The field of dermatology extensively overlaps that of oncology, although dermatologists are not often charged with cancer detection other than that of the skin. Although dermatologists have long managed the cutaneous adverse effects experienced by most patients treated from systemic cancers, they can also be a primary detectors of paraneoplastic manifestations of cancers originating from other major organ systems.

Since 2010, when a spate of publications addressed paraneoplastic manifestations, dermatology has been recognized as having a primary role in identifying and potentially arresting multiple cancers types before they reach later, often untreatable, stages.

Paraneoplastic diseases are generally defined as clinical disorders that manifest in association with the presence of underlying malignancies, but without direct association to a primary tumor or metastases. Since 1868, when it was first suggested that hyperpigmentation of the skin might be a sign of undetected malignancy, more than 50 dermatoses have been identified as possible cancer markers.1,2 The dermatalogic manifestations are not themselves malignant; they appear benign and are extremely heterogenous in presentation and are, therefore, often ignored by patients and clinicians.


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The main criteria for identifying paraneoplastic dermatoses are2:

  • onset before or near the beginning of the neoplasia
  • specific dermatosis aligns with a specific tumor
  • parallel of the tumor course
  • is not part of any genetic syndrome
  • cutaneous condition is rare
  • high-grade association with the tumor

Paraneoplasias involving the skin are particularly important to aiding in cancer detection and improving outcomes. As skin is readily accessible and can be examined often without invasive procedures, the signs are likely to be detected earlier by patients, and often with routine dermatologic care. Cutaneous lesions also tend to appear quite early in a neoplastic process before the formation of a tumor, although clinical manifestations may also be delayed and appear concurrent with diagnosable malignancies.2-4

Cutaneous Paraneoplastic Manifestations

Acanthosis Nigricans (AN)

A recognized sign of malignancy that in a more common benign form is associated with the presence of metabolic disorders such as insulin resistance and obesity, AN typically develops suddenly in people over 40 years of age as a large symmetrical area of hyperpigmentation.1,2, The neck is the most common site, and AN quickly evolves into hyperkeratonic plaques and often acronchordons.2 It is most commonly associated with tumors of the gastrointestinal system, as well as carcinomas of the lung, kidney, bladder, ovaries, pancreas, and mycosis fungiodes.5 The skin signs appear before the tumor in about 20% of patients, simultaneously in 60%, and after cancer diagnosis in the remaining 20%.4

Erythema Gyratum Repens (EGR)

In this rare condition, the skin develops migrating erythematous bands, giving a wood-grained patterned appearance that may cover much of the trunk and proximal extremities.4 ERG is seen more commonly in men than women, at an average age of 63 years and is largely indicative of cancer.1 It is most commonly associated with malignancies of the lung, esophagus, breast, and other sites, but may also accompany cystic hypertrophy of the breast and pulmonary tuberculosis.1,4

Leser-Trélat Sign (LTS)

The appearance of multiple seborrheic keratoses on the thorax and dorsum, occurs often before, after, or at the same time as a diagnosis of gastrointestinal malignancy and pancreatic cancer and lymphoma.2,4 LTS occurs equally in men and women of all ethnicities, and at an average age of 61 years.1 Because keratoses are benign and a common occurrence in older people, it is often ignored.1,4 It has been recommended that “all patients with LTS should be screened for neoplasms.1

Necrolytic Migratory Erythema (NME)

Characterized by a pinkish annular or arciform lesions with irregular edges that assemble into a polycytic pattern, NME represents the earliest signs of glucagonoma, an endocrine tumor of the pancreas with a high secondary risk of thromboembolism.1,4 Less commonly, NME may be associated with small cell lung cancer, liver cancer, insulin-secreting tumors, and duodenal cancers. The lesions appear on the trunk including the abdomen, perineum, thighs, buttocks, and groin, but also on the perioral region and the nails. The disorder is believed to be caused by deficiencies in zinc, amino acids, and essential fatty acids that are alternatively implicated in liver failure, inflammatory bowel disease, celiac disease, and other malabsorption syndromes.4

Paraneoplastic Pemphigus (PNP)

PNP,a rare skin condition involving severe blistering of the mucus membranes, most often affects men and women aged 45 to 70 years.2 The mouth is always affected, but other regions including the lips, oropharynx, nasopharynx, conjunctivae, anogenital region, and esophagus may also be affected, after which cutaneous lesions may appear. Nearly 84% of patients with PNP  have concurrent hematologic malignancies including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, Castleman’s disease, and thyoma, which are often detected as a result of the clinical appearance of the dermatosis.

Sweet’s Syndrome (SS)

The sudden occurrence of erythematous, painful plaques and nodules on the upper body, particularly the face, trunk and limbs, and usually accompanied by fever and leukocytosis, defines SS. SS is associated with malignancies in 10% of patients, including leukemia, hairy cell leukemia, mylodysplastic syndrome, adenocarcinomas of the breast, genitourinary, and gastrointestinal tract, and solid tumors of the bladder, prostate, and cervix.2,4

Summary

Careful evaluation of dermatoses of the skin are important to the early detection of many systemic forms of cancer. Familiarity with cutaneous manifestations of internal malignancies can hasten diagnosis and improve treatment outcomes of associated cancers. As such, dermatologists can play a significant role in identifying important clinical markers that often present before diagnosis of neoplasms.

References

1. da Silva JA, Mesquita Kde C, Igreja AC. Paraneoplastic cutaneous manifestations: concepts and updates. An Bras Dermatol. 2013 Jan-Feb;88(1):9-22. doi: 10.1590/s0365-05962013000100001.

2. Didona D, Fania L, Didona B, Eming R, Hertl M, Di Zenzo G. Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis. Int J Mol Sci. 2020 Mar 21;21(6):2178. doi:10.3390/ijms21062178.

3. Yuste-Chaves M, Unamuno-Pérez P. Cutaneous alerts in systemic malignancy: part I. Actas Dermosifiliogr. 2013 May;104(4):285-98. English, Spanish. doi:10.1016/j.adengl.2012.03.027.

4. Wick MR, Patterson JW. Cutaneous paraneoplastic syndromes. Semin Diagn Pathol. 2019 Jul;36(4):211-228. doi:10.1053/j.semdp.2019.01.001.