Review of Mucocutaneous Paraneoplastic Syndromes
PNP is an example of a mucocutaneous paraneoplastic syndrome (MCPS). These syndromes comprise a group of dermatoses that exhibit variable morphology, pathology, and etiology, and that may be associated with solid tumors or hematological malignancies. Here we focus on the MCPS associated with hematological malignancies (Table 2). We have organized our discussion of these syndromes using the schema proposed by Cohen and Kurzrock in 1997; this classification of MCPS is based on the predominant pathological change and includes the following categories: dermal depositions, neutrophilic dermatoses, papulosquamous disorders, proliferative reactions, reactive erythemas, vacuolar degeneration of the basal layer, vasculitis, and vesiculobullous disorders.
Amyloidosis is characterized by purpura, papules, hyperpigmentation, macroglossia, tongue papules, periocular purpura, and alopecia. The papules are formed from dermal depositions of immunocyte amyloid. Of patients with primary amyloidosis, 13% to 26% have or will develop multiple myeloma. A biopsy of clinically involved skin will yield a diagnosis in almost 100% of patients. Paraneoplastic amyloidosis carries a poor prognosis, with a mean survival of less than 1 year.
Pyoderma gangrenosum and Sweet syndrome are paraneoplastic dermatoses that are associated with hematological malignancy. Infiltration of the dermis by mature neutrophils is the key pathological change in these syndromes. Pyoderma gangrenosum starts as a painful papule or pustule that develops into a nodule; this then ulcerates and forms violaceous borders with purulent exudates and a necrotic base. Bullous or atypical pyoderma gangrenosum is associated with an underlying hematological malignancy (acute myelogenous leukemia, myelodysplasia, myeloproliferative disorders, and multiple myeloma) in 7% of cases. Treatment is aimed at the underlying malignancy; systemic corticosteroids have also been efficacious.
Paraneoplastic Sweet syndrome is most commonly associated with acute myelogenous leukemia, but it has also been reported with solid tumors of the genitourinary organs, the breast, and the gastrointestinal tract. Much as with idiopathic Sweet syndrome, manifestations may include erythematous, painful, raised cutaneous plaques that occur primarily on the upper extremities, face and neck; pyrexia; neutrophilia; and a variety of extracutaneous findings. Cytopenias and immature cells in the peripheral blood may be seen with paraneoplastic Sweet syndrome. It is thought to be secondary to hypersensitivity, and many patients respond promptly to corticosteroid therapy.
Papulosquamous disorders are characterized by large (plaques) and small (papules) raised skin lesions. This type of paraneoplastic dermatosis is commonly seen in the setting of solid tumors; however, acquired ichthyosis and pruritis have been reported in patients with hematological malignancies.
Acquired ichthyosis involves the skin of the extensor surfaces of the extremities and the trunk. The keratinized skin lesions are rhomboid scales with free edges. Ichthyosis is most commonly seen in male patients with Hodgkin lymphoma, but it has been described in patients with carcinoma of the breast, lung, or cervix; Kaposi sarcoma; leiomyosarcoma; and multiple myeloma. The diagnosis is made with a skin biopsy, which demonstrates hyperkeratosis with a decreased or absent granular layer, similar to what is seen in inherited forms of ichthyosis vulgaris. The paraneoplastic skin lesions tend to parallel the course of the underlying neoplasm, so the best treatment is that aimed at the underlying malignancy. Topical lubricating agents and keratolytics are generally only helpful with symptom control and not with lesion regression.
Pruritis of unknown origin is a persistent, daily itchiness that can lead to excoriations, prurigo nodularis, and lichen simplex chronicus. An underlying malignancy is the etiology in 11% of pruritis patients. Polycythemia vera is the malignancy most commonly associated with pruritus, followed by Hodgkin lymphoma, cutaneous T-cell lymphoma, Sézary syndrome, leukemia, and a variety of solid tumors. In 40% of patients with meningioma, astrocytoma, and cerebral glioma, pruritis localized to the nares is seen.
Reactive erythemas are a group of skin conditions that are characterized by red skin, which may appear as flat macules and patches, expanding annular lesions, or erythema with marked scaling. Erythroderma and exfoliative dermatitis is associated with malignancy in 8% to 23% of cases. It is most often linked to lymphoma (cutaneous T-cell and Hodgkin) or leukemia, but it has also been seen in cases of cancer of the uterus, lung, stomach, prostate, thyroid, liver and larynx. The manifestations can include generalized erythema with or without scaling, alopecia, nail dystrophy, lymphadenopathy, pruritis, fever, eosinophilia, and leukocytosis. Skin changes are typically seen prior to the diagnosis of malignancy. Repeat skin biopsies are likely, since the findings are frequently nonspecific, but biopsy specimens can show a dense perivascular lymphocytic infiltrate. It is thought that the interactions of cytokines with cellular adhesion molecules are related to the formation of erythroderma. Treatment is targeted at the underlying malignancy, since the course of erythroderma parallels the course of the malignancy. Lukewarm soaks, narrow-band ultraviolet B (UVB) phototherapy, topical emollients and corticosteroids, as well as antihistamines, are also indicated.
Erythromelalgia is another paraneoplastic reactive erythema. Adult-onset erythromelalgia is related to a myeloproliferative disorder with thrombocytosis in 20% of cases, and its onset is generally several months prior to the diagnosis of malignancy. Erythromelalgia is defined by severe attacks of burning pain, erythema, and warmth of the distal extremities that can be relieved by cold exposure and/or elevation of the extremities. As a consequence of intravascular platelet activation and aggregation, the distal arterioles become occluded, which is why a daily 500-mg dose of acetylsalicylic acid can alleviate symptoms.
Inflammation of blood vessels, which may lead to necrosis, defines vasculitis. The most common paraneoplastic vasculitis is leukocytoclastic vasculitis. Associated cutaneous lesions are polymorphous and include nonblanchable purpura, erythematous papules and nodules, ulcers, and pruritic plaques. Patients may also present with abnormal blood counts, lymphadenopathy, splenomegaly, and joint involvement. Approximately 18% of patients have an underlying malignancy. Leukocytoclastic vasculitis involves the small vessels of the upper dermis, and it is associated with hairy cell leukemia, chronic myelogenous leukemia, myeloma, lymphoma, myelodysplastic syndrome, and non–small-cell lung cancer. Skin biopsies demonstrate leukocytoclasia, endothelial swelling, fibrinoid necrosis of the vessels, and extravasation of erythrocytes into the surrounding dermis. Paraneoplastic vasculitis tends to mirror the state of the underlying malignancy, so initial treatment should target the driving process. Improvement has also been seen with the use of methylprednisolone(Drug information on methylprednisolone), prednisone(Drug information on prednisone), dapsone, colchicine(Drug information on colchicine), methotrexate(Drug information on methotrexate), azathioprine(Drug information on azathioprine), and IVIg; however, patients who are over 50 years of age and who present suddenly do not tend to respond to therapy.
While the primary cutaneous lesions in vesiculobullous disorders are blisters, the appearance of these disorders is varied. PNP typically resembles erythema multiforme, with polymorphous pruritic papules and blisters as well as painful cutaneous and mucosal erosions. The details of PNP are described in the above case report. Pemphigus vulgaris, on the other hand, manifests as large intraepidermal bullae of the skin with oral blisters and erosions, and pemphigus foliaceus is characterized by superficial crusted erosions.
Pemphigus vulgaris has been reported in patients with Hodgkin and non-Hodgkin lymphoma, Kaposi sarcoma, chronic lymphocytic lymphoma, breast cancer, and thymic cancer. The palms and soles are typically not involved in paraneoplastic pemphigus vulgaris, which helps to distinguish this syndrome from PNP. The treatment of pemphigus vulgaris is similar to that of PNP in that a wide variety of immune-modulating agents have been utilized with varying effect.
Mucocutaneous paraneoplastic syndromes can occur before, after, or at the time of the cancer diagnosis; they can also be idiopathic entities. It is our job as physicians to recognize these conditions and to screen for a new or recurrent malignancy when they are identified. Prompt treatment of any underlying malignancy provides the patient with the best chance for improvement in most MCPS—except for PNP, which does not tend to mirror the neoplastic process. Overall, the presence of a MCPS is associated with a poor prognosis. As the general population lives longer and more cancers are diagnosed, it can be expected that the incidence of paraneoplastic conditions will increase.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.