and pro-proliferative cellular pathways [66]. These interactions with cancer cells may facilitate ovarian cancer cell survival and metastasis [66]. Moreover, platelets can increase chemoresistance and stimulate DNA repair processes [66]. These various interactions pave the way to the use of therapeutic agents directed against platelets in ovarian cancer, such as anti-interleukin-6 and anti-platelet antibodies [65]. 3.5.4. Neutrophilia Paraneoplastic leukemoid reaction is rare in the field of gynecology [67]. It should be suspected when a focus of infection cannot be identified, and when neutrophilia is progressive despite antibiotic treatment [67]. Mature neutrophils are usually predominant. Neutrophilia is probably due to autonomous secretion by the tumors of IL-6 and G-CSF, which are known hematopoietic growth factors [68]. Secretion of G-CSF by the tumor cells is the main hypothesis, because abnormally high serum levels of G-CSF have been reported in almost all cases of paraneoplastic neutrophilia and G-CSF concentration tends to correlate with tumor bulk [67]. Expression of IL-6 and G-CSF and of their respective receptors has been detected in tumor samples, providing further support for the association between G-CSF-producing tumors and neutrophilia [68]. G-CSF secretion and the presence of G-CSF receptors on the cell surface suggest a possible autocrine stimulation usually associated with an aggressive malignant course [68]. 3.5.5. Erythrocytosis Erythrocytosis results in plethora, aquagenic pruritus, headache, dizziness, visual disturbances, hypertension and cardiac symptoms caused by the elevated hematocrit. Thrombotic events from high viscosity or bleeding from platelet dysfunction can also occur. Control of the polycythemia preoperatively with phlebotomies can help reduce the incidence of adverse events [69]. Erythrocytosis is reported in a variety of benign or malignant tumors, originating from the kidney in more than half cases [70]. In the female genital tract, it has been reported with ovarian tumors, including dermoid cyst [71] and steroid cell tumor [69], with uterine leiomyoma [70], and with placental-site trophoblastic tumor [72]. The paraneoplastic basis of this manifestation is supported by the fact that erythrocytosis resolves after tumor resection [70]. Different mechanisms can be involved. Erythropoietin is probably involved in most cases, but as erythropoietin is not ubiquitously present in paraneoplastic erythrocytosis, an erythropoietin-like substance or a substance enhancing erythropoietin effect may also be responsible [70,72]. Other mechanisms include the secretion of androgens by steroid cell tumor [69] or human placental lactogen by placental-site trophoblastic tumor [72].

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3.5.6. Autoimmune hemolytic anemia Hemolytic anemia is one of the various aetiologies of anemia in patients with cancer. The two types of acquired hemolytic anemia related to cancer are autoimmune hemolytic anemia (AIHA) and microangiopathic hemolytic anemia (MAHA), which occurs secondarily to disseminated intravascular coagulopathy. In both conditions, as a result of hemolysis, unconjugated bilirubin, a breakdown product of heme, and lactate dehydrogenase levels are elevated. Levels of haptoglobin, a protein that bounds free hemoglobin released from erythrocytes, may be low. Also, reticulocytosis is found in response to red cell destruction [73]. AIHA can be idiopathic or caused by disorders such as autoimmune diseases or infections. It is characterized by autoantibodies directed against red blood cells [73]. Secondary AIHA is more common in lymphoproferative disorders, but is known to happen in a variety of solid cancers, mostly renal cell cancer and Kaposi sarcoma [73,74]. Although rare in gynecologic oncology, AIHA has been predominantly reported with ovarian cancer, but also with cervical and uterine carcinomas [74]. Moreover, association between AIHA and dermoid cyst is well recognized [74]. Some cases of AIHA occurred in early stage cancers, where surgery can bring a complete remission of AIHA. However, most patients with AIHA have metastatic disease [75], but can potentially improve with removal of the primary tumor or treatment with systemic steroids [74]. 3.5.7. Thrombocytopenia Immune thrombocytopenic purpura (ITP) is more common in lymphomas, but has been occasionally reported in solid tumors, mostly lung and breast cancers, but also with gynecological cancers including cervical, endometrial [76], and ovarian carcinomas [77]. Pathophysiology of this association is not well understood [77]. Treatment of the underlying malignancy usually has little influence over the paraneoplastic ITP, however some patients were cured by treatment of a local tumor [77]. Nevertheless, most patients will improve with steroid treatment or splenectomy [77]. Another cause of paraneoplastic thrombocytopenia found in literature is a case of idiopathic thrombocytopenic purpura precipitated by a splenic recurrence of an ovarian serous adenocarcinoma [78]. 3.5.8. Pancytopenia Pancytopenia is a rare paraneoplastic syndrome. However, it has been reported once in the presence of a myxoid leiomyosarcoma, without disseminated intravascular coagulation [79]. Hematologic parameters improved after surgical resection of the tumor, but pancytopenia reappeared with progression of the disease. 3.6. Nephrology 3.6.1. Paraneoplastic glomerulopathy Paraneoplastic glomerulopathies are rare manifestations of malignancies. The nephrotic syndrome is the most frequent presentation of paraneoplastic glomerulopathies [80]. It is characterized by proteinuria, hyperlipidemia, and edema resulting from hypoproteinema. This condition leads to hypercoagulable state from increased pro-thrombotic factors and loss of anti-thrombotic factors such as antithrombin III, Protein C and Protein S in urine. Nephrotic syndrome results in hypertension and acute renal failure. This syndrome can be caused by a number of drugs, infections, and systemic diseases, in addition to paraneoplastic aetiology. Gynecologic malignancies are rare causes of nephrotic syndrome. Membranous nephropathy is the most common glomerulopathy associated with solid tumors, and has been described with carcinoma of the uterine cervix, of the endometrium, and with choriocarcinoma [80]. Rare association between ovarian cancers and other glomerulopathies, such as minimal change disease, membranoproliferative glomerulonephritis, and rapidly progressive glomerulonephritis can be found in

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literature [80]. Secondary amyloidosis associated with a poorly differentiated ovarian carcinoma has also been reported to precipitate a nephrotic syndrome [26]. In case of paraneoplastic glomerulopathy, the primary treatment must be directed to the cancer, but consultation with a nephrologist is mandatory for proper management of the renal condition [80]. 3.6.2. Hyperaldosteronism Extra-adrenal aldosterone secretion is an uncommon aetiology of primary aldosteronism. Ectopic aldosterone secretion in the female genital tract, however rare, has been reported in few cases of sex cord-stromal tumors of the ovary [81]. Other tumors have been found to secrete renin and caused secondary hyperaldosteronism by activating the renin-angiotensin-aldosterone system. Most renin-secreting tumors arise in the kidney, although leiomyosarcomas [82], adnexal adenocarcinoma [83], and ovarian sex-cord stromal tumor [84] have been shown to produce renin. Hypersecretion of these hormones results in refractory hypertension, hypokalemia and metabolic alkalosis. In most cases, removal of the tumor corrects the hypertension and electrolytic disturbances. 3.7. Miscellaneous 3.7.1. Demons-Meigs' syndrome Nomenclature used to define this uncommon syndrome and its variants is inconsistent. Classic Demons-Meigs' syndrome refers to ascites and pleural effusions caused by a benign fibroma or fibroma-like ovarian tumor [85]. The fluids must be sterile and without malignant cells, and they both rapidly disappear after the removal of the tumor. Some authors have used a wider definition of the syndrome, including other benign ovarian or broad ligament tumors [85]. As for pseudo Meigs' syndrome, it results from any other pelvic or abdominal tumor, benign or malignant [85]. Furthermore, a pseudo-pseudo Meigs' (or Tjalma) syndrome defined by ascites, pleural effusion, systemic lupus erythematous and elevated CA-125 has been described [85]. Physiopathology of this syndrome is unclear. Ascites may be elicited by obstruction of the lymphatic channels, peritoneal irritation, leakage of protein from increased vessel permeability or imbalance between arterial and venous blood flow of the tumor. It was hypothesized that pleural effusions may develop from ascites passing through lymphatic vessels or interstices. However, most pleural effusions are exudates, usually right-sided [85]. 4. Conclusion Paraneoplastic syndromes include a wide range of manifestations and can involve all systems. Clinicians should be aware of the existence of these syndromes, as they often precede the discovery of the underlying cancer. Rapid cancer-directed treatments are essential as they may improve the symptoms in some paraneoplastic syndromes. These syndromes are also part of the differential diagnosis of a variety of clinical manifestations in patients with known malignancies. No conflicts of interest to disclose. Acknowledgements We would like to thank Dr. Marie-Marthe Thibeault from the Dermatology Service, L'Hôtel-Dieu de Québec, for her advice and for providing graphic material. References [1] A.A. Ashour, C.F. Verschraegen, A.P. Kudelka, J.J. Kavanagh, Paraneoplastic syndromes of gynecologic neoplasms, J. Clin. Oncol. 15 (1997) 1272–1282. [2] R.B. Darnell, J.B. Posner, Paraneoplastic syndromes involving the nervous system, N. Engl. J. Med. 349 (2003) 1543–1554.

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