Cutaneous manifestations of internal malignancy.

BACKGROUND: Many malignancies affecting the internal organs display cutaneous manifestations which may be either specific (tumor metastases) or nonspecific lesions. AIMS: The study is aimed at determining the frequency and significance of cutaneous manifestations among patients with internal malignancy.
MATERIALS AND METHODS: 750 cases of proven internal malignancy, who attended a cancer chemotherapy center in South India, were studied. Specific infiltrates were confirmed by histopathology, fine needle aspiration cytology (FNAC) and marker studies.
RESULTS: Out of the 750 patients with internal malignancy, skin changes were seen in a total of 52 (6.93%) patients.
CONCLUSION: Cutaneous metastases (specific lesions) were seen in 20 patients (2.66%): contiguous in 6 (0.8%), and non-contiguous in 14 (1.86%). Nonspecific skin changes were seen in 32 patients (4.26%). None of our patients presented with more than one type of skin lesions. Herpes zoster was the most common nonspecific lesion noticed in our patients, followed by generalized pruritus, multiple eruptive seborrheic keratoses, bullous disorder, erythroderma, flushing, purpura, pyoderma gangrenosum, insect bite allergy and lichenoid dermatitis.

Introduction

Cutaneous metastasis from an internal malignancy is rare and it indicates the later stage. Malignancies which affect internal organs may display cutaneous manifestations, which may be the presenting symptoms and signs of the underlying malignancy.

The aims of the study were to determine the frequency and significance of cutaneous manifestations of internal malignancies among the patients attending a cancer chemotherapy center.

Materials and Methods

Seven hundred and fifty patients with internal malignancies involving various organs, attending the Cancer Chemotherapy Department of Government General Hospital, Chennai, were recorded for a period of 3 years from 2005 to 2008. In our Institution, during the study period, it was not considered mandatory to obtain approval of Ethical Committee for conducting clinical study, and hence it was not obtained.

Data regarding history about the duration of the malignancy and the duration between the onset of malignancy and the skin changes, relapse of malignancy and the symptoms of cutaneous lesions were obtained. Clinical examination including the cutaneous and systemic examination, hematological, radiological and cytological investigation was done to confirm the nature and site of malignancy. Histopathology of the cutaneous lesions, suggestive of metastasis from an internal organ, was obtained. Fine needle aspiration cytology (FNAC) and T cell marker studies were done wherever necessary.

Results

Out of the 750 patients studied, 52 (6.93%) had cutaneous manifestations, 20 (2.66%) had cutaneous metastases (specific lesions) and 32 (4.26%) had nonspecific skin lesions.

65% were males and 35% were females. The most common age group affected was in fifth and sixth decades of life. Overall, the most common malignancies were leukemia and lymphomas (19.2%), followed by carcinoma breast (13.46%), carcinoma stomach (11.5%), carcinoma cervix (5.76%), carcinoma of the prostate (5.76%) and carcinoma of the buccal mucosa (5.76%). The other malignancies encountered in our study in descending order of frequency were malignant melanoma, seminoma, carcinoma esophagus, carcinoma pharynx, hepatocellular carcinoma, astrocytoma, pheochromocytoma, secondaries in the neck with unknown primary.

In males, non-Hodgkin's lymphoma (NHL) (26.47%) [Figure 1] was the most common malignancy producing skin lesions, followed by leukemias (14.7%) and carcinoma stomach (14.7%).

Figure 1

A case of non-Hodgkin's lymphoma having inguinal nodes and skin-colored nodules over chest and abdomen

In females, the most common malignancy was carcinoma breast (38.88%) [Figures 2a, b], followed by leukemia (27.77%), carcinoma cervix (16.66%), NHL (5.55%), carcinoma stomach (5.55%) and astrocytoma (5.55%).

Figure 2

(a) Metastatic carcinoma breast showing multiple nodules and papules following surgery. (b) CA breast (right) with ulcerative plaque eroding nipple and areola

Of the specific skin infiltrates, contiguous cutaneous metastases were seen in 6 (11.53%) patients and non-contiguous metastases in 14 (26.92%) patients [Tables 1 and 2]. Skin-colored nodules were the most common, followed by erythematous and hyperpigmented papules and plaques.

Table 1

Contiguous metastases

Table 2

Non-contiguous metastases

Of the nonspecific lesions, herpes zoster was the most common (11 patients) followed by generalized pruritus, multiple eruptive seborrheic keratoses, bullous disorders, erythroderma, flushing, purpura, systemic lupus erythematosus, pyoderma gangrenosum, insect bite allergy and lichenoid dermatitis.

Discussion

Skin often mirrors changes in the internal milieu. Skin metastases may herald the recurrence of malignancy after treatment. Cutaneous metastasis can arise at any age. However, most cutaneous metastases occurred during or after the fifth decade as in the present study.[1] The period of interval between the onset of symptoms of the primary malignancy and the onset of cutaneous metastases ranged from 2 months to 5 years. The shortest duration was 2 months in the case of acute myleoid leukemia and the longest was 5 years in the case of carcinoma breast.

Cutaneous metastatic lesions are usually multiple and may range from 1 to 100.[2] In our study, 5 out of 6 cases with contiguous metastases and 11 out of 14 cases of non-contiguous metastases had multiple lesions. Skin-colored nodules at multiple sites were the most common clinical presentation of cutaneous metastases. We also encountered plaques, papules, and ulcers in decreasing order of frequency. The site of localization of metastasis depends upon mode of spread of the primary tumor, whether it is by lymphatics or hematogenous.

The common malignancies that give rise to cutaneous metastases are carcinoma of the lung and colon in males and carcinoma of the colon and ovary in females. Overall, melanomas are the most common, followed by carcinoma breast, carcinoma oral cavity, lungs, colon, and ovary.[3] In this study, NHL was the most common neoplasm to produce cutaneous metastases, followed by carcinoma breast and leukemia. However, this observation could not be taken as actual reflection of prevalence in South India, as our hospital is a tertiary referral center.

Contiguous spread was more common in females (66.6%) than males (33.3%), while non-contiguous metastases were more common in males (85%) than females (15%). This difference could be because the malignancy encountered in both sexes is different.

In the present study, carcinoma breast was the most common (66%) neoplasm causing direct extension to skin, followed by carcinoma buccal mucosa and amelanotic melanoma [Figures 3a, b]. This finding corroborates with the literature reports.[4] NHL was the most common neoplasm to produce non-contiguous metastases, followed by gastrointestinal malignancies (28.5%) [Figure 4a, b] and leukemia (21.4%), especially acute myeloid leukemia. The most common sites involved by cutaneous metastases in their order of occurrence were as follows:

Figure 3

(a, b) Amelanotic melanoma over right cheek with multiple nodules over neck

Figure 4

(a) A case of carcinoma stomach showing a single nodule over neck. (b) Histopathology of the nodule shows collection of atypical epithelial cells in upper dermis

Anterior chest wall, anterior abdominal wall, lower limb, neck, back, upper limb, face, pelvis, scalp.

This finding corroborates with similar findings reported by Brownstein et al.,[3] Rajagopal et al.[5] and Tharakaram[6] [Table 3].

Table 3

Comparison of sites of cutaneous metastases

Among the nonspecific skin manifestations with internal malignancy, herpes zoster (27%) came first. Carcinoma breast was the most common malignancy associated with herpes zoster, while carcinoma cervix (18%) was the second. Among 11 patients, 6 had single dermatomal involvement, 2 had disseminated and 3 had multidermatomal involvement. According to literature, disseminated herpes zoster is commonly associated with underlying malignant disease.[7]

We encountered paraneoplastic pemphigus in two patients. One of them had NHL which was reported as the most common neoplasm associated with paraneoplastic pemphigus in a study by Anhalt et al.[8] The other patient had paraneoplastic pemphigus in association with secondaries in the neck. In this patient, FNAC of the neck showed atypical squamous cells. Both the patients expired. Skin manifestation as the first sign of internal malignancy was noted in another two patients. One of them was a case of hepatocellular carcinoma presenting with pruritus. Another was an elderly man who presented with erythroderma and was diagnosed to have Sézary syndrome on further systemic examination and investigations. One of our patients with carcinoma prostate developed bullous pemphigoid which is also reported in the literature.[4] In the present study, generalized pruritus was noticed in three patients with hepatocellular carcinoma, polycythemia vera and carcinoma stomach. Pruritus was observed as a common manifestation among patients with internal malignancy compared to controls in the study by Rajagopal et al.[5] Three patients had multiple eruptive seborrheic keratoses and the most common malignancy associated was carcinoma stomach which corroborates with the literature reports.[4] We encountered a patient with pronounced flushing involving the face and chest, associated with pheochromocytoma, and similar association is reported in literature.[4] A known case of acute myeloid leukemia presented with purpura, which is a well-known association.[4]

Survival period in patients with cutanenous metastasis is said to be around 3 months.[9] Early death in these patients could be due to undetected secondaries in visceral organs and high-grade malignant nature of the primary tumor. In our study, 23 out of 52 patients (44%), were lost to follow-up, and among the remaining 29 patients, 13 (44%) succumbed to their illness during the study period. Seven patients (54%) showing specific cutaneous metastasis expired in the period of 2–6 months, whereas 6 patients (37%) showing nonspecific cutaneous changes expired during the period of 14 days to 8 months [Table 4].

Table 4

Period of survival

Shortest survival period (2 months) was seen in a patient who had a recurrence of NHL. Two patients with carcinoma breast, who developed recurrence of malignancy after surgery, expired in 4 months and 6 months, respectively. Shortest survival period in patients showing nonspecific cutaneous metastases was 14 days in a patient with hepatocellular carcinoma. Both the paraneoplastic pemphigus patients expired within 6 months and 8 months, respectively.

Conclusion

Cutaneous metastases indicating a sign of recurrence and widespread metastases have poor prognosis and the survival period is reduced. Though the skin is an infrequent site for metastasis and is only the 18th most common site, skin lesions offer easily accessible tissue for biopsy and histopathologic examination.[10] Systemic response to any particular chemotherapeutic agent can be assessed by the visible regression of skin metastasis. Cutaneous metastases are important to recognize because they may precede internal visceral metastases and early recognition helps in prolonging the survival of the patient.