Cutaneous metastases-beyond skin deep, what is lurking beneath?

INTRODUCTION

Cutaneous metastases (CMs) are defined as the spread of a tumor from its primary site of origin to the skin.^[1] Skin metastases may be an indicator of advanced cancer or a sign of cancer recurrence.^[2] It is considered a poor prognostic factor and can occur in a wide variety of internal malignancies.^[3] The risk of cutaneous metastatic deposits increases with advancing age.^[4] Skin metastases can occur in 0.6–10.4% of all patients, which accounts for 2% of all cancers.^[3] The most common cancers that can cause CM are breast, lung, and gastrointestinal malignancies.^[4] Fine-needle aspiration cytology (FNAC) is a rapid, non-invasive technique that acts as a valuable tool in diagnosing such lesions.^[5] Histopathology is considered the gold standard in confirming the diagnosis. FNAC and histopathology help in differentiating metastatic deposits from other skin lesions, because it may be the only sign in clinically indolent cancers.^[6] Hence, a high index of suspicion is needed for early diagnosis and appropriate treatment. The objective of this study was to describe the clinicopathologic profile of patients with CM diagnosed by cytology and histopathology.

MATERIALS AND METHODS

This retrospective study was conducted in the Department of Pathology in a tertiary care hospital in Southern India over 5 years. A total of 118 cases of CM diagnosed by cytology (91 cases) and histopathology (27 cases) were included in this study. The clinical details and laboratory data were acquired from the requisition forms and hospital information system. The biopsies and FNACs were requested from various clinical departments such as General surgery, Dermatology, and Medical Oncology with a diagnostic intent. The biopsies and FNAC were done after obtaining consent from the patient according to the Institute guidelines. Age, gender, site of metastases, type of lesion, histological type, and the possible primary sites were analyzed. Cases of primary malignant tumors of the skin, hemato-lymphoid malignancies involving the skin, and scar site recurrences of internal malignancies were excluded from the study.

FNAC was performed by a standard technique using a 22-gauge needle and a 20 mL disposable plastic syringe using a Cameco syringe holder. Multiple air-dried and ethanol-fixed smears were prepared from the aspirate and stained with May–Grunwald–Giemsa (MGG) and Papanicolaou stains (PAP), respectively. The cell block was made wherever feasible. Special stains such as Mucicarmine, Periodic Acid Schiff (PAS), and relevant immunocytochemistry (ICC) were used whenever required.

For Histopathology, the hematoxylin and eosin-stained sections of skin biopsies received during the study period were reviewed. Immunohistochemistry (IHC) markers were performed in cases whenever needed. The Institute Ethics Committee approval was obtained (JIP/IEC-OS/2022/360).

RESULTS

In this study, 118 cases were studied in total, which include 91 cases diagnosed on FNAC and 27 cases diagnosed with biopsy. The age group ranged from 12 to 85 years. The majority was seen in adults (98.2%); 2 cases (1.7%) of CM were seen in patients <18 years old. The male-to-female ratio was 1:2.1, with males accounting for 38 cases (32%) and females 80 cases (68%). The most common clinical manifestation was nodules in 108 cases (93.1%), and multiple nodules were noted in five out of 108 cases. The other clinical presentations were papules in 4 cases (3.4%), plaque (three cases), ulcer (two cases), and cystic swelling (one case).

Distribution of cases

Of 118 cases, 98 cases (83%) had a previous history of a primary tumor, while 20 cases (17%) had no known primary malignancy. The most common primary carcinoma was breast cancer (42.8%), followed by carcinoma stomach (12.2%) and carcinoma colon (8.1%). The other malignancies noted were from the oral cavity, thyroid, genitourinary, and others [Figure 1].

Close

Figure 1:

The distribution of the most common primary site in cases of cutaneous metastases.

Export to PPT

The most common histological type was epithelial malignancy-adenocarcinoma, followed by squamous cell carcinoma, whereas sarcoma was seen in four cases. The sarcoma group (4.1%) consists of Ewing sarcoma (chest) metastasizing to the scalp; chondrosarcoma of the chest wall showing chest wall recurrence, epithelioid sarcoma of the para-testicular area, and undifferentiated uterine sarcoma metastasizing to the abdominal wall.

Sites of metastasis

The most common site of metastases was the chest wall in 46/98 cases (46.9%), and breast carcinoma was the most common primary, accounting for 35/46 (76%) cases. The second most common site was the abdominal wall (including the umbilicus) in 27/98 cases (27.5%), and the most common primaries were the stomach and colon, accounting for 15/27 (55.5%) cases. Both the chest wall and abdominal wall had loco-regional metastasis. Scalp metastasis was most commonly seen as distant metastasis in 9/98 (91.8%) of cases. Other sites included were the forearm, neck, shoulder region, back, labia majora, and knee. Multiple sites of metastases were seen in five cases [Table 1 and Figure 2].

Table 1: Distribution of cases of known primary tumor and their sites of cutaneous metastasis.

S. No	Primary tumor	No. of cases n=98	Site of metastasis	Final diagnosis
1	Breast	43	Chest wall-35 Scalp-3, neck-2, face -2, vulva -1	Infiltrating ductal carcinoma (38), Malignant phyllodes tumor (2)
2	GIT	22	Stomach: 12 Umbilicus-9 chest wall-2 Back-1 Colon: 8 Anterior abdominal wall-5 Back-1, chest wall-1 Inner thigh-1 Gallbladder: 2 Anterior abdominal wall-1, face and back-1	Adenocarcinoma
3	Oral cavity Frontal sinus	7	Face-3; Neck-2; Chest wall-1, Scalp-1	Squamous cell carcinoma
4	Cervix	6	Labia majora-3; Scalp-2; Abdominal wall-1	Squamous cell carcinoma
5	Kidney	5	Abdominal wall-1, Chest wall-3, Shoulder-1	Clear cell RCC-4 Wilms tumor-1
6	Thyroid	4	Scalp-1, Shoulder-1, Face-1, Chest wall-1	Follicular ca-3; Pap ca-1
7	Esophagus	1	Scalp-1	Squamous cell carcinoma
8	Larynx	1	Face-1	Squamous cell carcinoma
9	Bladder	1	Chest wall-1	Urothelial carcinoma
10	Ovary	2	Chest wall-1; Abdominal wall-1	Papillary serous carcinoma
11	Sarcomas	4	Chest wall-1, Scalp-1; Anterior abdominal wall-2	Chondrosarcoma, Ewings sarcoma, Epithelioid sarcoma of para testis, Undifferentiated uterine sarcoma

RCC: Renal cell carcinoma, GIT: Gastrointestinal tract The numbers in parantheses represent no. of cases of each category

Close

Figure 2:

Known cases of primary malignancies with cutaneous metastasis (a) Known case of carcinoma breast with chest wall nodule; (b) FNAC from the chest wall nodule shows features of adenocarcinoma X MGG 200x; (c) Known case of carcinoma stomach with umbilical nodule; (d) FNAC from the umbilical nodule shows features of adenocarcinoma X MGG 400x and (e) Known case of carcinoma oral cavity with scalp nodule; (f) FNAC from the scalp nodule shows features of squamous cell carcinoma metastasis X PAP 400x). MGG: May–grunwald–giemsa, PAP: Papanicolaou stains, FNAC: Fine needle aspiration cytology.

Export to PPT

Cases of unknown primary

There were 20 cases in which the diagnosis was CM with unknown primary. Among the 17 cases of unknown primary subjected to FNAC, we were able to suggest primary sites in ten cases with the help of IHC markers and clinico-radiological correlation. The panel of ICC and IHC markers used was PanCK, vimentin, S100, and Leucocyte Common Antigen (LCA). Depending on the results, further panels of cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF1), CDX2, Napsin A, and paired box gene 8 (PAX 8) were used. In three cases, where the biopsy was done, in two cases, the primary tumor was suggested [Table 2 and Figure 2]. As most of these patients were lost to follow, further evaluation and identification of the primary could not be done.

Table 2: Distribution of unknown primary with cutaneous metastasis (n=20).

Site	Cytomorphological diagnosis (n=17)
	Adenocarcinoma (09)	Squamous cell carcinoma (5)	Others (3)
Chest wall	1	1	2-Poorly differentiated carcinoma
Abdominal wall	4	–	–
Scalp	1	1	1–Follicular ca of thyroid
Back	3	–	–
Face	–	1	–
Neck	–	1	–
Arm	–	1	–
Histopathological diagnosis (n=3)
Multiple sites chest wall, Scalp, Neck, back	1-Ovarian origin	–	1-Poorly differentiated carcinoma
	1-Gastrointestinal origin	–	–
		–	–

Close

Figure 3:

(a) A 61-year-old female with multiple indurated plaques over her neck, chest, and extremities; (b) Biopsy shows single-cell infiltration of malignant cells x hand E 200; (c) Biopsy shows single-cell infiltration of malignant cells x hand E 400; (d) GATA binding protein 3 (GATA3) positive X DAB 400x.

Export to PPT

DISCUSSION

Skin is an uncommon site for the development of metastases.^[8] CM may be the initial manifestations of the clinically silent malignant tumor, or represent the recurrence of the disease process following the failure of therapy, or it can be the terminal stage of the disease.^[9] In some patients, it may be the only external manifestation representing the occult internal malignancy. Hence, early diagnosis is of tremendous importance in clinical practice.

In our study, the age group ranged from 12 to 85 years. As breast carcinoma was the most common primary showing CM, females outnumbered males in our study. Most of the cases were seen after the fifth decade of life. In the present study, 60.7% of cases were above 50 years of age.

Clinically, the CM presents as a single nodule, mostly with a few multiple-nodule presentations. The clinical spectrum of lesions varies and includes papules, nodules, plaques, telangiectatic lesions, and ulcers.^[6] In the present study, 108 cases presented as nodules, with five cases showing multiple nodular presentations, whereas the remaining cases presented as plaques, papules, cystic swellings, and ulcers.

Eighty-one percent (81%) of the patients had a previous history of primary malignancy. The predominant site involved was the chest wall, followed by the abdomen (including the umbilicus). This was in concordance with the study done by Rajashree Verma et al. and Aldret and Cotton, where the predominant sites were the chest wall, abdomen, and scalp.^[10,11]

An extensive literature search reveals that breast and lung are the most common primary sites in females and males, respectively.^[12] In the present study, the breast was the most common primary site in females, as was found in many other series reported earlier.^[2,4] In males, gastrointestinal tract (GIT) was the most common primary site in the present study, which is also on par with other studies in the literature.^[13] Some series have reported the lung as the most common primary site in males.^[2,8,10] However, in our study, we have three cases of malignancy of unknown origin, in which we suggested a lung primary based on IHC; however, we did not get a follow-up biopsy in these patients for confirmation.

Locoregional metastasis is more common than distant metastasis, as seen in our study. CM can occur by the lymphatic and hematogenous routes. CM occurs near to primary organ by the lymphatic route of spread, whereas distant metastases can occur by the hematogenous route of spread. When it occurs by lymphatic spread, the surrounding and nearby skin is involved. For example, gastrointestinal carcinoma to the umbilicus and renal cell carcinoma (RCC) to the back.^[13] In our study, 27 cases showed distant metastases; the phenomenon is unusual and is more likely due to the hematogenous spread of the tumor.

Seven cases presented as disseminated CM – six cases of adenocarcinoma, one case of squamous cell carcinoma, and one case of poorly differentiated carcinoma. Among these, five cases presented as unknown primary tumors, and the most common presentation is multiple site nodules presented in the scalp, followed by the forearm.

Although cases with known primary tumors are easy to diagnose, cases presenting as a single nodule with an unsuspected primary tumor may impose a diagnostic challenge to both the treating clinician and the pathologist. Metastatic adenocarcinoma can be suspected by morphological clues such as the presence of extracellular mucin, signet ring cell morphology, and three-dimensional papillae. There are a few more morphological clues, such as dirty luminal necrosis (colon carcinoma), evidence of intracellular keratinization (squamous cell carcinoma), stippled chromatin (neuroendocrine carcinoma), and clear cytoplasm to suspect the primary site of malignancy. However, when metastatic lesions show undifferentiated patterns and single-cell or cord-like infiltration, it can be suspected of hemato-lymphoid malignancies or poorly differentiated visceral malignancies. IHC helps in these circumstances. Always in undifferentiated/poorly differentiated patterns, we should resort to broad panel markers such as PanCK, LCA, and S100. Further, it can be worked up depending on the marker’s positivity. As of now, we have many site-specific markers such as TTF1 (lung and thyroid), GATA binding protein 3 (GATA3) (breast, salivary gland, and Bladder), CDX2 (Colon), and PAX8 (ovary), which can be used in relevant clinical and morphological settings [Figures 3 and 4].

Close

Figure 4:

Approach to a case of cutaneous metastasis. IHC: Immunohistochemistry, PanCK: Pancytokeratin, LCA: Leucocyte common antigen, CK7: Cytokeratin 7, CK 20: Cytokeratin 20, CK 15: Cytokeratin 15, TTF1: Thyroid Transcription factor, GATA 3: GATA binding protein 3, PAX8: Paired box gene 8

Export to PPT

Cases presenting as a single nodule can have clinical differentials of a soft-tissue tumor or a primary skin adnexal tumor. Differentiating from primary skin adnexal tumors is very challenging, as there is an overlap in the morphological and immunohistochemical patterns. Eccrine sweat gland tumors can show tubular differentiation with squamoid and clear cell change, which can mimic ductal carcinoma of the breast and clear cell RCC. However, RCC shows the presence of PAS-positive glycogen and diastase-sensitive reaction, which helps in the differentiation of these mimicking tumors. Metastatic squamous cell carcinoma showed a positive reaction on PAS stain and negativity for oil red O stain, which helps to differentiate from primary skin adnexal tumors showing squamoid differentiation.^[14] Sweat gland tumors are difficult to differentiate from sweat gland adenocarcinomas as there is a morphological and immunohistochemical overlap.^[15] Both these tumors show p63, CK14, CK5, and CK17 positivity. It becomes more challenging in triple-negative breast carcinomas. Hence, if the tumor is in the axilla, a breast primary is considered. If it is in any other site, a thorough clinic-radiological examination is necessary to rule out a breast primary.

Osteen et al. have reported that in many cases of CM, despite thorough clinical investigation and even an autopsy, a primary may not be found.^[16] Treatment of CM is palliative, which includes either this alone or in combination of surgery, chemotherapy, and radiotherapy.^[17] Therefore, morphology in conjunction with the clinical details and ancillary techniques such as special stains, ICC, and IHC can help to locate the primary site in cases with unsuspected primary tumors.

CONCLUSIONS

Metastatic cutaneous lesions bear an important role in the therapeutic and prognostic implications of patient management and are amenable to visual inspection and detection. Prompt recognition of the histopathological type of malignancy is important as it provides a clue to an underlying unsuspected malignancy. The critical evaluation of morphology, along with ancillary techniques, can help to identify the unknown primary cases and to confirm the metastases in cases with known primary tumors.