Frequency and Spectrum of Cutaneous Metastases of Visceral Malignancies: A Retrospective Observational Study of Three Years Duration in a Tertiary Care Hospital.

BACKGROUND: In spite of the skin being the largest organ of the body, cutaneous malignancies are uncommon especially in people of color as compared to the white population. The incidence of cutaneous metastases of visceral malignancies is further low and accounts for 0.5% to 10% of cancer cases as per written literature. Cutaneous metastasis as the presenting sign of underlying internal malignancy is extremely rare and is a marker of poor prognosis. Limited data is available in written literature about the frequency and spectrum of metastatic skin lesions in the Asian population.
OBJECTIVE: 1) To find the frequency of metastasis of visceral malignancies in skin biopsies. 2) To evaluate the clinicopathological presentation and immunohistochemistry (IHC) profile of cutaneous metastases. SUBJECTS AND METHODS: It is a retrospective analysis of all the skin biopsies received in our department of Pathology for HPE from 01 Jan 2017 till 31 Dec 2019. Cases of cutaneous malignancy were segregated into primary and metastatic categories. Clinical details of the cases of cutaneous metastases were retrieved and analyzed. All the cases of cutaneous metastases were studied in detail for their clinical presentation, histomorphological features, and findings on IHC.
RESULTS: Out of a total of 484 skin biopsies in 3 years, 9.7% showed features of malignancy. Total ten cases of cutaneous metastases (2%) were found, out of which three were the primary presentation of silent visceral malignancy. The lung, breast, colon, and ovary were the common primary sites to manifest as cutaneous metastases with the abdominal wall being the commonest site. Histomorphological features aided by the IHC panel helped in diagnosing the cutaneous metastases and site of the primary malignancy.
CONCLUSION: Cutaneous metastasis as the primary presentation of visceral malignancy is rare and should not be missed as it indicates a poor prognosis. Clinico-pathological correlation and histomorphological features assisted by IHC markers help pathologists in diagnosing the site of primary malignancy in cases of cutaneous metastases. Copyright:

Introduction

Cutaneous lesions have varying etiologies ranging from infective, allergic to autoimmune; however, cutaneous metastatic lesions are very uncommon. The development of cutaneous metastases (CM) in course of visceral malignancy is an indicator of poor prognosis. Rarely, cutaneous lesions can be the primary manifestation of underlying undiagnosed visceral malignancy. The incidence of CM as reported in written literature is in the range of 0.5% to 10% in cancer patients.[1234] Skin involvement as a presenting sign of visceral malignancy is reported in only 0.8% of cases.[5] On extensive search of written literature, limited large studies are done on skin biopsies for cutaneous metastases in the Asian population.

The aim of this study was to 1) find the frequency of metastasis of visceral malignancies in skin biopsies.

2) To evaluate the clinicopathological presentation and immunohistochemistry (IHC) profile of cutaneous metastases.

Subjects and Methods

It is a retrospective, observational, and descriptive study done in the Department of Pathology of a tertiary care hospital having a fully functional Dermatology and Malignant Disease Treatment Centre (MDTC). All the skin biopsies received for histopathological examination (HPE) in the department of pathology from 01 Jan 2017 till 31 Dec 2019 were reviewed. The Hematoxylin and Eosin (H and E)–stained sections and tissue sections subjected to IHC were re-evaluated by two pathologists to minimize any potential bias. The skin biopsies reported as malignant were segregated and further subdivided as primary and metastatic. The inclusion criteria were cases of cutaneous metastases with or without known primary malignancy. Cases with contiguous spread and direct extension of primary malignancy into the overlying skin were excluded. The clinical details including physical and dermatological examination and imaging studies for the cases of CM were obtained from the patients' record files kept in respective departments and through HPE requisition forms. The details available regarding the primary tumor site were evaluated. All the cases of CM were studied in detail for their clinical presentation, histomorphological features, and findings on IHC.

The study was approved by the Institutional Ethics Committee.

Results

A total of 484 skin biopsies were received during 3 years duration i.e., 01 Jan 2017 to 31 Dec 2019 in the Department of Pathology for HPE. Out of total biopsy specimens received for HPE, skin biopsies accounted for 5.43% of total cases in 3 years. Yearly distribution of skin biopsies for 2017, 2018, and 2019 were 5.92% (144/2429), 4.98% (162/3251), and 5.52% (178/3223), respectively.

Out of a total of 484 skin biopsies, 316 (65.29%) were biopsied from male patients. Females made the remaining 34.71% of cases. There was a gradual increase in the total number of skin biopsies over 3 years; however, the male gender predominated in representation.

Most of the skin biopsies belonged to patients in the reproductive age group and tampered off in extreme of ages, with a peak in the age bracket of 31–40 years [Figure 1].

Figure 1

AgeWise Distribution of Skin Biopsies

The biopsied skin lesions were submitted from different parts of the body with the face, trunk, and limbs having maximum representations [Figure 2].

Figure 2

Anatomical distribution of sites of skin biopsy

Most of the skin biopsies were benign and made 90.3% of total cases. Primary skin malignancies accounted for 7.6% of skin biopsies, whereas cutaneous metastases were reported in 2.1% of skin biopsies [Table 1].

Table 1

Histopathological Character of Skin Biopsy

Categories of skin lesions	2017	2018	2019
Benign	130 (90.27%)	145 (89.50%)	162 (91.01%)
Malignant- Primary	12 (8.33%)	14 (8.64%)	11 (6.18%)
Malignant- Metastatic	02 (1.40%)	03 (1.86%)	05 (2.81%)
Total	144	162	178

Basal cell carcinoma was the commonest amongst primary cutaneous malignancies accounting for 62.2% of total cases of skin malignancies (23/37) [Table 2]. Ten cases of cutaneous metastasis were identified in our 3-year study with three cases presenting as the initial presentation of the underlying unknown visceral malignancy. The lung was the commonest organ with cutaneous metastasis and was responsible for three cases (03/10). Breast and colorectal carcinoma were responsible for two cases of cutaneous metastases each [Table 3].

Table 2

Spectrum of malignant skin lesions

	2017	2018	2019
Primary Malignant Lesions
Basal Cell Carcinoma	07	06	10
Squamous Cell Carcinoma	01	03	01
Melanoma	01	02	00
Adnexal Carcinoma	00	01	00
Paget’s Disease	01	02	00
Hemato-lymphoid malignancy	02	00	00
Secondary Malignant lesions
Cutaneous Metastasis	02	03	05
Total	14 (9.7%)	17 (10.49%)	16 (9.9%)

Table 3

Clinicopathological presentation and IHC profile of cutaneous metastases

Age (Years)	Sex	Site of cutaneous metastasis	Type of cutaneous lesion	The primary organ of malignancy	Type of malignancy	Presentation	IHC* Profile
61	M	Back	Ulcerated, single large nodule	Lung	Adenoca	Primary	CK7+, TTF-1+, Napsin A±, CK20-
76	F	Chest wall	small, multiple nodules	Breast	Ductal ca	Secondary	CK7+, CK20- ER±, Mamm+
46	M	Abd wall (Periumbilical)	Single nodule	Colorectal	Adenoca	Secondary	CK7-, CK20+, CDX2+
60	M	Neck	Small nodules	Larynx	SCC	Secondary	P63+, CK 5/6+, P40+
78	F	Abd wall	Erythematous Plaque	Breast	Ductal ca	Secondary	CK7+, CK20- ER±, Mamm+
45	F	Abd wall (epigastrium, near port)	Small nodules	Gall bladder	Adenoca (Cholangioca)	Secondary	CK7+, CK20-CDX2-
62	M	Forearm	Big nodule	Lung	SCC	Secondary	P63+, CK7±CK5/6+, P40+
63	F	Abd wall	Multiple small nodule	Colorectal	Mucinous Adenoca	Secondary	CK7-, CK20+, CDX2+
52	F	Abd wall	Hard, small nodule	Ovary	Papillary Adenoca	Primary	CK7+, WT-1+, PAX8+, CK 20-
76	M	Scalp	Single nodule	Lung	Adenoca	Primary	CK7+, TTF1+, Napsin A±, CK20-

*p63, CK15, and D2-40 panel done to exclude primary adnexal tumors. Abbreviations: CD, Cluster of differentiation; CK, Cytokeratin; CDX2, Caudal type homeobox 2; ER, Estrogen receptor; Mamm, Mammaglobin; PAX 8, Paired box gene 8; SCC, Squamous cell carcinoma; TTF-1, Thyroid transcription factor 1; WT 1, Wilms tumor 1

The gender distribution was equitable in cases of cutaneous metastases in our study. The age range was found to be 46–78 years with a mean age of 62 years. The clinical presentation showed that the nodular lesions were most frequent with the abdominal wall as the commonest site of cutaneous metastases [Table 3].

The histomorphological features assisted by IHC Panel significantly helped in diagnosing the parent organ of malignancy in cases of CM [Table 3]. In two cases of undiagnosed lung carcinoma with CM, histomorphological features of glandular differentiation and nuclear positivity of glandular cells with transcription factor-1 (TTF-1) helped in diagnosis which was confirmed following positron emission tomography and computed tomography (PET-CT) of the whole body with lung revealing fluorodeoxyglucose (FDG) avid lung lesion [Figure 3]. Adenocarcinoma was the dominant and commonest morphologic type to metastasize; hence, CM had a close differential of primary adnexal tumors. IHC panel of p63, CK 15, and D2-40 were put to differentiate from adnexal tumors. Histomorphological features like dirty luminal necrosis of neutrophilic karyorrhexis in colorectal adenocarcinoma, psammoma bodies in papillary adenocarcinoma, and extensive desmoplasia in pancreatobiliary metastatic adenocarcinoma assisted by IHC helped in diagnosis [Table 3 and Figure 4].

Figure 3

Cutaneous metastases of Lung carcinoma (a) Ulcerated nodular metastatic skin lesion on back as the primary presentation (b) On HPE Dermal based metastatic adenocarcinoma (H and E, 100 ×) (c) On IHC, the glands of metastatic adenocarcinoma showed nuclear positivity for TTF-1 (d) PET-CT image revealed FDG avid Lung lesion (e and f) Metastatic nodular lesion on forearm and scalp in patients of carcinoma lung

Figure 4

(a) Multiple small cutaneous metastatic nodules of ductal carcinoma breast on the chest (b) Metastasis of high-grade ductal carcinoma of the breast (H and E, 100×) (c) Nuclear positivity for ER on IHC in Ductal carcinoma (d) Dermal metastasis of serous papillary adenocarcinoma of ovary (H and E, 100×) (e) Periumbilical metastatic nodule of Carcinoma Colon (f and g) Metastatic adenocarcinoma with mucin pools (h) Metastatic Squamous cell carcinoma (H and E, 200×)

Discussion

Metastasis of visceral malignancies to the skin is rare and usually occurs in a later stage of the disease. It can rarely be the primary presentation of an underlying silent malignancy.[1] The incidence of CM in cancer patients is documented in written literature as 0.5% to 10%.[1234] In our present study on biopsied skin lesions, 90.3% of skin biopsies were reported to be benign; in the remaining, 9.7% of malignant skin lesions, most were primary cutaneous malignancies [Tables 1 and 2]. Ten cases out of 484 cases over 3 years in our setup were found to have CM making the incidence 2.06% in patients having skin lesions. Three out of ten cases had CM as primary presentation of underlying undiagnosed cancer (1.05%) which was close to findings of Lookingbill et al.[5] Brownstein et al.[6] found that lung, kidney, and ovary cancers were the most common cancers to present with CM. In our study, lung and ovary cancers were found responsible for primary CM [Table 3].

The incidence of various tumors that are metastatic to the skin correlates well with the frequency of occurrence of the primary malignant tumor in each gender.[7] Adenocarcinoma is the commonest type of malignancy in CM with primary being commonly from the lung, breast, and colon.[4] Earlier studies by Lookingbill et al.[5] and Hu et al.[3] in cancer patients found carcinoma breast to most frequently develop cutaneous metastases followed by lung. Saeed et al.[8] found lung to be the most frequent organ to throw CM. In males, primary lung cancer and colon cancer show cutaneous spread and in females, breast cancer is the most common with cutaneous spread.[91011] In our study, metastasis from the lung outnumbered other organs with three cases. The breast and colon were primary organs in two cases each. The remaining three cases had ovary, gall bladder, and larynx as the primary organ of malignancy [Table 3].

As per earlier studies, CM was found to occur more commonly in men (37%) than women (6%).[12] However, a retrospective study on CM by Sittart et al.[11] found incidence more in women (68.89%) than men (31.10%). In our study, the male-dominated in the representation of total skin biopsies making 65.29% of total cases; however, both genders were equally affected by cutaneous metastases [Table 3]. Cutaneous metastatic lesions are known to present in a wide morphologic spectrum and usually are limited to single anatomic distribution.[512] CM could be in form of nodules, ulcers, plaques, or inflammatory eruptions. In our study, most of the CM presented in the nodular form of varying sizes; military to lemon sized, and were single to multiple. The abdominal wall was the commonest anatomic location of CM in our cases [Table 3]. In the literature, the cutaneous metastatic lesions could be present on the chest wall, abdomen, scalp, and umbilicus.[61113] The regional distribution of CM depends on the location of the primary tumor and mechanism of spread whether direct, through lymphatic or hematogenous, or infrequently due to implantation following surgical or diagnostic procedure.[7]

The morphologic appearance of CM generally depicted broad-based architecture with dermal dominance and epidermal sparing.[48] Primary cutaneous adnexal malignancies were the close morphologic differential of CM and IHC marker Panel of P63, CK 15, and D2-40 helped in differentiation.[414] Along with clinical details, IHC was a useful adjunct to ascertain the parent organ of the CM. The primary cutaneous mucinous carcinoma, an uncommon adnexal tumor of eccrine gland origin, is morphologically similar to metastatic deposits of mucinous carcinoma of the breast, lung, and GIT; however, immunohistochemically, the cells of the adnexal tumor are negative for CK 20, CDX2, and TTF 1 and show positivity for CK 7, CK 5/6, and p63.[15]

In our study, three cases presented primarily with CM, out of which two were from lung and one from ovary [Figures 3 and 4]. About 1%–12% of lung cancer patients develop cutaneous metastases.[5161718] All histologic types of lung cancer can develop skin involvement.[19] Some studies pitch adenocarcinoma as the most common type to develop skin metastases,[618202122] whereas other studies found the rate of CM higher for large cell carcinoma and low for squamous cell and small cell variant.[2023] In our study, out of three cases of lung carcinoma with CM, two were adenocarcinoma, and one was squamous cell carcinoma [Table 3 and Figure 4]. The panel of IHC markers helped in reaching the diagnosis following which the patient underwent whole-body PET-CT which confirmed lung as the primary site of malignancy [Figure 3].

The ovarian tumors are known to throw cutaneous metastases in 2%–-5% of cases which is an indicator of poor prognosis.[2425] One case of primary CM in our study had its origin in the ovary. Simultaneous examination of the patient yielded the presence of moderate ascites, left adnexal mass, and raised CA-125 levels. Histologic sections from the abdominal nodule showed papillary adenocarcinoma with the presence of Psammoma bodies clenching the diagnosis [Figure 4].

Breast carcinomas have approx. 18.6% to 26.5% rate of cutaneous metastases, and they mostly occur on the abdomen or chest wall.[2627] The two cases of breast carcinoma that had CM in our study were both postoperative and developed a lesion on the chest and abdominal wall [Figure 4]. In the present study, Paget's disease was not considered under the umbrella of CM considering its pathology to be varied and could involve the skin by direct extension or colonization of lactiferous ducts by malignant cells.[28] Only cases with distinct distant skin involvement by malignancy were included.

Amongst gastrointestinal malignancies, colorectal primary is known to metastasize more commonly.[293031] In our study of CM, two cases out of ten had colorectal primary. HPE of metastatic abdominal nodule confirmed the presence of adenocarcinoma [Figure 4] and IHC Panel of CK 20, CK7, and CDX2 helped in confirmation of primary [Table 3]. Metastasis of cholangiocarcinoma could be differentiated from other GIT adenocarcinoma on IHC as it was CK7 positive and lack diffuse expression of CDX2[32] [Table 3].

The skin is the largest organ of our body and is easily accessible too; however, it accounted for only about 5% of the total biopsies submitted for HPE in our department over 3 years. The commonest primary cutaneous malignancy in our study was basal cell carcinoma (62.2%) followed by squamous cell carcinoma (13.5%) [Table 1]. Other reported primary cutaneous malignancies were melanoma, adnexal carcinoma, Paget's disease, and cutaneous hemato-lymphoid malignancy. The face was the commonest site for basal cell carcinoma accounting for 78.3% of cases. For squamous cell carcinoma, the foot with Marjolin ulcer was the commonest bed of origin as established in the literature other than sun-damaged skin.[33]

The limitation of our study is the short retrospective period which could not be prolonged due to limited access and poor record keeping. On review of written literature, most of the previous studies on cutaneous metastasis were done on known cancer patients, unlike our study which analyzed all the skin biopsies done during the period not limited by the presence of known malignancy. A further longer study with the prognostic follow-up of the patients is needed in this field.

In conclusion, we recommend that all the nonhealing and suspicious skin lesions should be biopsied for HPE. Malignancies with cutaneous metastasis are already metastatic to other sites and signals advanced stage with poorer prognosis. Uncommonly, cutaneous metastasis may be the primary presentation of a silent internal malignancy and for diagnosing that clinician needs to be aware and have to have a high index of suspicion. Suspicious cutaneous lesions should be biopsied, and a pathologist armed with clinical knowledge, with help of histomorphological features and guiding panel of IHC can direct towards the primary site of malignancy. Early recognition and timely diagnosis help the patient with a better survival rate.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.