Skin signs: Internal disease can be associated with cutaneous symptoms

January 8, 2010

Bethesda, Md. ? The skin is the window to the body and often, internal disease processes can be associated with cutaneous symptoms. A number of cutaneous signs are linked to internal malignancies and the timely recognition of these signs and their associations with either genodermatoses or paraneoplastic syndromes can significantly impact the prognosis and treatment of patients.

Bethesda, Md. - The skin is the window to the body and often, internal disease processes can be associated with cutaneous symptoms. A number of cutaneous signs are linked to internal malignancies and the timely recognition of these signs and their associations with either genodermatoses or paraneoplastic syndromes can significantly impact the prognosis and treatment of patients.

“Though reaching the proper diagnosis of cutaneous manifestations is routine for dermatologists, it can sometimes prove to be challenging to link skin signs with internal disease. Often, employing clinical guidelines such as Curth’s postulates can help the physician in this regard,” says Edward W. Cowen M.D., M.H.Sc., of the dermatology branch at the National Cancer Institute, Bethesda, Md.

The list of paraneoplastic syndromes and genodermatoses that are associated with internal malignancies is long and can sometimes be overwhelming for the clinician. Curth’s postulates are a series of criteria which may serve as a guide for physicians to better gauge and evaluate whether or not cutaneous manifestations are potentially linked to internal findings. These postulates include a concurrent onset of cutaneous manifestations and internal malignancy, a parallel disease course, a uniform neoplasm (site or cell type) that is associated with that skin sign and a statistical as well as a genetic association of symptoms.

As the diagnosis implies, malignant acanthosis nigricans (MAN) is associated with internal malignancy. Leser-Trélat syndrome (eruptive seborrheic keratoses), tripe palms and florid cutaneous papillomatosus (likely a severe variant of MAN) are other paraneoplastic syndromes that may present in association with MAN. Both MAN and Leser-Trélat typically occur in an older patient population and characteristically have a sudden clinical onset. MAN is most closely linked to intra-abdominal malignancy, particularly gastric malignancy. Leser-Trélat syndrome is most frequently associated with GI adenocarcinoma and lymphoproliferative diseases.

According to Dr. Cowen, dermatologists should also have a heightened awareness of certain benign skin lesions and think about the associations they may have with internal malignancies.

Birt-Hogg-Dubé (BHD) syndrome is characterized by fibrofolliculomas, trichodiscomas and acrochordons. According to Dr. Cowen, approximately 15 percent to 30 percent of the patients with this syndrome will develop renal neoplasias.

“Skin tags are a common skin finding in the general population and therefore, are not useful for identification of patients with BHD. In addition, skin biopsies of pedunculated papules resembling acrochordons may reveal histologic features of fibrofolliculoma. Therefore, it is the diagnosis of fibrofolliculoma or trichodiscoma, which should prompt further evaluation for BHD. Making this association can prove invaluable in the timely diagnosis and treatment of the potential underlying renal malignancy” Dr. Cowen says.

Hereditary leiomyomatosis is another genodermatosis that can be associated with renal cell cancer. According to Dr. Cowen, there is still uncertainty in the dermatologic community about how to evaluate a patient who presents with multiple cutaneous leiomyomas. Patients with hereditary leiomyomatosis harbor a mutation in the fumarate hydratase gene, which is associated with an aggressive form of renal cell cancer. Although the risk of renal cell cancer is considered low, it remains unclear which patients who present with cutaneous leiomyomas will also develop renal cell cancer. Nevertheless, dermatologists should be aware of this disease association and a careful follow-up of patients presenting with leiomyomas is warranted because of the mortality associated with this form of renal cell cancer.

Genetic analyses done in a past study in a group of randomly collected patients who presented with multiple cutaneous leiomyomas found that the majority of these patients harbored mutations in the fumarate hydratase gene.

“We do not know the actual prevalence of renal cell cancer in this population however, now that we have identified the gene and its definite link to renal cell cancer, this is an important association that dermatologists need to aware of and consider. Dermatologists should take a careful family history, perform a complete skin exam and consider whether genetic counseling would be appropriate in this patient population,” Dr. Cowen tells Dermatology Times.

Though helpful, Curth’s postulates do have their limitations, particularly for genodermatoses. According to Dr. Cowen, the skin manifestations seen in genodermatoses often do not present in the same temporal sequence as paraneoplastic skin disease. The cutaneous leiomyomas in leiomyomatosus, for instance, may present years before the patient actually develops renal malignancy. Therefore, concurrent onset and parallel disease course are two postulates that do not necessarily hold true in all settings and scenarios. Nevertheless, Dr. Cowen said that Curth’s postulates do prove to be very helpful to clinicians and despite the rarity of paraneoplastic syndromes, it behooves the dermatologist to be aware of the cutaneous manifestations that are associated with them.

“Dermatologists can play an important role in detection of an internal malignancy as well as determining the potential that a patient may have for a future underlying malignancy. A thorough skin and physical examination as well as a careful history may allow them to make a more complete diagnosis for their patients,” Dr. Cowen says.

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