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The Oncologist, Vol. 12, No. 10, 1178-1182, October 2007; doi:10.1634/theoncologist.12-10-1178
© 2007 AlphaMed Press

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Genitourinary Cancer

Localized Palmar–Plantar Epidermal Hyperplasia: A Previously Undefined Dermatologic Toxicity to Sorafenib

Matthew Beldnera, Michael Jacobsonb, Gene E. Burgesb, Deborah Dewaayc, John C. Maize, Jr.d, Uzair B. Chaudharya

Departments of aHematology/Oncology, bDermatology, and cMedicine, Medical University of South Carolina, Charleston, South Carolina, USA; dDermpath Diagnostics Maize Center for Dermatopathology, Mt. Pleasant, South Carolina, USA

Key Words. Cutaneous manifestations • Tyrosine kinase inhibitors • Dermatologic toxicity • Sorafenib Palmar–plantar erythrodysesthesia • Hand–foot syndrome

Correspondence: Matthew Beldner, M.D., Department of Hematology/Oncology, Medical University of South Carolina, 903 CSB, 96 Jonathan Lucas Street, Charleston, South Carolina 29425, USA. Telephone: 843-792-7834; Fax: 843-792-0644; e-mail: beldner{at}musc.edu

Received March 2, 2007; accepted for publication July 2, 2007.

Disclosure: U.B.C. has acted as consultant to Amgen, Genentech, Wyeth, Bristol-Myers Squibb, and Novartis, and has performed contract work for Amgen and Bristol-Myers Squibb within the last 2 years. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   ABSTRACT
Top
 Abstract
Introduction
 Case Report
 Discussion
 References
 
The development of multitargeted tyrosine kinase inhibitors has provided significant advances in the treatment of renal cell carcinoma. This case describes initial therapy for managing renal cell cancer with the administration of sorafenib, a multitargeted tyrosine kinase inhibitor. We report the development of localized palmar–plantar epidermal hyperplasia, a rare but significant cutaneous adverse event from sorafenib therapy. Mild-to-moderate dermatologic toxicity from sorafenib has been well described in the literature. We also review the current knowledge and the proposed hypothesis for the development of cutaneous events related to tyrosine kinase inhibitors. This particular case represents a unique form of dermatologic toxicity to sorafenib that has not previously been described in the literature.


   INTRODUCTION
Top
 Abstract
 Introduction
Case Report
 Discussion
 References
 
The treatment of renal cell carcinoma has dramatically advanced with the advent of multitargeted tyrosine kinase inhibitors (TKIs). These agents have been approved for advanced renal cell carcinoma and are currently under investigation in the adjuvant setting. This case illustrates a previously undefined cutaneous toxicity to sorafenib, an oral TKI approved for advanced renal cell cancer.

The primary modality for treatment of patients with localized renal cell cancer is surgical resection. Survival benefits have been achieved with radical nephrectomy, or in select cases, nephron-sparing surgery. Following complete surgical resection, there has been no proven disease-free survival or overall survival benefit with the use of adjuvant immunotherapy [1]. Attempts to combine chemotherapy with immunotherapy have been unsuccessful in improving disease free survival and actually appear to be detrimental to overall survival [2]. In patients with metastatic or recurrent disease, immunotherapy with high-dose interleukin-2 (IL-2) has received U.S. Food and Drug Administration (FDA) approval, with initial trials indicating a 14% response rate with a 5% complete response rate. Patients who achieved a complete response had a durable response, and may essentially be cured of the disease, having a median survival duration extending beyond 80 months [3]. Unfortunately, the toxicity can be severe, with hypotension, arrhythmias, oliguria, pruritus, fevers, renal failure, and chills occurring frequently. The mortality rate associated with treatment has been estimated at 2%–4% [4]. Because of the severe toxicities and low response rates, only select patients are considered candidates for high-dose IL-2 therapy.

Investigations of tumorigenesis in renal cell cancer, primarily by cloning of the von Hippel-Lindau tumor suppressor gene, have led to the discovery of upregulation of Raf-1, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptor (VEGFR) activity [5]. The overexpression of VEGF and EGFR has been associated with a poorer prognosis [6]. Recently, multitargeted small molecules, monoclonal antibodies, and mammalian target of rapamycin (mTOR) inhibitors have shown promise in treatment for advanced renal cell cancer [7].

Sorafenib, an oral TKI, initially developed as a Raf-1 inhibitor, was discovered to have activity against B-Raf, VEGFR-2, platelet-derived growth factor receptor (PDGFR), Flt-3, and c-Kit. In July 2000, the first phase I trial using sorafenib in advanced solid tumors demonstrated significant antitumor activity in renal cell cancer, with one patient achieving a partial response and two patients maintaining stable disease [8].

A phase II randomized discontinuation trial compared sorafenib, 400 mg orally twice daily, with placebo [9]. The primary endpoint was to ascertain the effect on tumor growth inhibition rather than tumor shrinkage. Patients received sorafenib for 12 weeks, and were assessed for response to therapy. Patients who had at least a 25% tumor shrinkage continued on therapy, whereas those with a <25% decrease or <25% increase in tumor size were randomly assigned to either continue sorafenib for 12 additional weeks or change to placebo. Patients with a ≥25% increase in tumor size were removed from study. The median progression-free survival time from random assignment was significantly longer with sorafenib (24 weeks) than with placebo (6 weeks). Adverse effects included skin rash, hand–foot skin reaction, and fatigue [10]. The incidence of grade 3 skin toxicity was low, with 13% of patients developing a hand–foot skin reaction and 2% developing a desquamative rash. Skin toxicity was described as mild to moderate and easily reversible by either interruption of the dosing schedule or dose reductions. The study demonstrated significant disease-stabilizing activity and tolerability [9].

These findings resulted in a phase III randomized trial comparing sorafenib with placebo. Approximately 900 patients with refractory metastatic renal cell carcinoma were accrued [8]. A planned interim analysis demonstrated that the median duration of progression-free survival was 24 weeks with sorafenib, compared with 12 weeks with placebo (p < .000001). The response data demonstrated that 80% of patients were progression free in the sorafenib arm (2% partial response and 78% stable disease) compared with 55% in the placebo arm (0% partial response and 55% stable disease). The most common adverse effects included hand–foot skin reaction (26%), diarrhea (30%), alopecia (23%), fatigue (18%), nausea (14%), and hypertension (8%) [8]. This led to FDA approval of sorafenib for advanced renal cell cancer in December 2005.

Additional targeting agents include sunitinib, a small molecule that acts on the kinase portion of the tyrosine kinase receptors VEGFR and PDGFR. Sunitinib was found to have activity in metastatic renal cell carcinoma in a randomized phase III trial in comparison with interferon {alpha} (IFN-{alpha}), achieving a progression-free survival duration of 11 months, versus 5 months, and response rate of 37%, versus 6%, leading to FDA approval for first-line therapy in metastatic renal cell carcinoma [10].

Bevacizumab, a humanized monoclonal antibody agent that binds to VEGF, has been evaluated in a randomized, double-blind, phase II trial compared with placebo. The primary endpoint was time to disease progression. The investigators noted a significantly longer time to disease progression, 4.8 months versus 2.5 months, for patients receiving bevacizumab at a dose of 10 mg/kg administered every 2 weeks [11].

Currently under investigation is temsirolimus, an mTOR inhibitor, that showed initial activity in renal cell cancer in preclinical models [12]. In a randomized phase III trial comparing temsirolimus with IFN-{alpha} and with temsirolimus plus IFN-{alpha} as first-line therapy in patients with poor-risk features, the investigators noted a significantly longer median survival duration of 10.9 months, versus 7.3 months with IFN-{alpha} alone and 8.4 months with temsirolimus plus IFN-{alpha} [13].

Cutaneous side effects are very commonly reported with the usage of TKIs for the treatment of various malignancies. Acneiform eruptions, paronychia, and xerosis have been the most commonly described cutaneous adverse events with erlotinib and gefitinib as well as with cetuximab, a monoclonal antibody EGFR inhibitor [14]. Eruptions affecting the hands and feet have frequently been described with the multitargeted TKIs and have been commonly referred to as hand–foot syndrome, indicating a similarity to the acral erythema or palmar–plantar erythrodysesthesia seen with other chemotherapeutic agents such as cytarabine, fluorouracil, capecitabine, or doxorubicin. In a recent review, Robert et al. [15] suggested that distinct findings consisting of more localized and hyperkeratotic lesions may be seen with EGFR inhibitors. We report here a case of a similar reaction to sorafenib, which we feel substantiates that this is a different finding from the classically described hand–foot syndrome or palmar–plantar erythrodysesthesia.


   CASE REPORT
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 Abstract
 Introduction
 Case Report
Discussion
 References
 
A 39-year-old white man presented with hematuria in October 1999. He was found to have a 7-cm right kidney mass with inferior vena caval involvement. He underwent right radical nephrectomy and the pathology was consistent with clear cell carcinoma of the kidney. He was free of disease until July of 2002, when he was found to have recurrent disease in the left adrenal gland. This lesion was resected and he was monitored without evidence of disease. In June 2004, he presented with anemia and fatigue and was found to have a new colonic lesion, jejunal lesion, and mesenteric implants. An exploratory laparotomy was performed and all disease was resected. In September 2004, he was found to have disease recurrence in the left rectus abdominus sheath.

He was enrolled in a clinical trial using pegylated IFN, GM-CSF, and thalidomide. After eight cycles, he was taken off therapy after achieving a complete response. Subsequently, 4 months later, surveillance scans identified fullness in the left rectus abdominus sheath, which was surgically resected and found to be consistent with recurrent disease. Shortly after resection, positron emission tomography imaging confirmed disease progression in the left rectus abdominus sheath and new pulmonary lesions. Sorafenib was initiated at 400 mg orally twice daily in March 2006. Approximately 2 weeks into therapy he developed a nonpainful acral eruption primarily on the palmar and lateral surfaces of the distal digits. The lesions appeared as multiple targetoid plaques having central yellow-to-brown hyperkeratosis surrounded by a rim of hypopigmentation, and more peripheral erythema (Fig. 1). The largest lesion measured 1.9 cm x 1.2 cm. The lesions were firm to palpation giving the impression of a callus. No fluid was appreciated within the lesions, though they were somewhat compressible as if there was an air space below the thickened epidermis. On the plantar heel was one isolated, ill-defined, reddish brown patch lacking the striking epidermal change seen on the hands.


Figure 1
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  		Figure 1. Palmar lesions appearing as targetoid hyperkeratotic plaques with surrounding rims of hypopigmentation and erythema. Photograph by Michael Jacobson, M.D.

 
Four-millimeter punch biopsies were taken from two lesions on the hands reported by the patient to represent the newest and the oldest lesions. Microscopically, both biopsies showed similar findings (Fig. 2). The lesions were dome shaped with prominent parakeratosis beneath a layer of compact orthohyperkeratosis in the stratum corneum. Serum and a few lymphocytes and neutrophils were found within the parakeratotic areas. The vital epidermis demonstrated marked irregular hyperplasia with foci of hypergranulosis. The hyperplasia was most prominent centrally and tapered toward the edge of the lesion. There was intercellular edema with exocytosis of lymphocytes into the hyperplastic epidermis. Rare dyskeratotic keratinocytes were present in the midspinous layer. No vacuolar changes or dyskeratotic cells at the dermal–epidermal junction were observed. The dermis was remarkable for mild papillary dermal edema with a superficial perivascular infiltrate of lymphocytes and many eosinophils.


Figure 2
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  		Figure 2. The lesion shows alteration of the stratum corneum by parakeratosis, and there is marked epidermal hyperplasia. The dermis shows a moderate superficial perivascular mixed inflammatory infiltrate (original magnification x 40). Inset: There are pyknotic cells in the epidermis with spongiosis and lymphocyte exocytosis (original magnification x 200). Photograph by John C. Maize, Jr., M.D.

 
The sorafenib dose was reduced to 400 mg orally each morning and 200 mg orally each evening, with significant improvement in the skin lesions. He had a near complete response to sorafenib and is currently being maintained on a reduced dose.


   DISCUSSION
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 Abstract
 Introduction
 Case Report
 Discussion
References
 
Several terms have been used to describe the hand–foot findings seen in patients on various chemotherapeutic agents. These include acral erythema, hand–foot syndrome, and palmar–plantar erythrodysesthesia. Both clinical and histologic findings to which these terms refer have been poorly defined and the terms have been used interchangeably.

Hand–foot syndrome has generally been used to describe the cutaneous reaction to sorafenib. Although there may be variability in the lesions seen on physical exam, painless localized lesions with epidermal hyperplasia, as seen in the patient described here, appear to be a relatively unique manifestation with the use of this kinase inhibitor.

This reaction differs from that described with such chemotherapeutic agents as fluorouracil, doxorubicin, capecitabine, docetaxel, and cytarabine. In the classic description, paresthesias and marked tenderness are prominent findings accounting for the use of the term erythrodysesthesia. The visible eruption consists of diffuse erythema and edema with subsequent desquamation and, in some cases, ulceration. One report on two patients on docetaxel describes more well-demarcated lesions similar to fixed drug eruption and having distinctive histologic features of epidermal dysmaturation, a perivascular and perieccrine mononuclear infiltrate with neutrophils, and syringosquamous metaplasia [16].

Histologic findings with doxorubicin, and in general with hand–foot syndrome, have been described as marked hyperkeratosis with parakeratosis in the stratum corneum, spongiosis with numerous pyknotic cells in the viable epidermis, vacuolization in the basal layer, and a mild perivascular lymphocytic infiltrate in the dermis [17]. Similar findings with less involvement of the epidermis are noted with 5-fluorouracil. As hand–foot syndrome progresses in intensity, more prominent vacuolar necrosis of keratinocytes develops in the lower epidermis, with eventual separation from the dermis.

The histology in our case revealed serum with inflammatory cells within the parakeratotic horn. Epidermal hyperplasia was a prominent feature. Spongiosis and the presence of pyknotic cells were similar to the previous descriptions with other agents; however, the moderately dense inflammatory infiltrate containing numerous eosinophils was not noted previously.

A direct toxic effect of the chemotherapeutic agents is hypothesized as the etiology of the cutaneous eruption seen with EGFR inhibitors. The severity of the reaction is correlated with the dosage of the drug and decreasing the dosage or discontinuing the drug results in clearing of the eruption. Increased capillary density and blood flow in the skin of the palms and soles may account for a greater concentration of the drug in those areas and thus visible damage. Hand–foot syndrome has also been reported with exposure to fire ant stings, another condition in which the etiology of the eruption is likely related to toxic effects [17].

Sorafenib inhibits VEGFR and Flt-3, but neither is known to be expressed on keratinocytes [18]. Thus, the direct mechanism of action of the drug seems unlikely to be the cause of the cutaneous side effect of this kinase inhibitor. Descriptions of hand–foot syndrome in response to other drugs have noted the absence of inflammatory cells in the areas of pyknotic cells in the epidermis, thus militating against inflammatory cell damage. Our case, however, showed spongiosis and inflammatory cells within the epidermis as well as eosinophils within a moderately dense dermal infiltrate. This may signify a different mechanism involving inflammatory cells in this reaction to sorafenib.

Both clinical and histologic findings in this reaction to sorafenib indicate that it differs from the earlier described hand–foot syndrome seen with other chemotherapeutic agents. Further observations of larger numbers of patients on this drug may help to elucidate the pathogenesis of this side effect and aid in the discovery of effective treatment that might allow continuation of drug administration at higher therapeutic dosages. Additionally, deeper insight into the effects of sorafenib may stimulate the development of alternative therapeutic usages of the drug.


   REFERENCES
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 Abstract
 Introduction
 Case Report
 Discussion
 References
 

  1. Messing EM, Manola J, Wilding G et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: An Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol 2003;21:1214–1222.[Abstract/Free Full Text]
  2. Atzpodien J, Schmitt E, Gertenbach U et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: Results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer 2005;92:843–846.[CrossRef][Medline]
  3. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000, suppl 1):S55–S57.
  4. Verra N, Jansen R, Groenewegen G et al. Immunotherapy with concurrent subcutaneous GM-CSF, low-dose IL-2 and IFN-alpha in patients with progressive metastatic renal cell carcinoma. Br J Cancer 2003;88:1346–1351.[CrossRef][Medline]
  5. Bardos JI, Ashcroft M. Hypoxia-inducible factor-1 and oncogenic signalling. Bioessays 2004;26:262–269.[CrossRef][Medline]
  6. Wilhelm S, Carter C, Lynch M et al. Discovery and development of sorafenib: A multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006;5:835–844.[CrossRef][Medline]
  7. Motzer RJ, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma. J Clin Oncol 2006;24:5601–5608.[Abstract/Free Full Text]
  8. Kane RC, Farrell AT, Saber H et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006;12:7271–7278.[Abstract/Free Full Text]
  9. Ratain MJ, Eisen T, Stadler WM et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505–2512.[Abstract/Free Full Text]
  10. Motzer RJ, Hutson T, Tomczak P et al. Phase III randomized trial of sunitinib malate (SU 11248) versus interferon-alfa (IFN-{alpha}) as first line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol 2006;24:930s.
  11. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–434.[Abstract/Free Full Text]
  12. Frost P, Moatamed F, Hoang B et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004;104:4181–4187.[Abstract/Free Full Text]
  13. Hudes GR, Carducci M, Tomczak P et al. A phase III randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). J Clin Oncol 2006;24:930s.
  14. Hu JC, Sadeghi P, Pinter-Brown LC et al. Cutaneous side effects of epidermal growth factor receptor inhibitors: Clinical presentation, pathogenesis, and management. J Am Acad Dermatol 2007;56:317–326.[CrossRef][Medline]
  15. Robert C, Soria JC, Spatz A et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005;6:491–500.[CrossRef][Medline]
  16. Eich D, Scharffetter-Kochanek K, Eich HT et al. Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in breast cancer. Am J Clin Oncol 2002;25:599–602.[CrossRef][Medline]
  17. Gordon KB, Tajuddin A, Guitart J et al. Hand-foot syndrome associated with liposome-encapsulated doxorubicin therapy. Cancer 1995;75:2169–2173.[CrossRef][Medline]
  18. Carr ME. Hand-foot syndrome in a patient with multiple fire ant stings. South Med J 2004;97:707–709.[CrossRef][Medline]



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