Obligate and facultative paraneoplastic dermatoses: an overview

Dermatological paraneoplastic syndromes are a group of cutaneous diseases associated with malignancy, but not directly related to the primary tumor itself or to its metastases. It is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. In this overview, skin conditions that are highly correlated with malignancy, whose recognition implies a mandatory investigation of internal cancer, are described.


Introduction
The skin is the most accessible organ of the body and can be easily examined using noninvasive techniques, providing the doctor with clues that can be suggestive of systemic disturbances, thus contributing to the diagnosis of many diseases, including malignancies [1,2]. The skin may be directly or indirectly involved in malignancies. Direct involvement is due to the presence of tumor cells in the skin caused by direct tumor extension or metastasis. Indirect involvement of the skin can be determined by a variety of polypeptides, hormones, cytokines, antibodies, or growth factors related to the neoplasia. These inflammatory, proliferative, or metabolic factors act as mediators, interfering with cell communication and, consequently, with its activity. In this case, there is no presence of neoplastic cells in the skin, and this involvement is considered a dermatological paraneoplastic syndrome [1]. Thus, paraneoplastic syndromes are a group of diseases associated with a malignancy, but not directly related to the primary tumor itself or to its metastases.
It is not always easy to determine the correlation between a dermatologic finding and an internal neoplasm. The following criteria, defined by McLean in 1986 [3], should be verified to assess the causal relationship between the dermatosis and the potential underlying malignancy: (1) development of a dermatosis only after the development of a malignant Dermatological paraneoplastic syndromes are a group of cutaneous diseases associated with malignancy, but not directly related to the primary tumor itself or to its metastases. It is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible. In this overview, skin conditions that are highly correlated with malignancy, whose recognition implies a mandatory investigation of internal cancer, are described.
ABSTRACT mar, eyelids, perioral) and even mucosal surfaces, including neoplasm and (2) both the dermatosis and the malignant neoplasm follow a parallel clinical course, so the cutaneous symptoms disappear when the tumor is treated and reappear in cases of recurrence or metastasis [3].
Paraneoplastic syndromes occur in about 7% to 15% of patients with cancer and may be the presenting sign of an unknown neoplasm, precede the diagnosis of malignancy, occur late in the course of illness, or be the first sign of recurrence. Their recognition may result in earlier diagnosis and better prognosis for the patient, prolonging life expectancy [4][5][6][7][8].
A few rare paraneoplastic dermatoses are consistently associated with malignancies in almost 100% of the cases (obligate paraneoplastic dermatoses) ; others are more common skin disorders, associated with tumors in only 3% to 30% of the cases, so the coexistence of these dermatoses and neoplasms may be coincidental and the causal link is more controversial (facultative paraneoplastic dermatoses) [9,10,30] (Table 1).
In this overview, dermatoses that highly correlate with malignancy and that, when recognized, require mandatory investigation of internal cancer-excluding those disorders In a retrospective study, 49% of cancers involved the oropharynx and larynx, followed by the lung (17%) and esophagus (10.6%) [1]. Additional isolated cases associated with breast cancer, cholangiocarcinoma, colon adenocarcinoma, and Hodgkin lymphoma have been reported [1]. Case reports also describe SCCs of the thymus, vulva, and skin [13,14].
Its underlying mechanism is not well understood. Immunological factors with antibodies directed against the tumor in a cross-reaction with the epidermis or basement membrane have been considered. Possibly, a tumor production of a keratinocyte growth factor such as TGF-α may be involved [1].
Paraneoplastic acrokeratosis generally responds to successful treatment of the underlying tumor, and fails to improve when the neoplasm persists. Topical corticosteroids and systemic retinoids may be helpful.
The physician should inquire regarding risk factors for malignancy (smoking habits, alcohol consumption, weight loss, family history) and perform a complete physical examination, including head and neck and endoscopic and pelvic examination in women [13,14].
the palate. Palmar and plantar keratoderma with prominent fingerprint markings known as pachydermatoglyphy or tripe palms may be seen [10,11] (Figure 1). Skin biopsy is rarely necessary.

Acrokeratosis Paraneoplastica (Bazex Syndrome)
Patients affected by acrokeratosis paraneoplastica are typically men older than 40 years [11]. Cutaneous lesions are psoriasiform and manifest as asymptomatic, symmetrical erythematous-violaceous scaly patches. However, their distribution is not typical of psoriasis: in initial stages, the dermatosis involves the bridge of the nose, auricular helices, and distal ends of the extremities. As the disease progresses, desquamation may affect the dorsal and palmoplantar regions, producing a violaceous keratoderma. In advanced stages, In patients with EGR who did not have an underlying

Necrolytic Migratory Erythema or Glucagonoma Syndrome
Necrolytic migratory erythema (NME) is more common in women more than 45 years of age, with an average age of onset of 52 years [1]. NME presents as a pruritic and sometimes painful mucocutaneous eruption with a pinkish,

Erythema Gyratum Repens
Erythema gyratum repens (gyrate from the Greek, meaning "a circle"; repens from the Latin, meaning "to creep") (EGR) is a rare paraneoplastic dermatosis, usually occurring in patients older than 40 years, with a mean age of about 60 years; the male-to-female ratio is 2:1 [1,11,15].
The primary lesion is a pruriginous, macular erythema.
Numerous serpiginous bands are arranged in a parallel configuration of red swirls over most of the body, producing concentric figures that resemble a wood surface ("wood-grained" appearance) (Figure 2). The edges of the lesions migrate at a rapid rate, about 1 cm/day. A slight scale can be found along the trailing edge of erythema. The hands, feet, and face are often spared [1,15]. Peripheral eosinophilia is frequent.
The presentation of EGR is so typical that a differential diagnosis is difficult to generate. Another gyrate erythema, erythema annulare centrifugum (EAC), demonstrates polycyclic erythematous rings with a trailing edge of scale.
Similarly, this eruption can be pruritic. Unlike EGR, EAC migrates slowly and is usually localized to smaller areas on the trunk and extremities [11,16] (Figure 2  interferon, minoxidil, phenytoin, spironolactone, and cetuximab) [1,20]. An extensive clinical history and physical examination are necessary, in conjunction with blood tests, laboratory screening, and imaging (chest radiography, CT, colonoscopy, and, in women, mammography) [1]. Pathogenesis of AHL is unclear. Prolongation of the anagen phase of vellus hairs by a tumor-induced serum growth factor has been hypothesized [1,10].

Ichthyosis Acquisita
Ichthyosis acquisita is a cutaneous keratinization disorder, characterized by small white or brownish rhomboidal scales that rise above the skin surface, particularly localized symmetrically on the extensor surfaces of the extremities and on the trunk and scalp. The dry scales may be also thickened and widespread [13]. Flexures, palms, and soles are spared [21].
It has been suggested that TGF-α secreted from the tumor cells, may be implicated in the pathogenesis [22]. Treatment of ichthyosis includes removal of exacerbating factors and of related systemic diseases, as well as applying moisturizers and keratolytics [13].

P a t i e n t s o f t e n m a n i f e s t p i t y r i a s i s r o t u n d a ( P R )
between 20 and 45 years of age (range of 2 to 89) [23], except among the Sardinian cohort, in which patients presented during childhood [24]. Incidence is equal among men and women. The disease lasts from several months to more than 20 years, with reports of exacerbation during winter months [25]. PR is a rare disease characterized by round or oval, well-defined, scaly, hypo-or hyperpigmented patches or thin plaques typically found on the trunk, back, buttocks, or arms, but that can occur in every area of the body. Lesions number ranges in number from 1 to over 100, and the diameter from 1-10 cm. The hands, feet, and face are usually spared. Lesions are asymptomatic but may be associated with minimal pruritus [13]. NME is typically associated with glucagonoma syndrome.
A CT scan may be useful in the diagnosis. About 95% of glucagonomas are positive in somatostatin receptor scintigraphy. Somatostatin positivity may be useful in the treatment of the symptoms and signs of glucagonoma (octreotide, a somatostatin analogue, inhibits glucagon production) [1].
Celiac arteriography is considered most sensitive to locate the tumor because of its vascularity [10].
Histological findings of NME are nonspecific (edema and

Acquired Hypertrichosis Lanuginosa
Acquired hypertrichosis lanuginosa (AHL) is a rare paraneoplastic condition characterized by the sudden appearance of long, thin, soft, unpigmented, lanugo-like hair initially on the face and ears and then on the trunk, axillae, and extremities, with sparing of the palms, soles, and genital area [2]. It is more common in women than in men. Other symptoms are painful glossitis, angular cheilitis, and papillary hypertrophy of the tongue [2,20].
In men, AHL is most commonly associated with lung cancer, followed by colorectal cancer. In women, the most common neoplasms are, in order of frequency, colorectal cancer, lung cancer, and breast cancer. However, AHL has also been described in association with other cancers (ovary, uterus, bladder, pancreas, kidney, lymphomas, and leukemia) [2,20].
AHL must be differentiated from hypertrichosis associated with endocrine or metabolic alterations and use of medication (cyclosporine, penicillamine, glucocorticoids, ing [1]. The diagnostic criteria for PNP can be distinguished into major criteria and minor criteria (

Conclusions
Skin, being the most visible and external organ of the body, may be considered as a mirror for many systemic diseases [7].
It is of utmost importance for the dermatologist to recognize the major cutaneous paraneoplastic syndromes to diagnose the underlying tumors that trigger them as early as possible.
One-third of patients have an underlying disease, including tuberculosis, leprosy, and liver, kidney, heart, and lung diseases. Associated neoplasms include hepatocellular, gastric and esophageal carcinoma, prostate cancer, chronic lymphocytic leukemia, and multiple myeloma [1].
PR has been classified into 2 distinct subtypes. Lesions are typically hypopigmented and more numerous. Type 2 PR is often self-limiting and improves through adulthood [26]. PR can be treated with retinoids, salicylates, or lactate emollients.

Paraneoplastic Pemphigus
Paraneoplastic pemphigus (PNP) is a severe acantholytic mucocutaneous syndrome characterized by painful mucosal erosions, ulcerations, and polymorphous skin lesions that progress to blistering eruptions on the trunk and extremities [27,28]. Oral involvement with persistent, painful stomatitis is seen in almost all cases and can often be the first symptom.
Oral lesions may be severe, and affect the entire mouth, with diffuse areas of shallow ulceration, and lips, with hemorrhagic crusting, and also the hypopharynx and esophagus; they may also involve other mucosa (conjunctival and anorectal) with ulcers and erosions. Contrary to pemphigus vulgaris, acral and paronychial involvement is common in PNP. Cutaneous manifestations can be classified in several groups: (1) pemphigus-like, (2) bullous pemphigoid-like, (3) erythema multiforme-like, (4) graft-versus-host disease, and (5) lichen planus-like [27,28].
The prognosis of PNP is severe. Some patients have respiratory complications, such as bronchiolitis obliterans, responsible for dyspnea and respiratory failure. The high mortality rate of PNP (75%-80%) is also secondary to sepsis and bleed-