March 2010

Second Malignant Neoplasm Occurring Years After Hyperthermic Isolated Limb Perfusion for Melanoma

Author Affiliations

Author Affiliations: Institut National de la Santé et de la Recherche Medicale U725, Etablissement Français du Sang Alsace, Strasbourg (Dr Lenormand), Department of Dermatology, Hôpital Robert Debré, Reims (Drs Pelletier and Grange), Laboratory of Histopathology, Hôpital Maison Blanche, Reims (Dr Goeldel), and Department of Pathology, Hôpital de Hautepierre, Strasbourg (Dr Chenard), France.


Copyright 2010 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2010

Arch Dermatol. 2010;146(3):319-321. doi:10.1001/archdermatol.2010.3

Background  Hyperthermic isolated limb perfusion (HILP) is a useful therapeutic option in patients with locally advanced melanoma of the extremities. Because HILP allows very high doses of cytotoxic agents to be administered without systemic leakage, the theoretical risk of a secondary malignant neoplasm is real, particularly in the treated limb. Such an event has never been reported to our knowledge, however, possibly in part because survival in these patients is often too short to permit the development of chemo-induced cancers.

Observations  We describe 2 cases of secondary rare cancers in 2 elderly women: 1 fatal pleomorphic sarcoma and 1 Merkel cell carcinoma, which developed on the same limb 16 years after HILP for melanoma. The first patient had an exceptional prolonged complete response after HILP for unresectable regional metastases, while the second had been overtreated with HILP and dacarbazine in an adjuvant setting for an early-stage melanoma.

Conclusions  Because long-term survivors of regionally advanced melanoma, although rare, do exist, candidates for HILP should be warned of the risk of long-term development of nonmelanoma secondary cancers. The risk-benefit balance of high-dose local chemotherapy should be carefully evaluated in the light of these findings, especially in patients with early-stage melanoma or other non–life-threatening medical conditions.

Hyperthermic isolated limb perfusion (HILP), a form of regional chemotherapy used since the 1950s, is effective as a pal liative procedure in patients with locally advanced, unresectable malignant melanoma of a limb1 and has been used in other regionally advanced neoplasms such as soft-tissue sarcoma2 and Merkel cell carcinoma.3 It consists of surgically isolating the affected extremity by vessel cannulation to perfuse chemotherapy in mild hyperthermia conditions (ie, limb temperature, 38°C-40°C). Because systemic leakage of the drug is prevented by applying a tourniquet at the root of the limb, very high concentrations—up to 30-fold the level tolerated in systemic infusion—can be administered without causing excessive toxic effects. Because melphalan, the main antiproliferative drug used in HILP, is a known dose-dependant carcinogen, the theoretical risk of secondary cancer is real. Herein, we describe the first 2 cases (to our knowledge) of secondary cancer occurring years after HILP for malignant melanoma.


A 49-year-old woman was diagnosed as having malignant melanoma on her left leg in 1968. A large resection of the lesion was performed, along with chemotherapy, and the patient experienced a long period of remission, which was frequently interrupted by episodes of in-transit cutaneous metastasis that were treated by iterative excisions. In 1988, she had multiple cutaneous metastases on her left leg that were too numerous for serial excisions. She refused the suggested amputation of her leg. The use of HILP with melphalan was then proposed and accepted. The outcome was excellent: the patient subsequently experienced a 16-year period of complete remission.

In 2004, at the age of 85 years, she presented with a nonpigmented fast-growing tumor on the external side of her left leg (Figure 1). The findings of histologic examination of a biopsy specimen were suggestive of an undifferentiated neoplasm. Immunohistochemical stains were negative for S-100 protein, HMB-45, and B-cell– and T-cell–associated antigens and positive for CD68. A diagnosis of myeloid sarcoma was suspected, and radiotherapy (4900 rad [to convert to grays, multiply by 0.01]) was administered, without any effect. A large surgical resection, followed by a graft, was then performed. Histologic examination of the entire piece confirmed the final diagnosis of high-grade pleomorphic sarcoma with focal rhabdoid differentiation (Figure 2). Further evolution was marked by a local recurrence, followed in a few months by rapidly fatal lung metastases despite amputation of the patient's left leg.

Figure 1.
Image not available

Voluminous fast-growing tumor located on the left leg. Note the scars resulting from iterative resections of former in-transit metastases of melanoma.

Figure 2.
Image not available

High-grade pleomorphic sarcoma. Hypercellular malignant subcutaneous tumor composed of spindle cells with moderate nuclear pleomorphism and mitoses (hematoxylin-eosin, original magnification ×100).


A 57-year-old woman presented with a pigmented lesion on her left leg in 1991. Excision and histologic examination revealed a nodular malignant melanoma with a Breslow thickness of 1.4 mm. The patient underwent intensive adjuvant therapy consisting of prophylactic radical lymph node dissection of the left inguinal area, HILP with melphalan, and systemic chemotherapy with dacarbazine (10 cycles). She then experienced a 16-year period of complete remission and was assessed by regular clinical monitoring.

She presented in April 2008, at the age of 73 years, with a purple nodule measuring 1 cm in diameter on the external side of her left leg. There was no apparent lymphedema. Histologic examination of a biopsy specimen showed features of a typical Merkel cell carcinoma, and immunostains were positive for cytokeratin 20. A large excision along with a sentinel node biopsy did not show any lymph node involvement. Adjuvant local radiotherapy was then administered to the tumor site.

In May 2009, the patient presented with 3 palpable subcutaneous nodules measuring 1 to 4 cm in diameter on her left leg (Figure 3), distributed both above and below the previous tumor. Because the clinical diagnosis was considered uncertain, a biopsy specimen was obtained from each nodule. The findings of histologic examination of the specimens were consistent with a deeply invasive Merkel cell carcinoma (Figure 4). Because there were no distant metastases, a surgical resection, followed by another local radiotherapy regimen, was planned.

Figure 3.
Image not available

Recurrence of Merkel cell carcinoma, presenting as a subcutaneous palpable nodule, above the scar of melanoma resection.

Figure 4.
Image not available

Sheets of small cells with hyperchromatic nuclei in the dermis, consistent with Merkel cell carcinoma (hematoxylin-eosin-safran, original magnification ×250).


We report 2 exceptional cases of nonmelanoma skin cancers (ie, pleomorphic sarcoma and Merkel cell carcinoma) that developed 16 years after HILP for malignant melanoma. These malignant neoplasms are not known to be associated with malignant melanoma, and their location on the same limb where the procedure had been performed was highly suggestive of a causal role of HILP in their oncogenesis. Also, the clinical presentation in case 2, which was characterized by a very small primary lesion followed 1 year later by multiple subcutaneous nodules, some of which were located 20 cm below the primary lesion, is compatible with multifocal chemo-induced primary tumors as well as with metastases of the previous tumor. In both patients, high doses of melphalan had been used.

Melphalan, a derivative of nitrogen mustard, is a dialkylating agent that is widely used to treat various cancers and other medical conditions and is also known as a potent carcinogenic drug. It exerts an antiproliferative effect by cross-linking the DNA double-helix strands, impairing the DNA replication, and leading to apoptosis. Beyond its ability to induce lymphosarcoma, lung tumors, and peritoneal sarcomas after peritoneal injection in murine models, melphalan has been shown to dramatically increase the relative risk of acute nonlymphocytic leukemia developing in patients who have been treated for ovarian cancer, breast cancer, or multiple myeloma, and this risk increases with increasing doses.4 Furthermore, secondary sarcomas have already been described in childhood cancer survivors who were treated with high doses of alkylating agents.5

To our knowledge, the occurrence of secondary malignant neoplasms after HILP with melphalan has never been reported. This is not surprising, as (1) HILP is rather an infrequent treatment and is restricted to tertiary care centers; (2) little data are available about long-term (ie, >10 years) follow-up of patients after HILP; and (3) since the publication more than 10 years ago of a large controlled trial that showed no benefit of prophylactic HILP after complete resection of localized (high-risk) melanoma,6 most patients treated with HILP had American Joint Committee on Cancer stage III (or even stage IV) disease with unresectable regional limb metastases and therefore a life expectancy that is probably too short for later events such as secondary cancers to occur. In our report, the duration of 16 years after HILP in both patients was remarkably long: patient 1 had an unexpected response to therapy and an exceptional survival considering the staging of her melanoma when the procedure was performed (American Joint Committee on Cancer stage IIIB), whereas patient 2 had undoubtedly been overtreated according to the current French guidelines for the management of nonmetastatic melanoma.7 In any case, the long period after treatment with HILP may have allowed the development of such secondary tumors.

In contrast with other cancers in which secondary malignant tumors have emerged as a major concern because of the prolonged survival that can be observed after the administration of very efficient but carcinogenic chemotherapies, such a risk is rarely considered in patients with melanoma. In view of our observations and previous studies,6 HILP should definitely be discontinued in a prophylactic setting, and the benefits and risks of this treatment should be carefully evaluated in other situations. Although rare, long-term survivors of advanced, unresectable stage III or even stage IV melanoma do exist. In a recent population-based study of stage IV melanoma,8 10 of 316 patients had a survival time of more than 4 years after the occurrence of distant metastases. Three of the 10 patients finally died of melanoma, and 1 died of chemo-induced leukemia after having received numerous maintenance infusions of alkylating agents. We conclude from such observations that the potential carcinogenic effects of chemotherapies must be considered in melanoma as in other cancers.

Hyperthermic isolated limb perfusion remains a useful therapeutic option in patients with recurring, nonresectable in-transit metastases of limb melanoma, a subgroup of whom will experience prolonged complete remission.9 However, such patients should be informed of the long-term risk of secondary nonmelanoma skin cancers developing, even decades after treatment. Finally, we are concerned that the use of isolated limb infusion—a less complex, hence more available, alternative to HILP also involving high doses of melphalan—has been recently proposed in the treatment of refractory extensive warts of the extremities.10 In view of our findings, the risk-benefit balance of such a treatment in nonmalignant conditions should be carefully reassessed.

Back to top
Article Information

Correspondence: Florent Grange, MD, PhD, Department of Dermatology, Hôpital Robert Debré, Avenue du Général Koenig, 51092 Reims CEDEX, France (fgrange@chu-reims.fr).

Accepted for Publication: November 6, 2009.

Author Contributions: Drs Lenormand and Grange had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Grange. Acquisition of data: Lenormand, Pelletier, Goeldel, Chenard, and Grange. Analysis and interpretation of data: Lenormand, Pelletier, Goeldel, and Grange. Drafting of the manuscript: Lenormand, Pelletier, and Grange. Critical revision of the manuscript for important intellectual content: Lenormand, Pelletier, Goeldel, Chenard, and Grange. Study supervision: Grange.

Financial Disclosure: None reported.

Vrouenraets  BCNieweg  OEKroon  BB Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg 1996;83 (10) 1319- 1328
Cherix  SSpeiser  MMatter  M  et al.  Isolated limb perfusion with tumor necrosis factor and melphalan for non-resectable soft tissue sarcomas: long-term results on efficacy and limb salvage in a selected group of patients. J Surg Oncol 2008;98 (3) 148- 155
Duprat  JPDomingues  ALCoelho  EGLeal  RMNishinari  KNeves  RI Long-term response of isolated limb perfusion with hyperthermia and chemotherapy for Merkel cell carcinoma. Eur J Surg Oncol 2009;35 (6) 568- 572
 Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs: Volumes 1 to 42: Supplement 7.  Lyon, France International Agency for Research on Cancer1987;
Henderson  TOWhitton  JStovall  M  et al.  Secondary sarcomas in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2007;99 (4) 300- 308
Koops  HSVaglini  MSuciu  S  et al.  Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial: European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 1998;16 (9) 2906- 2912
Saiag  PBosquet  LGuillot  B  et al. Société Française de Dermatologie, Management of adult patients with cutaneous melanoma without distant metastasis: 2005 update of the French Standards, Options, and Recommendations guidelines: summary report. Eur J Dermatol 2007;17 (4) 325- 331
Tchen  TLeonard  FDerancourt  C  et al.  Long-term survivors in stage IV melanoma: a regional population-based study in France. Eur J Dermatol 2009;19 (1) 38- 43
Sanki  AKam  PCThompson  JF Long-term results of hyperthermic, isolated limb perfusion for melanoma: a reflection of tumor biology. Ann Surg 2007;245 (4) 591- 596
Wilks  DJPeach  AH Isolated limb infusion as a novel treatment for extensive plantar warts. Dermatology 2009;218 (4) 367- 369