What Is The Cause Of This Red Scalp Nodule?

Case Report

A 63-year-old man presented for evaluation of a new asymptomatic lesion on his head. His past medical history was significant for renal cell carcinoma, diagnosed 15 years earlier, with subsequent treatment and no further evidence of residual disease. Cutaneous examination revealed a 6 x 6-mm firm and painless erythematous nodule on the frontal scalp (Figure). There was alopecia in the area occupied by the nodule. Complete cutaneous examination did not reveal any other nodules, and there were no palpable lymph nodes. A shave biopsy of the nodule was performed.  

What Is The Diagnosis?

Check your answer by hitting "Next" below!

Diagnosis: Metastatic renal cell carcinoma with cutaneous metastasis   

Cutaneous metastases portend a poor prognosis and are estimated to occur in 1% to 10% of cancer patients.^1-9 They may be the initial sign of an undiagnosed visceral malignancy, develop in the setting of a progressive neoplastic disease, or present as the harbinger of recurrent malignant disease in a known oncology patient.⁷ Lung and breast cancer are among the most common etiologies for cutaneous metastases in men and women, respectively.^4,8,9 In contrast, renal cell carcinoma (RCC) is a less common cause of cutaneous metastases and represents about 6% of all cutaneous metastases. Approximately 30% of patients with RCC present with metastatic disease, and 1% to 3% of patients with metastatic disease have cutaneous involvement.^2,4 Mean survival time in individuals with cutaneous metastatic RCC is 7 months.¹⁰  

Clinical Presentation
The morphology of cutaneous metastases is variable.¹¹ They can present as papules or nodules, cellulitis-like erythematous plaques, morphea-like indurated plaques, and/or alopecia of the scalp.^4,8 In patients with metastatic RCC, cutaneous lesions typically present as solitary, rapidly growing, red to violaceous, shiny papules or nodules that have a vascular appearance¹² (Figure). Similar to our patient, the head is the most common site of cutaneous metastases for RCC.¹²

Differential Diagnosis
The clinical differential diagnosis for cutaneous metastases is extensive. The conditions that may mimic red nodules on the scalp are listed in Table 1.^2,4,10,12-17 The pathologic differential diagnosis of metastatic RCC includes tumors with clear cytoplasm (Table 2).^{2,10,12-15,18}

Pathology
The microscopic examination of a cutaneous metastasis has similar features to those of the primary cancer. Typically, the tumor is located in the dermis with no connection to the epidermis.¹⁴ Most RCCs are of the clear cell subtype,² with tumor cells containing an abundance of glycogen.¹⁴ The tumor cells form glandular, trabecular, papillary, or cystic patterns.⁴ There is also an abundance of endothelial-lined vascular spaces with extravasation of red blood cells within the fibrovascular stroma.^4,14 Periodic acid-Schiff staining can be used to detect cytoplasmic glycogen.¹⁴ Immunohistochemical studies may show positive staining with antibody to cytokeratin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), vimentin, cluster of differentiation (CD) 10, CD31, and RCC marker (RCC-Ma).^2,4,14

Pathogenesis
There are several pathways through which metastatic disease can occur. The first is direct extension, in which the tumor directly invades the overlying epithelium of the skin. The second and third are hematogenous and lymphatic spread, in which the tumor spreads to a distant site through blood and lymphatic vessels, respectively.^4,9,11,19 

Treatment
The detection of cutaneous metastases may warrant systemic evaluation of the individual. In an oncology patient—in whom a prior assessment has determined him or her to be in remission—the skin lesion may be the presentation of recurrent cancer. Typically, management of cutaneous metastasis is predicated by systemic treatment of the primary visceral malignancy. Indeed, resolution of the residual cutaneous metastases may provide a visual measure of the patient’s response to treatment. Occasionally, metastasis-directed therapy may be initiated.¹⁰ 

In the case of cutaneous metastatic RCC, treatment options are palliative in many cases.¹⁷ Radiotherapy may help devascularize lesions and partially reduce tumor volume.^{2,10,12-14,20} Interferon alfa and IL-2 were initially the mainstay of treatment in systemic disease but have been replaced by antiangiogenic medications, such as bevacizumab,¹⁰ and tyrosine kinase (TYK) inhibitors, such as sorafenib, sunitinib, and pazopanib.¹² Additionally, Mohs micrographic surgery has been utilized to successfully remove solitary metastatic lesions.¹⁰ 

Our Patient 
After appropriate treatment of his RCC 15 years earlier, the patient had no further evidence of residual cancer. The shave biopsy of his red scalp lesion revealed a nodular proliferation of malignant tumor cells with clear cytoplasm, numerous dilated vascular spaces, and an epidermal collarette surrounding the central nodule (similar to that observed with pyogenic granulomas). No involvement of the overlying epidermis was seen.

Immunohistochemistry showed positive staining of tumor cells with antibodies to EMA and pankeratin AE1/AE3. The numerous dilated vascular spaces stained positively with antibodies to CD31 and CD34. There was negative staining with antibodies to p63 and cytokeratin 5/6, indicating the metastatic nature of the tumor instead of a primary epithelial neoplasm. There was also negative staining of antibodies to adipophilin, CEA, erythroblast transformation-specific-related gene (ERG), human herpesvirus-8, human melanoma black-45 (HMB-45), melanoma antigen recognized by T cells (MART-1), and sex-determining region Y-related high mobility group-box 10 (SOX10). Correlation of the clinical presentation and the pathologic findings established a diagnosis of RCC with metastasis to the scalp.

The patient was referred to an oncologist for complete systemic evaluation and subsequent treatment with an oral TYK inhibitor.

Conclusion
The skin can be the initial site of an unsuspected metastasis from a previously undiagnosed visceral cancer. In addition, cutaneous metastases can be the harbinger of metastatic neoplasm in a patient with a prior diagnosis of cancer. 

Mr Vazirnia is a senior at College of Letters & Science at the University of California, Los Angeles. Dr Cohen is an adjunct professor of dermatology at Touro University California College of Osteopathic Medicine in Vallejo, CA, and a dermatologist at San Diego Family Dermatology in National City, CA. 

Disclosures: The authors report no relevant financial relationships.

References
1. Lookingbill DP, Spangler N, Sexton FM. Skin involvement as the presenting sign of internal carcinoma. A retrospective study of 7316 cancer patients. J Am Acad Dermatol. 1990;22(1):19-26. doi:10.1016/0190-9622(90)70002-y
2. Abbasi F, Alizadeh M, Noroozinia F, Moradi A. Cutaneous metastasis of bilateral renal cell carcinoma. J Pak Med Assoc. 2013;63(1):111-113.
3. Tadashi T. Cutaneous metastasis of renal cell carcinoma: a report of two cases. Int J Clin Exp Pathol. 2012;5(2):175-178. 
4. Alcaraz I, Cerroni L, Rütten A, Kutzner H, Requena L. Cutaneous metastases from internal malignancies: a clinicopathologic and immunohistochemical review. Am J Dermatopathol. 2012;34(4):347-393. doi:10.1097/DAD.0b013e31823069cf
5. Brownstein MH, Helwig EB. Metastatic tumor of the skin. Cancer. 1972;29(5):1298-1307. doi:10.1002/1097-0142(197205)29:5<1298::aid-cncr2820290526>3.0.co;2-6
6. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol. 1995;33(2 Pt 1):161-182. doi:10.1016/0190-9622(95)90231-7
7. Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: a retrospective study of 4020 patients. J Am Acad Dermatol. 1993;29(2 Pt 1):228-236. doi:10.1016/0190-9622(93)70173-q
8. Habermehl G, Ko J. Cutaneous metastases: a review and diagnostic approach to tumors of unknown origin. Arch Pathol Lab Med. 2019;143(8):943-957. doi:10.5858/arpa.2018-0051-R
9. Gan EY, Chio MT, Tan WP. A retrospective review of cutaneous metastases at the National Skin Centre Singapore. Australas J Dermatol. 2015;56(1):1-6. doi:10.1111/ajd.12194
10. Anzalone CL, Cohen PR, Migden MR, Tannir NM. Mohs surgery in metastatic cancer: renal cell carcinoma solitary cutaneous metastasis and visceral tumor metastases to skin treated with microscopically controlled surgical excision. Int J Dermatol. 2013;52(7):856-861. doi:10.1111/ijd.12021
11. Sittart JA, Senise M. Cutaneous metastasis from internal carcinomas: a review of 45 years. An Bras Dermatol. 2013;88(4):541-544. doi:10.1590/abd1806-4841.20131165
12. Ferhatoglu MF, Senol K, Filiz AI. Skin metastasis of renal cell carcinoma: a case report. Cureus. 2018;10(11):e3614. doi: 10.7759/cureus.3614
13. Mahmoudi HR, Kamyab K, Daneshpazhooh M. Cutaneous metastasis of renal cell carcinoma: a case report. Dermatol Online J. 2012;18(5):12. 
14. Kandemir NO, Barut F, Yılmaz K, Tokgoz H, Hosnuter M, Ozdamar SO. Renal cell carcinoma presenting with cutaneous metastasis: a case report. Case Rep Med. 2010;2010:913734. doi:10.1155/2010/913734
15. Arrabal-Polo MA, Arias-Santiago SA, Aneiros-Fernandez J, Burkhardt-Perez P, Arrabal-Martin M, Naranjo-Sintes R. Cutaneous metastases in renal cell carcinoma: a case report. Cases J. 2009;2:7948. doi:10.4076/1757-1626-2-7948
16. Rogow L, Rotman M, Roussis K. Renal metastases simulating Kaposi sarcoma. Radionuclide scanning, an aid in diagnosis and treatment planning. Arch Dermatol. 1975;111(6):717-719. doi:10.1001/archderm.111.6.717
17. Fernández-Rueda P, Ruiz-López P, Ramírez-Negrín MA, Fuentes-Suárez A, Toussaint-Caire S, Vega-Memije ME. Cutaneous metastasis of renal cell carcinoma: a case report and review of the literature. Article in Spanish. Gac Med Mex. 2015;151(4):533-537. 
18. Volmar KE, Cummings TJ, Wang WH, Creager AJ, Tyler DS, Xie HB. Clear cell hidradenoma: a mimic of metastatic clear cell tumors. Arch Pathol Lab Med. 2005;129(5):e113-116. doi:10.1043/1543-2165(2005)129<e113:CCHAMO>2.0.CO;2
19. Riahi RR, Cohen PR. Clinical manifestations of cutaneous metastases: a review with special emphasis on cutaneous metastases mimicking keratoacanthoma. Am J Clin Dermatol. 2012;13(2):103-112. doi:10.2165/11590640-000000000-00000
20. Jindal T, Sinha RK, Mukherjee S, Karmakar D. Calvarial and cutaneous metastasis as the primary presentation of a renal cell carcinoma. BMJ Case Rep. 2014;2014.doi:10.1136/bcr-2013-202830