The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 93, Issue 2

Case Reports | January 19, 2011

Rapidly Growing Squamous-Cell Carcinoma of the Hand in a Renal Transplant Recipient: A Case Report

James Rose, BS¹; Samuel Harms, MD¹; Jennifer Moriatis Wolf, MD¹

¹ Department of Orthopaedic Surgery, University of Colorado School of Medicine, 12631 East 17th Avenue, Room 4602, Aurora, CO 80045. E-mail address for J.M. Wolf: Jennifer.Wolf@ucdenver.edu

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Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Investigation performed at the University of Colorado School of Medicine, Aurora, Colorado

J Bone Joint Surg Am, 2011 Jan 19;93(2):199-202. doi: 10.2106/JBJS.J.00337

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More than 17,500 renal transplant operations are being performed in the United States each year, with a five-year survival rate of 82% for cadaveric and 91% for living donor sources^1,2. Although the risk for the development of all forms of cancer rises after transplant, the risk for nonmelanoma skin cancer increases most dramatically, rising sixtyfold to ninetyfold in the first three years after renal transplant³. In renal transplant recipients, squamous-cell carcinomas are the predominant form of skin cancer^4-6, and these tumors have a greater tendency than both basal-cell carcinoma and melanoma to grow and become rapidly invasive in this population^6-9. Because cancer is the third leading cause of death in renal transplant recipients in the United States (with heart disease and infection leading the list)¹, and because deaths as a result of rapid metastases in this population have been reported¹⁰, recognition of and early treatment for this malignant disease are extremely important. We present the case of a rapidly enlarging squamous-cell carcinoma of the hand in an immunosuppressed renal transplant recipient. The patient was informed that data concerning the case would be submitted for publication, and he consented.

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Introduction

Introduction | Case Report | Discussion | References

Case Report

Introduction | Case Report | Discussion | References

A sixty-two-year-old man presented to the orthopaedic hand clinic in June 2009 with a mass on the dorsum of his right hand. One year earlier, he had received a living-donor renal transplant, performed for chronic renal failure secondary to glomerulonephritis, and, per protocol, he had been maintained on immunosuppressive medications, including tacrolimus, mycophenolic acid, and prednisone, since the transplant procedure. Approximately six months after the transplant operation, the patient noticed a rapidly enlarging lesion on the dorsum of the right hand. The lesion was initially treated as an infection by the nephrologist and internist but showed no response to oral antibiotics. The patient then underwent a biopsy of the lesion by a dermatologist in May 2009, and the diagnosis of well-differentiated infiltrating squamous-cell carcinoma was made. At the time of the patient's presentation to the hand clinic, the lesion measured 4 × 6 cm (Fig. 1). The remainder of the physical examination revealed normal finger, hand, and wrist range of motion with intact sensation in the median, radial, and ulnar nerve distributions. There was no evidence of lymphadenopathy or metastatic lesions. Radiographs of the right hand revealed no involvement of osseous structures, and a computed tomographic scan of the chest showed no evidence of metastatic disease.

Fig. 1

Squamous-cell carcinoma on the dorsum of the hand. (Photograph courtesy of Joel L. Cohen, MD, Denver, Colorado.)

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Because of the malignant nature of the lesion, the patient was managed with surgical excision of the lesion, with 1-cm tumor-free margins circumferentially and to a depth allowing for complete excision of the lesion. Intraoperative frozen-section analysis demonstrated negative margins. All extensor tendons remained intact along with a superficial layer of overlying fascia. Full-thickness skin grafts harvested from the volar aspect of the ipsilateral forearm and medial aspect of the ipsilateral upper arm were placed over the large defect (Fig. 2). These skin-graft donor sites were closed primarily. The final histologic evaluation revealed a well-differentiated invasive squamous-cell carcinoma of skin extending to the deep margin of the dermis with absence of tumor at the surgical margins.

Fig. 2

Defect on the dorsum of the hand has been treated with skin-grafting after resection of the squamous-cell carcinoma.

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Postoperatively, the hand and wrist were splinted for four weeks to allow healing of the skin graft. After four weeks, the patient began range-of-motion exercises and resumed activities as tolerated. He returned to manual labor at two months with no limitations. At six months postoperatively, he had pain-free, full range of motion and strength of the hand, with no evidence of recurrence of the lesion (Fig. 3).

Fig. 3

The final outcome of resection and skin-graft coverage of squamous-cell carcinoma of the dorsal aspect of the hand.

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Discussion

Introduction | Case Report | Discussion | References

Nonmelanoma skin cancer is the most common neoplasm to occur in kidney transplant recipients, and, of these cancers, squamous-cell carcinoma is by far the most common. This is the reverse of what is found in the general population, in which basal-cell carcinoma is the predominant skin cancer^4-6,11,12. Twenty years after transplant surgery, the cumulative incidence of nonmelanoma skin cancer ranges from 41% to 70%, depending on geographic location, with one study showing a mean annual incidence of 3.45% over the first seven years after transplant surgery^5,13. In the general population, squamous-cell carcinomas are the most common malignancy of the hand¹⁴, and the relative risk for upper-limb invasive nonmelanoma skin cancer in renal transplant recipients increases fifty-ninefold⁶. Compared with women, men are at a higher risk of the development of squamous-cell carcinoma^5,15. Overall, the age group in which squamous-cell carcinoma is most commonly found is fifty to fifty-nine years⁶. Several studies show a bimodal distribution of relative risk on the basis of the patient's age at the time of transplant^4,6,15. In patients who are fifty years of age or greater at the time of transplant, the risk of the development of squamous-cell carcinoma rises steadily in the years immediately after transplant, with the main peak occurring after the first six to eight years¹⁶, whereas in patients who are less than fifty years of age at the time of transplant, the risk of the development of squamous-cell carcinoma remains relatively low for the first five to eight years, with a peak occurrence at ten to twelve years after the time of transplant⁶. Moloney et al. noted a second peak in the older group, also occurring at ten to twelve years after transplant, but representing a smaller increase in relative risk than that of the younger group⁶. It is likely that the earlier peak in older patients represents the proliferation of preexisting malignant cells previously held in check by the immune system, while the later peak in both groups represents malignancies originating after the onset of immune suppression^4,6. This second peak, in younger men ten to twelve years after the time of transplant, represents the group that is at the highest risk, in whom the relative risk for nonmelanoma skin cancer is more than 200 times that of the general population⁶.

Several factors are responsible for the pathogenesis of squamous-cell carcinoma in renal transplant patients. Ultraviolet radiation is a well-described etiologic factor in the development of squamous-cell carcinoma. In addition to being mutagenic, ultraviolet radiation also has pro-proliferative effects and appears to inactivate tumor-suppressor genes^4,17. One study found 61% of squamous-cell carcinomas in renal transplant recipients to contain p53 mutations, 78% of which were definitively induced by ultraviolet radiation¹⁸. In addition, most squamous-cell carcinomas in renal transplant recipients occur in heavily sun-exposed areas^5,6,13, and occupational ultraviolet radiation exposure has been found to be an independent risk factor for the development of squamous-cell carcinoma in heart-transplant recipients in one study¹⁹. Ultraviolet-B radiation also appears to mediate the release of interleukin-10¹¹, promoting a Th2 immune response, which has less robust antitumor properties than its Th1 counterpart²⁰.

The effect of the immunosuppressive regimen is the major factor in the occurrence of squamous-cell carcinoma tumors in patients who have had renal transplant surgery. At the present time, there is still major disagreement regarding the nature of this increased risk. Many studies support the hypothesis that the total immunosuppressive load, and not specific immunosuppressive drugs, confers an increased risk of squamous-cell carcinoma^4,8,11,19. There are other studies, however, that show significant differentiation between certain drug regimens and others in the development of squamous-cell carcinoma¹⁵. Cyclosporine appears to have less association with an increased risk of the development of squamous-cell carcinoma in post-transplant patients than azathioprine and prednisone do. A plausible mechanism for tumorigenic properties is associated with all three of these drugs. Azathioprine has been shown to sensitize DNA to the effects of ultraviolet radiation, while calcineurin inhibitors such as cyclosporine and tacrolimus decrease the ability of the cell to perform DNA repair and mutation-induced apoptosis. Prednisone acts to suppress the antitumor immune response⁶. Newer medications, such as sirolimus and everolimus, show some promise for immunosuppression without an increased risk of malignancy, but further trials are needed^8,21.

After the head, the hand is the most frequent location for squamous-cell carcinoma in renal transplant recipients, in one study accounting for 27.4% of all squamous-cell carcinomas observed⁵. Squamous-cell carcinomas in post-transplant patients tend to grow more rapidly and cover more surface area than they do in the general population; in addition, they have a higher tendency to recur and metastasize^6-9. In the workup of these lesions, magnetic resonance imaging has been used successfully to evaluate nearby lymph nodes for the purpose of staging²². In addition, magnetic resonance imaging can also be used to gauge the degree of vascularization and perineural invasion in squamous-cell carcinoma²³. Total surgical resection with wide margins is the preferred therapy for most cutaneous squamous-cell carcinomas in the general population^8,14, although Joyner et al. recently reported marginal excision of squamous-cell carcinoma of the hand in thirty-two patients and noted no recurrence at a mean of thirty-one months, with 8% having positive margins and requiring further surgery²⁴.

Advanced stage at diagnosis has been linked to increased mortality. In the study by Barrett et al., in which nineteen of forty-four renal transplant patients had a diagnosis of late-stage, invasive nonmelanoma skin cancer, characterized by spread to lymph nodes and by distant metastasis, only one patient survived free of disease⁷. Another study noted lymph-node invasion in five of 187 post-transplant recipients with nonmelanoma skin cancer, with two of those five patients dying secondary to cutaneous malignancy⁵. Close surveillance is recommended in renal transplant patients with squamous-cell carcinoma due to its high rate of recurrence¹⁹. In addition, folate and vitamin D may be protective against the carcinogenic effects of ultraviolet radiation⁴; therefore, because renal transplant patients are prone to the development of vitamin-D deficiency, proper dietary supplementation is recommended²⁵.

As more solid organ transplants are performed and the long-term survival of recipients improves, the need for awareness of the risk of nonmelanoma skin cancers is critical. Orthopaedic surgeons involved in the care of transplant recipients should have a high index of suspicion regarding skin lesions and should counsel this patient population on the need for regular surveillance.

References

Introduction | Case Report | Discussion | References

U.S. Renal Data System. USRDS 2009 annual data report: atlas of end-stage renal disease in the United States. Vol 2. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009.

2008 annual report of the U.S.Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: transplant data 1998-2007. Rockville, MD: U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2008. http://www.ustransplant.org/annual_reports/current/. Accessed 2010 Aug 5.

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Ho WL; Murphy GM. Update on the pathogenesis of post-transplant skin cancer in renal transplant recipients. Br J Dermatol. 2008;158:217-24.[PubMed][CrossRef]

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Moloney FJ; Comber H; O'Lorcain P; O'Kelly P; Conlon PJ; Murphy GM. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol. 2006;154:498-504.[PubMed][CrossRef]

Barrett WL; First MR; Aron BS; Penn I. Clinical course of malignancies in renal transplant recipients. Cancer. 1993;72:2186-9.[PubMed][CrossRef]

Ulrich C; Kanitakis J; Stockfleth E; Euvrard S. Skin cancer in organ transplant recipients—where do we stand today?Am J Transplant. 2008;8:2192-8.[PubMed][CrossRef]

Reichrath J; Nürnberg B. Solar UV-radiation, vitamin D and skin cancer surveillance in organ transplant recipients (OTRs). Adv Exp Med Biol. 2008;624:203-14.[PubMed]

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Ulrich C; Schmook T; Sachse MM; Sterry W; Stockfleth E. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients. Dermatol Surg. 2004;30( 4 Pt 2):622-7.[PubMed][CrossRef]

Agraharkar ML; Cinclair RD; Kuo YF; Daller JA; Shahinian VB. Risk of malignancy with long-term immunosuppression in renal transplant recipients. Kidney Int. 2004;66:383-9.[PubMed][CrossRef]

Ramsay HM; Reece SM; Fryer AA; Smith AG; Harden PN. Seven-year prospective study of nonmelanoma skin cancer incidence in U.K. renal transplant recipients. Transplantation. 2007;84:437-9.[PubMed][CrossRef]

TerKonda SP; Perdikis G. Non-melanotic skin tumors of the upper extremity. Hand Clin. 2004;20:293-301, vi.[PubMed][CrossRef]

Ingvar A; Smedby KE; Lindelöf B; Fernberg P; Bellocco R; Tufveson G; Höglund P; Adami J. Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma. Nephrol Dial Transplant. 2010;25:2764-71.[PubMed][CrossRef]

Tessari G; Naldi L; Boschiero L; Nacchia F; Fior F; Forni A; Rugiu C; Faggian G; Sassi F; Gotti E; Fiocchi R; Talamini G; Girolomoni G. Incidence and clinical predictors of a subsequent nonmelanoma skin cancer in solid organ transplant recipients with a first nonmelanoma skin cancer: a multicenter cohort study. Arch Dermatol. 2010;146:294-9.[PubMed][CrossRef]

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Queille S; Luron L; Spatz A; Avril MF; Ribrag V; Duvillard P; Hiesse C; Sarasin A; Armand JP; Daya-Grosjean L. Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene. Carcinogenesis. 2007;28:724-31.[PubMed][CrossRef]

Fortina AB; Piaserico S; Caforio AL; Abeni D; Alaibac M; Angelini A; Iliceto S; Peserico A. Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients. Arch Dermatol. 2004;140:1079-85.[PubMed][CrossRef]

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Topics

renal transplantation ; squamous cell carcinoma ; transplantation ; squamous cell carcinoma of hand

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James Rose, Samuel Harms, Jennifer Moriatis Wolf; Rapidly Growing Squamous-Cell Carcinoma of the Hand in a Renal Transplant RecipientA Case Report. The Journal of Bone & Joint Surgery. 2011 Jan;93(2):199-202.

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