Skin is the largest organ of the human body, with a total area of approximately two square meters.1 The skin also serves as a site for the manifestation of systemic conditions for which specific and non-specific histo-morphological characteristics can be identified. Metastases are defined as neoplastic lesion arising from another neoplasm with which it is no longer in contiguity or in close proximity with the same tissue.2 Cutaneous metastases (CMs) are rare as compared to other organs such as liver, lungs and bones. The reported incidence of cutaneous metastasis varying from 0.7 to 10 % of all patients with cancers, excluding leukemia and lymphoma.3,4 They are usually seen in advanced disease but may represent the first sign of internal malignancy and can be difficult to diagnose without perceptive observatory skills.3,4,5 Cutaneous metastases can be classified into three distinct groups, based mostly on the mechanism of invasion. Thus, tumoral cells can affect the skin by contiguity, by lymphatic, or by hematogenous spread.6,7 The first and largest group represents cutaneous metastases originating from primary cutaneous malignant tumors, such as primary skin melanoma, squamous cell carcinoma, Merkel cell carcinoma, and adnexal carcinomas. The second group is the metastases of internal malignancies. The last group is manifestations of systemic hematological neoplasms (leukemia and lymphomas) in the skin.8 CMs has various clinical presentations; diagnoses can be easily overseen as CMs can mimic other dermatologic diseases. They usually present as single or multiple nodules,4 but other variants such as inflammatory or erysipeloides carcinoma, telengiectatic and “en cuirasse”, alopecia neoplastica,9 and zosteriform10 pattern especially in breast carcinoma are also reported. The presence of cutaneous metastases represents a grave prognostic sign with a median survival of 7.98 months; approximately 74% of patients present with concomitant visceral metastases.11 It is essential to establish a prompt diagnosis to ensure early treatment; hence, clinical recognition and skin biopsy of the suspicious lesions are crucial. While several case reports and small series exist in the literature, there are only a few cohort-based analyses concerning this topic. This study aims to evaluate the clinic-morphological features of cutaneous metastases of internal neoplasms, diagnosed in Department of Dermatology of an academic hospital in North India, and to examine the diagnostic challenges. Aims and objectives The aim of this study was to examine the incidence and characteristics of cutaneous metastases of internal malignancies.

A prospective study was conducted on patients diagnosed with internal malignancy attending the outpatient department of Dermatology and Regional Cancer Treatment and Research Center, Rajasthan, India over a period of one year. A total of 1000 patients were consecutively included in this study. Physical and dermatological examinations were performed on all the patients. Skin biopsies and histopathological examinations were performed from suspected lesions. The patients were followed up until their biopsy results were obtained. Photographs of lesions were also taken. Patients with malignant melanomas, squamous cell carcinomas, primary cutaneous T-cell lymphomas, basal cell carcinomas and other primary cutaneous malignancies were excluded from the study. Master chart was made from the details recorded on the proforma by using Microsoft excel. The type of malignancy, the time of diagnosis of the malignancy, the period between the appearance of the primary malignancies and cutaneous metastases were obtained from the records. The clinico-morphological presentation and localization sites of cutaneous metastases were also noted.

A total of 1000 patients with internal malignancies were evaluated: age of the patients ranged between 3-85 years. Maximum number of patients was above 40 years of age. 523 (52.3%) were female and 477 (47.7%) were male. A total of 27 types of malignancies were found in all patients which were classified under eight groups, as shown in figure-1. Genito-urinary carcinomas were the most common malignancy in 293 (29.3%) patients, followed by hematological malignancies in 207 (20.7%) patients, carcinoma breast in 204 (20.4%) and carcinomas of head and neck region in 172 (17.2%) patients. In males, commonest malignancy was hematological in 189 (18.9%) patients, followed by carcinoma of head and neck region in 153 (15.3%) patients and Broncho-pulmonary carcinomas were found in 61 (6.1%) patients. Commonest malignancy in female was Genito-urinary carcinomas in 257 (25.7%) and carcinoma breast in 204 (20.4%) patients. Cutaneous Metastases were seen in 16 (1.6%) of all cases with malignancies. The internal malignancies underlying cutaneous metastases are listed in figure 2 & table 1. Cutaneous metastases were most frequently (2.6%) seen in cases with carcinoma breast. When studied with respect to gender, cutaneous metastases were most frequently observed in breast cancer in females and hematological malignancies in males. Five of 16 cases (31.25%) with cutaneous metastases had also internal metastases. There were 3 cases of metastatic nodules manifesting as presenting sign of internal malignancy. First was in the case of carcinoma breast where multiple hard nodules were present over inferior quadrant of left breast. Second case was also of breast carcinoma presented with hard nodulo-ulcerative plaque over right anterior chest wall. The third case was of carcinoma of testis, which presented as hard subcutaneous nodules over neck whereas all other cases were found 1-9 months after the diagnosis of internal malignancy. Internal malignancy and cutaneous metastasis were diagnosed concurrently in one patient with bilateral breast cancer which presented as carcinoma en cuirasse. Clinico-morphological data of cutaneous metastases (biopsy proven) are shown in table-2. Out of 16 patients, 9 (56.2%) patients showed contiguous metastases from underlying carcinoma while 7 (43.75%) patients had non-contiguous metastases occurring at a distant site. Most common site of cutaneous metastases was anterior chest wall in 6 (37.5%) cases. Nodules and nodulo- ulcerative plaques were the most frequent presentation (table-2). The period between the diagnosis of internal malignancy and cutaneous metastases varied between 1 and 12 months, except in the 3 cases where the skin findings heralded a diagnosis of internal malignancy. Table 2. Clinico-morphological data of cutaneous metastases S.No. Type of skin lesion Number of lesions Site of lesions Associated internal malignancy Time of diagnosis 01 Nontender, firm to hard nodules Multiple Lt anterior chest wall (inferior quadrant) Carcinoma breast Before 02 Hard nodulo-ulcerated plaque (pic 1) Single Rt anterior chest wall Carcinoma breast Before 03 Erythematous, nontender, firm, papulo-nodules and fungating ulcer Multiple Lt anterior chest wall Carcinoma breast After 9 months 04 Ulcerated nodulo-plaque Single Rt anterior chest wall Carcinoma breast After 2 months 05 Nontender, skin colored nodule Single Axilla Carcinoma breast After 9 months 06 Large hard bulky plaque (pic 4) Single Pubic region Carcinoma cervix After 3 months 07 Nontender, hard, grouped nodules (pic 5) Multiple Mental area Carcinoma oral cavity (gingivo buccal sulcus) After 2 months 08 Nontender, firm to hard, skin-colored nodules (pic 7 a & b) Multiple All over body Nasopharyngeal carcinoma, NHL After 4 months 09 Hard ulcerated nodules Multiple Anterior neck, submandibular area Laryngeal carcinoma (pyriform fossa) After 10 Hard, nodules (pic 2) Multiple Lt side of Neck Ca testis Before 11 Ulcerated plaque Single Penis NHL After 1 month 12 Soft to firm erythematous to violaceous, non-itchy occasionally tender nodules Multiple Face, upper extremities NHL After 4 months 13 Erythematous, Edematous, Hard Skin (carcinoma en cuirasse) (pic 3) Single Right Side of Chest, Back & Right Upper Limb CA Breast B/L Concurrent 14 Erythematous, tender plaque with ill-defined margins (pic 8) Single Left hypochondrium NHL After 12 months 15 Erythematous firm to hard nodules Multiple Lower limb NHL After 5 months 16 Diffuse erythematous edematous plaque (inflammatory carcinoma) (pic 6) Single Lt anterior chest wall and upper limb CA Breast After 2 months

Cutaneous metastases from internal tumours are relatively rare, appearing in 0.7-10% of the cases,3,4,9,11,12,13 but their recognition is important. Even though they usually appear during a known neoplastic disease, they may be the presenting sign of a hitherto unknown tumour. They may also constitute the first manifestation of relapse of a tumour considered to be in complete remission. Therefor, the early diagnosis of cutaneous metastasis and the under lying tumor has significance for both the patient and the clinician. The prevalence of CMs in our study was 1.6% which is in line with previous reports on Caucasian populations. 3,4,13 This prevalence was high as compared to previous Asian studies including Taiwan (1.02%) 14 and India (0.5%).15 This difference may be due to sample size, frequency of primary tumor, age, sex and ethnicity. Cutaneous metastases are reported as initial manifestation of underlying cancer in 34% patients in a study conducted by Gan EY et al.16 In our study, cutaneous metastasis was the presenting feature in 18.75% patients which was similar to 18.62% in a previous study.6 Carcinoma breast and testis showed skin involvement as the presenting sign in our study. On the other hand, one patient with carcinoma breast developed cutaneous metastases concurrently and others developed skin metastatic deposits after a period ranging from one months to nine months after being diagnosed with primary malignancy. Brownstein MH and Helwing EB, reported that lung, kidney and ovary cancers are the most common type of cancers with skin involvement as the presenting sign.17 In literature, the frequencies of primary tumors developing cutaneous metastases differ.14,16,18,19,20,21 Breast cancer is known to be the second most frequent source of cutaneous metastases after melanoma, with an incidence ranging from 23% to 34% in patients with metastatic disease.22 According to the data reported in Dermnet site,23 the percentage of skin metastases from primary malignancies is as follows: melanoma has a 45% chance of developing cutaneous metastasis (but only 15–20% of melanomas metastasize, so the overall chance of skin metastasis is about 7–10%); 30% for breast cancer; 20% for nasal sinus cancers; 16% for larynx cancer; and 12% for oral cavity cancer. While Brownstein et al.17 showed that lung carcinoma is the most common primary tumor developing cutaneous metastases in men, Alcaraz et al.24 specified malignant melanoma as the most common original tumor of skin metastases. Both groups described breast carcinoma as the most common primary for cutaneous metastases in women. The present study results also highlight that breast cancer is the primary tumor to metastasize to the skin in women. The higher incidence of cutaneous metastases in breast cancer can be attributed to several factors. The anatomical proximity of the breast to the skin ensures direct extension and lymphatic spread to the dermis and subcutis.25 In our study hematological malignancies were the most common internal malignancy with cutaneous metastases in men which is similar to the results seen in a study by Gul et al.22 Although the term "metastasis" is generally not applied to skin infiltration by leukemia or lymphoma, these lesions will nonetheless be reported due to their significant prognostic implications, as they represent true cutaneous dissemination of internal hematologic malignancies. Skin metastasis from uterine and cervical carcinoma is a rare event with the reported incidence ranging from 0.1 to 2%.26 Our study also reported a single case of cutaneous metastasis from carcinoma cervix which is quite rare. It has been observed that many carcinomas spread through the lymphatic route to areas having common lymphatic drainage as that of the primary site.6,7 In our study as well, the skin deposits from breast carcinoma were mainly localized to the chest wall in seven patients. Three patients had head and neck metastasis, one of whom had gingivo-buccal carcinoma, one had laryngeal carcinoma and one had carcinoma testis. Clinically, cutaneous metastases often present as solitary or multiple papules, nodules, infiltrated plaques, or ulcers.4,25 In our study nodulo ulcerated plaque were the most common presentation while carcinoma en cuirasse and inflammatory carcinoma were seen in one each case. Generally, cutaneous metastases herald poor prognosis and low survival rate. They are usually indicative of disseminated, progressive disease or rarely recurrence of the primary tumor. A skin biopsy should be performed for suspicious lesions, particularly rapidly growing nodules of undetermined nature, persistent indurated erythema, and nonhealing ulcers in case of an existing carcinoma. Although CMs usually have a histological pattern similar to its primary tumor, there may also be more undifferentiated cells. So early detection of CMs can serve as a tool in staging the original cancer and reducing overall morbidity. Limitation Our study has some potential limitations, not least the relatively low number of CMs cases. Also, we lack data on follow-up for survival. A prospective multicenter study with the complete documented data, including the histopathologic results with the optimal immunohistochemistry panel in larger population should be recommended to elucidate more accurate information in CMs patients.

CMs, although relatively uncommon, represent a critical clinical indicator of advanced systemic malignancies. Clinical recognition is essential, but is challenging, especially in patients without a history of visceral neoplasia. It may still be an indicator for changing cancer patients’ treatment. Hence, early detection of CMs could prolong survival, especially in patients with no other widespread metastases, this requires a careful histopathological examination or the optimum immunohistochemistry staining and a multidisciplinary approach to help determine optimal care towards improving patients’ quality of life.

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