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Merkel cell carcinoma: An unusual indication for isolated limb perfusion

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Merkel cell carcinoma: An unusual indication for isolated limb perfusion
Pedro Ponte MD1, João Vargas Moniz MD2, Victor Farricha MD2, José Bívar Weinholtz MD2
Dermatology Online Journal 14 (7): 6

1. Department of Dermatology, Hospital de Santo António dos Capuchos, Lisbon, Portugal
2. Department of Surgery, Instituto Português de Oncologia Dr. Francisco Gentil, Lisbon, Portugal.


Isolated limb perfusion (ILP) is a surgical technique that enables the administration of high-dose chemotherapy while minimizing serious systemic side effects. The clinical value and indications are well established for skin and soft tissue tumors on limbs. For skin tumors, this technique is mainly indicated for melanoma with in-transit metastasis. For soft tissue tumors – sarcoma and osteosarcoma – it is useful as a palliative technique to reduce the tumoral mass. Limb perfusion can also be an option in other tumors, such as advanced stage squamous cell carcinoma or Merkel cell carcinoma. We present a case report of a 68-year-old man with Merkel cell carcinoma on the right tibiotarsical region, with in-transit metastasis throughout the whole lower limb. Regional chemotherapy involving ILP with melphalan and tumor necrosis factor-alpha (TNFα) was performed in order to avoid amputation; the primary tumor was not excised. A steady regression of the disease was observed, with complete resolution of all visible in-transit metastases at the 45th day post-perfusion. However, systemic metastasis leading to fatal outcome occurred 4 months later. Although there was no change in the patient's prognosis, ILP was able to avoid limb amputation as it controlled local-regional disease and produced complete regional remission. The addition of TNFα to melphalan in ILP appears to produce greater efficacy in the treatment of patients with bulky tumors or a large number of in-transit metastases.


Isolated limb perfusion (ILP) is a surgical procedure that achieves regional chemotherapy concentrations up to 25 times higher than systemic chemotherapy, with minimal systemic side effects [1, 2]. ILP with melphalan is effective in the treatment of multiple, small, in-transit melanoma metastases and is used widely for this indication. The treatment is much less effective against bulky melanoma metastases and has uniformly failed in the treatment of unresectable extremity soft tissue sarcomas [3]. The addition of tumor necrosis factor-alpha (TNFα) has greatly expanded the successful application of ILP against large, bulky soft tissue tumors [4].

Merkel cell carcinoma (MCC) is a rare, aggressive, primary skin cancer with a high incidence of local, regional, and distant recurrences [5]. The mortality rate is reported to be as high as 65 percent [6]. Mohs micrographic surgery and wide margin surgical excision followed by wide-field radiation are the treatment modalities for the primary tumor that provide the best chance of removing not only the tumor but also nearby subclinical deposits [6, 7]. Treatment of advanced local-regional disease has not been clearly defined[ 5]. Numerous, bulky in-transit metastases of MCC pose a difficult challenge in the choice of the optimal treatment strategy.

We describe a patient with locally advanced MCC treated with ILP as a limb salvage attempt.

Case Report

A 68-year-old male Caucasian patient was admitted to our department with a 5 cm violaceous, solitary dome-shaped tumor on the tibiotarsical region with a 2-month evolution (Fig. 1). Histopathology was compatible with MCC. On the 10th day, there was an explosive progression of the disease with the appearance of over 100 nodules scattered throughout the whole lower limb (Fig. 2). Skin biopsy of some of these nodules revealed in-transit metastasis of MCC. Whole body computed tomography (CT) scan did not show distant metastases.

Figure 1Figure 2
Figure 1. Primary Merkel cell carcinoma on the right ankle
Figure 2. Merkel cell carcinoma in-transit metastasis on the lower limb

In an attempt to avoid limb amputation, the patient was then treated with ILP, consisting of a combination of melphalan and TNFα, because of the high number of in-transit metastases and large bulky lesions. We performed an iliac perfusion under temperatures ranging from 39.5º to 40ºC, using 90 mg of melphalan (10 mg/L limb volume) and 1 mg of TNFα. There were no complications during the procedure.

The regional chemotherapy effects were soon noticeable, with a steady regression of the disease after the procedure. Observations were recorded on days 2, 8, 11, and 15 post-perfusion (Figs. 3 to 6).

Figure 3Figure 4
Figure 3. Post-perfusion disease regression on day 2
Figure 4. Post-perfusion disease regression on day 8

Figure 5Figure 6
Figure 5. Post-perfusion disease regression on day 11
Figure 6. Post-perfusion disease regression on day 15

On the 45th day post-ILP, there was obvious primary lesion necrosis and a complete resolution of all in-transit metastases (Fig. 7). However, 2 weeks later, we observed sudden systemic progression of the disease. We chose not to re-intervene and the patient died 4 months later.

Figure 7
Figure 7. Complete response on day 45 post-perfusion


Merkel cell carcinoma management

Merkel cell carcinoma (MCC) is a very aggressive malignancy in which metastatic disease is not unusual. The tumor has a poor prognosis, with a higher mortality rate than melanoma. A useful approach to the treatment of MCC has been sought since its first description in 1972 [8]. The rarity and severity of these tumors have complicated treatment evaluations; large randomized trials cannot be easily performed.

Merkel cell carcinoma has been considered to follow a regional biologic behavior similar to that of an intermediate or thick melanoma, but with a worse overall prognosis. Similar therapeutic strategies have been employed to control local, regional, and systemic disease (Table 1). Surgery is the standard of care for primary MCC; Mohs micrographic surgery [9, 10] and wide local excision [11, 12] have both been employed. There are numerous studies that also support the use of adjuvant radiation therapy in improving local-regional control of the tumor and survival [13, 14].

Sentinel lymph node biopsy (SLNB) detects MCC spread in one-third of patients whose tumors would have otherwise been clinically and radiologically understaged and who may not have received treatment to the involved node bed [15]. SLNB is beginning to be considered a standard approach for staging patients with primary MCC. A complete lymph node dissection is done if the SLN is found to be positive [12]; successful treatment of the lymph node basin with radiotherapy has also been reported [16].

Adjuvant chemotherapy is given to many patients with MCC in analogy to the more common neuroendocrine tumor small-cell carcinoma of the lung. However, current data do not support its routine use in MCC due to its known side effects and lack of evidence for survival benefit [13]. Guidelines for the management of MCC have been recently published elsewhere and are detailed in Table 1 [17].

Patients with overt metastatic disease and a limb-threatening tumor form a special category. Apart from the generally unacceptable option of amputation, no other form of treatment (systemic, regional, or local) achieves response rates that are consistently as high as those obtainable by a palliative TNFα-based ILP [3].

Isolated limb perfusion

Isolated limb perfusion is a surgical technique that is conceptually simple but technically challenging. Its purpose is to achieve very high local-regional chemotherapy concentrations that would be impossible to use systemically. Vascular isolation of the limb is accomplished by clamping and cannulation of major vessels (iliac, femoral, popliteal or axillary artery and vein). They are connected to an oxygenated extracorporeal circuit and a tourniquet is applied around the proximal portion of the limb, thus reducing systemic leakage. A high concentration cytotoxic drug, most commonly melphalan [18], is then injected into the extracorporeal system, where it remains in circulation for 60 minutes. Mild local hyperthermia (38.5 - 40ºC), achieved by heating the perfusate and applying a heated blanket around the limb, increases drug uptake by the cells; this improves the anti-tumoral effect [19]. Temperature has to be closely monitored with temperature probes because true hyperthermia greatly enhances regional toxicity [20]. Protocols using micro-labeled albumin or technetium-labeled red blood cells are used for monitoring leakage during ILP [21, 22]. After establishing perfusion the isotope is injected into the perfusate. A gamma camera is positioned over the precordial area and any increase in counts over the background signifies a systemic leak. After 1 hour of perfusion, the limb is rinsed with an electrolyte solution, cannulas are removed, and the vessels are repaired. As was mentioned earlier, the addition of TNFα to melphalan has extended the application of ILP to large, bulky, soft tissue tumors.

TNFα-based isolated limb perfusion

Tumor Necrosis Factor Alpha targets the tumor-associated vasculature by inducing hyperpermeability and destruction of the vascular lining [23]. Besides causing extravasation of erythrocytes and lymphocytes leading to hemorrhagic necrosis, this results in an immediate effect of selective accumulation of the cytostatic drug inside the tumor and a late effect of destruction of the tumor vasculature.

Tumor Necrosis Factor Alpha-based ILP is currently indicated in melanoma in-transit metastases, as a curative treatment, and in soft tissue sarcomas, as a limb sparing neo-adjuvant treatment. Numerous studies have reported limb salvage rates ranging from 58 percent to 90 percent in cases that normally could only have been managed by amputation or by functionally debilitating resection plus radiotherapy [24]. Its efficacy has also been demonstrated in various other skin tumors such as squamous cell carcinoma [25] and bone sarcomas [26] (Table 2).

Isolated limb perfusion for Merkel cell carcinoma

To our knowledge, only 6 cases of MCC treated with ILP are reported in the literature [25, 27, 28, 29]. Limb salvage was achieved in all of them and 2 of the patients continued in remission for 18 and 66 months, respectively (Table 3).

In the present case of Merkel cell carcinoma, the disappearance of all in-transit metastases was considered an indicator of a successful outcome after treatment. Because the need for amputation was mitigated, we considered it an adequate response criterion in this tumor. The disseminated disease that later ensued might have been a result of metastatic systemic deposits undetected by imaging and clinical evaluation.

Despite its demonstrated regional efficacy, TNFα-based ILP is unlikely to have a great impact on survival. It was shown to have no effect on survival or time to distant metastases in the large prospective trial [30] comparing standard surgery plus adjuvant ILP with surgery alone for patients with melanomas ≥ 1.5 mm in thickness. A similar conclusion was drawn for soft tissue sarcomas [31, 32], in which survival of patients submitted to ILP was no different from a historical database control. In contrast, however, it was shown that the ability to attain a complete response with ILP for melanoma in-transit metastases was the strongest predictor of long-term survival [33].


Tumor Necrosis Factor Alpha-based ILP was an effective and well tolerated palliative treatment in our patient, even though it didn't appear to affect prognosis. It is established as a very successful treatment option in the management of advanced, multiple, or drug-resistant extremity tumors. This technique can represent a therapeutic option in patients with extensive, bulky, limb-threatening in-transit metastases of MCC. Further large-scale investigations are warranted to confirm this approach.


1 Creech O Jr, Krementz ET, Ryan RF, et al. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg. 1958;148:616-632. PubMed

2. Benckhuijsen C, Kroon BB, van Geel AN, et al. Regional perfusion treatment with melphalan for melanoma in a limb: an evaluation of drug kinetics. Eur J Surg Oncol. 1988;14:157-163. PubMed

3. Grünhagen DJ, de Wilt JH, van Geel AN, et al. Isolated limb perfusion for melanoma patients - a review of its indications and the role of tumor necrosis factor-alpha. Eur J Surg Oncol. 2006;32:371-380. PubMed

4. Grünhagen DJ, de Wilt JH, ten Hagen LM, et al. Technology Insight: Utility of TNF-Alpha-Based Isolated Limb Perfusion to Avoid Amputation for Irresectable Extremity Tumors. Nat Clin Pract Oncol. 2006;3:94-103. PubMed

5. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: Report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43:755-767. PubMed

6. Boyle F, Pendlebury S, Bell D. Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. Int J Radiat Oncol Biol Phys. 1995;31:315-323. PubMed

7. Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol. 2007;57:166-169. PubMed

8. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105:107-110. PubMed

9. Boyer JD, Zitelli JA, Brodland DG, et al. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol. 2002;47:885-892. PubMed

10. O'Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg. 1997;23:929-933. PubMed

11. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: Report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43:755-767. PubMed

12. Senchenkov A, Barnes SA, Moran SL. Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol. 2007;95:229-234. PubMed

13. Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol. 2007;57:166-169. PubMed

14. Decker RH, Wilson LD. Role of radiotherapy in the management of merkel cell carcinoma of the skin. J Natl Compr Canc Netw. 2006;4:713-718. PubMed

15. Gupta SG, Wang LC, Peñas PF, et al. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol. 2006;142:685-690. PubMed

16. Schmalbach CE, Lowe L, Teknos TN, et al. Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma. Arch Otolaryngol Head Neck Surg. 2005;131:610-614. PubMed

17. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: Critical review with guidelines for multidisciplinary management. Cancer. 2007;110:1-12. PubMed

18. Thompson JF, Gianoutsos MP. Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs. World J Surg. 1992;16:227-233. PubMed

19. Watanabe N, Niitsu Y, Umeno N, et al. Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia. Cancer Res. 1988;48:650-653. PubMed

20. Vrouenraets BC, Klaase JM, Kroon BB, et al. Long-term morbidity after regional isolated perfusion with melphalan for melanoma of the limbs. The influence of acute regional toxic reactions. Arch Surg. 1995;130:43-47. PubMed

21. Barker WC, Andrich MP, Alexander HR, et al. Continuous intraoperative external monitoring of perfusate leak using I-131 human serum albumin during isolated perfusion of the liver and limbs. Eur J Nucl Med. 1995;22:1242-1248. PubMed

22. Thom AK, Alexander HR, Andrich MP, et al. Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion (ILP) with high-dose TNF, interferon-gamma and melphalan. J Clin Oncol. 1995;13:264-273. PubMed

23. Lejeune FJ, Lienard D, Matter M, et al. Efficiency of recombinant human TNF in human cancer therapy. Cancer Immun. 2006;6:6. PubMed

24. Eggermont AM, Brunstein F, Grunhagen D, et al. Regional treatment of metastasis: role of regional perfusion. State of the art isolated limb perfusion for limb salvage. Ann Oncol. 2004;15 Suppl 4:iv107-112. PubMed

25. Olieman AF, Liénard D, Eggermont AM, et al. Hyperthermic isolated limb perfusion with tumor necrosis factor alpha, interferon gamma, and melphalan for locally advanced nonmelanoma skin tumors of the extremities: a multicenter study. Arch Surg. 1999;134:303-307. PubMed

26. Bickels J, Manusama ER, Eggermont AM, et al. Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for unresectable bone sarcomas of the lower extremity. Eur J Surg Oncol. 1999;25:509-514. PubMed

27. Dawson R, Williams OM, Mansel RE. Isolated hyperthermic limb perfusion chemotherapy in Merkel cell tumor: a case report. J R Coll Surg Edinb. 1996;41:255-256. PubMed

28. Gupta AS, Heinzman S, Levine EA. Successful treatment of in-transit metastases from Merkel's cell carcinoma with isolated hyperthermic limb perfusion. South Med J. 1998;91:289-292. PubMed

29. Grandpeix C, Bonvalot S, Petrow P, et al. [Continued complete remission of Merkel cell carcinoma with in-transit metastasis after treatment with isolated limb perfusion regional chemotherapy]. Ann Dermatol Venereol. 2006;133:700-703. PubMed

30. Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomised phase II trial. J Clin Oncol. 1998;16:2906-2912. PubMed

31. van Ginkel RJ, Thijssens KM, Pras E, et al. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma: three time periods at risk for amputation. Ann Surg Oncol. 2007;14:1499-1506. PubMed

32. Grunhagen DJ, de Wilt JH, Graveland WJ, et al. Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma. Cancer. 2006;106:1776-1784. PubMed

33. Aloia TA, Grubbs E, Onaitis M, et al. Predictors of outcome after hyperthermic isolated limb perfusion: role of tumor response. Arch Surg. 2005;140:1115-1120. PubMed

34. Lev-Chelouche D, Abu-Abeid S, Nakache R, et al. Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan. Surgery 1999; 126: 963-967. PubMed

35. Lev-Chelouche D, Abu-Abeid S, Merimsky O, et al. Isolated limb perfusion with high-dose tumor necrosis factor alpha and melphalan for Kaposi sarcoma. Arch Surg. 1999;134:177-180. PubMed

36. Lans TE, de Wilt JH, van Geel AN, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for nonresectable Stewart-Treves lymphangiosarcoma. Ann Surg Oncol. 2002;9:1004-1009. PubMed

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