Induction of durable responses by oral etoposide monochemotherapy in patients with metastatic Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an aggressive, rare tumour of the skin. For advanced cases with distant organ metastases several different regimens of chemotherapeutics have been described. Disease specific 5-year survival rates for these patients are approximately 11%. In this case series we report our experience with orally administered etoposide (100?mg at days 1 to 10 in a 31 day cycle) in 4 patients. We treated two male and two female patients with a median age of 68.5 years. In our four treated patients the disease control rate (complete remission, partial remission, stable disease) was 100%. Three out of four patients reached complete remission. Promisingly, two of our patients had long lasting, durable responses which, until now, have lasted for 16 and 36 months, respectively. The mean follow up time after start of therapy was 14.25 months (range 1-36 months). Etoposide treatment was generally well tolerated, the most common side effect was neutropenia, in one case CTC grade 3. In conclusion, orally administered etoposide in metastatic Merkel cell carcinoma was highly effective and well tolerated.     

Metastatic Merkel cell carcinoma to the soft tissues of the lower back

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. It has a propensity for both locoregional and distant recurrence despite treatment. We describe the case of a 51-year-old man diagnosed with MCC of the left forehead. At 14 months post surgery and adjuvant radiotherapy he developed an isolated deposit of metastatic MCC in the paraspinal soft tissues of his lower back. This atypical site of metastatic disease was treated with radiotherapy and combination chemotherapy. Atypical and isolated sites of metastatic MCC, although infrequently reported, highlight the often bizarre nature of this aggressive skin cancer. Treatment in such cases needs to be individualized.     

Radiotherapy for localised and advanced Merkel cell carcinoma of the skin: a single institution case series

Merkel cell carcinoma (MCC) is a rare malignant tumour of the skin with a tendency to rapid local progression, frequent spread to regional lymph nodes and distant metastases. We report results with radiotherapy in the treatment of MCC.Thirty-nine patients with histologically proven MCC were treated. Fifteen patients had stage I disease (12 primary, 3 recurrent tumours). Twenty-one patients had stage II disease (10 primary, 11 recurrent tumours). Thirty patients were treated with surgery and adjuvant radiotherapy. Six patients with inoperable disease received radiotherapy alone. Three patients in stage III with distant metastases were treated with palliative radiotherapy.For stage I patients, 3-year loco-regional control (LC), disease-specific survival (DSS) and overall survival (OS) rates were 90%, 100%, and 100%, respectively. For stage II patients, LC, DSS, and OS were 78%, 55%, and 29%, respectively. LC did not differ significantly between stage I and II patients. But, patients presented to radiotherapy directly after operation showed significantly improved LC compared to patients referred in recurrent situation (p = 0.039). Two of six inoperable patients treated with radiotherapy alone relapsed locally.In the current study, surgery and immediate adjuvant radiotherapy resulted in strong loco-regional control. Radiotherapy alone is suggested only in inoperable or metastatic MCC.     

Complete remission of Merkel cell carcinoma of the scalp with local and regional metastases after topical treatment with dinitrochlorbenzol

Merkel cell carcinoma (MCC) is a highly aggressive tumor with a high percentage of recurrence, metastatic spread, and mortality. Treatment of metastasized MCC is not standardized and prognosis of metastasized MCC is often poor. Current protocols recommend surgery, adjuvant radiation therapy, and often lymph node dissection to prevent recurrences. A few sporadic reports of spontaneous regression of MCC suggest a so far not yet characterized role and potential of the immune system in controlling this tumor. We describe a 69-year-old man with extended inoperable MCC of the scalp including multiple local and regional metastases who responded with complete remission to 4 weekly treatments of topically applied immune-modulating dinitrochlorbenzol. Together with subsequent irradiation, remission has now lasted for more than 1 year.     

Merkel cell carcinoma

Merkel cell carcinoma is an unusual primary cutaneous tumor with an aggressive biologic nature. Following surgical treatment, 40% of patients have local recurrences develop, 55% have regional lymph node metastases develop, and 49% have distant metastases develop. We have treated four patients with Merkel cell carcinoma; only one of the four patients was alive and well after 2 years. Two patients died of metastatic disease, one at 11 months following initial treatment and one at 39 months. The fourth patient had a rapid recurrence following initial treatment and is currently in remission following chemotherapy for regional metastases. Recent reports indicate that chemotherapy may be helpful in treating patients with recurrent or metastatic Merkel cell carcinoma.     

Metastasiertes malignes Melanom

A 73-year-old man, in whom 26 years ago a malignant melanoma with cervical lymph node metastases of the right retroauricular region was diagnosed, developed BRAF V600E-negative distant metastases, which progressed during both monochemotherapy and polychemotherapy. Therefore he was started on ipilimumab in a dose of 3 mg/kg body weight four times in intervals of 3 weeks. Subsequently, there was an almost complete regression of distant metastases. In several phase III trials a significant survival benefit has been identified for patients treated with ipilimumab. The human monoclonal antibody has been approved since July 2011 as a second-line treatment in Germany and was incorporated in January 2013 into the new guidelines for the treatment of malignant melanoma. The CTLA-4 antibody is the first drug that can improve significantly survival in patients with metastatic melanoma. In advanced (unresectable or metastatic) melanoma, immunostimulatory treatment with ipilimumab represents a new therapeutic option.     

Antitumour activity of paclitaxel and interferon-alpha in a case of metastatic eccrine porocarcinoma

BACKGROUND: Eccrine porocarcinoma (EP) is a rare malignant tumour arising in the acrosyringium, with about 50% of the cases developing local recurrence or metastatic disease. No standard therapy protocols for metastatic disease exist. In the past, only short remissions were achieved by applying combinations of cytotoxic agents, which were associated with severe side-effects. AIM OF THE STUDY: In the case reported here, the aim was to find a protocol with fewer side-effects for a patient who was not willing to undergo extensive polychemotherapy. SUBJECT: A 67-year-old male patient with local recurrence and regional lymph node metastases after resection of EP was treated with a combination of interferon-alpha (IFN-alpha) 9 million units s.c. three times per week and paclitaxel 100 mg/m(2) weekly i.v., which shows a side-effect profile similar to taxotere and is used in the treatment of a variety of neoplasms such as advanced squamous cell carcinoma. MAIN OUTCOME: This less aggressive treatment was tolerated well and the patient responded with minor remission and long-term stable disease.     

Merkel cell carcinoma in a human immunodeficiency virus-infected patient

In the general population, Merkel cell carcinoma (MCC) is a very rare neuroendocrine primary skin cancer, known for its high propensity for local recurrence and distant metastases. Treatment for this neoplasm is individualized on the grounds of clinical staging at presentation, and may include surgical excision, radiotherapy and chemotherapy. Several studies suggest that MCC occurs more frequently and with a more aggressive course in immunocompromised patients such as organ transplant recipients and those infected with human immunodeficiency virus (HIV). A case of this cutaneous malignancy, characterized by a short-term local recurrence and systemic fatal spread in spite of surgical treatment, radiotherapy and chemotherapy, is described in a patient with advanced HIV infection.     

An isolated Merkel cell carcinoma metastasis at a distant cutaneous site presenting as a second 'primary' tumor

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Disease progression usually occurs via lymphatic spread to regional lymphatic draining basins, followed by distant metastasis. We report the clinical course, histopathology and genetic analysis of a 69-year-old woman with likely hematogenous spread of cutaneous neuroendocrine carcinoma manifesting as a single metastatic lesion to a distant cutaneous site. Although the possibility of two cutaneous primary MCCs was considered, array comparative genomic hybridization (aCGH) identified identical distal amplification of a region of chromosome 12p, and synchronous loss of chromosomes 8p and 17p, effectively ruling out the possibility of independent primaries. We propose that this represents a primary cheek MCC with rapid, isolated cutaneous metastasis to the contralateral ankle via hematogenous spread. The distinction between a second primary MCC and a distant cutaneous metastasis clearly has important implications with regard to staging, treatment and prognosis. To our knowledge, this represents the first report of the use of aCGH to clarify the relationship of multiple synchronous cutaneous MCCs and the first report of a single distant cutaneous focus of hematogenous spread. Our data calls into question prior reports alleging multiple cutaneous primaries of this very rare tumor.     

PD‐1 blockade: a therapeutic option for treatment of metastatic Merkel cell carcinoma

The immune system is extremely important in the development and progression of Merkel cell carcinoma (MCC). Immune checkpoint blockade has recently been shown to enable efficacious treatment of a variety of tumours. We report the use of an anti‐programmed death receptor 1 (PD‐1) antibody for treatment of a patient with metastatic MCC. An 80‐year‐old patient with metastatic MCC received off‐label treatment with the anti‐PD‐1 antibody pembrolizumab after the disease had progressed during therapy with oral etoposide. A positron emission tomography (PET) computed tomography scan performed after three cycles of pembrolizumab revealed responses to therapy with reduced size of the adrenal gland metastases and less PET activity in the adrenal gland and lymph node metastases. Treatment was resumed owing to disease progression after a treatment‐free interval of > 4 months. During subsequent months of treatment, the size of the metastases stabilized and uptake of nuclide by all tumour sites once again decreased. These results reveal the potential efficacy of an anti‐PD‐1 antibody for treatment of metastatic MCC. Thus, they contribute to currently limited data on the use of anti‐PD‐1 antibodies for the treatment of MCC. Moreover, this is the first report of successful resumption of treatment of metastatic MCC with an anti‐PD‐1 antibody. Results from ongoing trials will contribute to determination of the relevance of PD‐1 blockade in metastatic MCC.     

Expression of CXCR4, E-cadherin, Bcl-2, and survivin in merkel cell carcinoma: an immunohistochemical study using a tissue microarray

Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous malignancy with a mortality rate exceeding that of melanoma. Although smaller studies of markers of progression have been performed, large-scale investigation has been difficult due to the rarity of this tumor. Investigation of 4 potential immunohistochemical progression markers using an MCC tissue microarray was performed. An immunohistochemical analysis of CXCR4, E-cadherin, Bcl-2, and Survivin was performed on a tissue microarray of two hundred twenty-seven 0.6-mm tumor cores-110 primary, 73 local/regional metastatic, and 44 distant metastatic-from 87 patients, 23 of which were sampled 2 or more times. There was a statistically significant increase in immunoreactivity to CXCR4 and Survivin in local/regional nodal MCC metastases compared with primary and distant metastatic lesions. No significant differences by disease location were found for either Bcl-2 or E-cadherin. These results suggest a potential role for CXCR4 and Survivin in MCC tumor progression. However, previous data from other studies suggesting a role for Bcl-2 and E-cadherin in MCC progression are not confirmed in this larger sample. Further discovery of additional markers are needed to better characterize this rare but deadly malignancy.     

Prognostic and therapeutic implications of sentinel lymphonodectomy and S-staging in Merkel cell carcinoma

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine neoplasm of the skin with a high propensity for early lymph node metastasis and subsequent distant spread. Optimal treatment and prognostic factors are poorly defined. OBJECTIVE: The purpose of this study is to assess the prognostic and therapeutic relevance of sentinel lymphonodectomy in MCC. METHODS: Five patients with biopsy-proven MCC underwent gamma-probe-guided sentinel lymphonodectomy assisted by lymphatic mapping. From each sentinel lymph node (SLN), a series of paraffin sections was histologically and immunohistochemically examined for the presence of micrometastases, which were then staged according to the recently published S classification. RESULTS: Four of the 5 patients showed metastatic disease in the SLNs, 3 of which were classified as S(2), 1 as S(3). Only 1 of the S(2) patients demonstrated additional positive nodes at completion lymphonodectomy. The patient staged as S(3) refused a radical lymph node dissection and died within 1 year due to widespread metastasis. CONCLUSIONS: Sentinel lymphonodectomy is a low-morbidity procedure which enables an early detection and exact staging of regional lymph node metastases with potentially high prognostic and therapeutic relevance in MCC.     

Dacarbazine, nimustine hydrochloride, cisplatin and tamoxifen combination chemotherapy for advanced malignant melanoma.

Melanoma is an uncommon disease in Japan. The incidence, however, has been gradually increasing in the last two decades, as in many other countries worldwide. Ten patients with metastatic malignant melanoma were treated between March of 1997 and April of 1998 in the Department of Dermatology, National Cancer Center Hospital, with a combination chemotherapy consisting of dacarbazine (DTIC), nimustine hydrochloride (ACNU), cisplatin (CDDP), and tamoxifen (TAM). The patients characteristics were as follows: four were males and six females; the age range was 33-70 years; all were Japanese; sites of primary disease: extremities 4, primary unknown 3, nasal cavity 1, anus 1, scalp 1; sites of metastases: lymph nodes 6, pulmonary system 5, skin 2, liver 3, gall bladder 1, adrenal gland 1. The chemotherapy regimen included DTIC 220 mg/m2/i.v. on days 1 through 3, ACNU 60 mg/m2/i.v. on day 1, cisplatin 25 mg/m2/i.v. on days 1 through 3, and tamoxifen 10 mg p.o. twice daily. One patient achieved a complete response and 3 showed partial responses. The response rate was 40%. The four responders included those with metastases to the nodes, lung, and liver. The main toxicities were nausea, vomiting, leucopenia, anemia, and thrombocytopenia. This regimen is a fairly effective combination against metastatic melanoma.     

Spontaneous regression of recurrent and metastatic Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a malignant neuroendocrine tumor with a high rate of recurrence and metastasis. Despite its high degree of malignancy, spontaneous regression has been documented. We report an 87-year-old woman who presented with recurrent MCC on her left cheek and regional lymph node metastasis. Although she received no treatment due to her poor condition, the recurrent metastatic lesion regressed spontaneously within 2 months.     

Advanced Merkel cell carcinoma—A focus on medical drug therapy

Merkel cell carcinoma (MCC) is a rare but aggressive non‐melanoma skin cancer with significant morbidity and mortality. Treatment of choice for primary and locoregional MCC is complete surgical removal with sentinel lymphonodectomy and postsurgical radiotherapy of tumor basin and locoregional lymph nodes. In nonresectable and advanced tumors, drug therapy is indicated. While cytotoxic chemotherapy has resulted in higher response rates, overall survival remained nearly unaffected. With a better insight into tumor development and biology, new treatment s became available. Immune checkpoint inhibitors result in durable responses with a better safety profile that classical combined chemotherapy. Combinations of immune checkpoint inhibitors with and without radiotherapy help to overcome acquired drug‐resistance. New compounds for vaccination and oral use are on the horizon. Despite all progress, treatment of MCC remains a challenge that needs close interdisciplinary teamwork.     

Merkel cell carcinoma: an unusual indication for isolated limb perfusion

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 (TNFalpha) 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 TNFalpha 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.     

Oral etoposide in the treatment of cutaneous large-cell lymphomas. A preliminary report of four cases

The favourable results of oral etoposide as single-agent therapy in four patients with a cutaneous lymphoma other than mycosis fungoides are reported. In all cases other chemotherapeutic options were limited because of prior chemotherapy or the age of the patients. Therapy with etoposide resulted in an initial complete remission in all patients, and was associated with minimal side-effects.     

Cutaneous gamma/delta T‐cell lymphoma

Only 40 cases of primary cutaneous gamma/delta T‐cell lymphoma (GD‐TCL) have been described. GD‐TCL was included as a provisional entity in the WHO‐EORTC classification of cutaneous lymphomas in 2005. GD‐TCL often failed to respond to polychemotherapy and radiation therapy and have a poor prognosis with a mean survival of only 15 months. We present a patient treated with surgery, immunomodulatory therapy, and polychemotherapy. He then received hematopoietic stem cell transplantation and has been in complete remission since. Allogeneic stem cell transplantation appears to be a promising therapeutic option for aggressive and generally fatal lymphomas like GD‐TCL.