Primary Cutaneous Neuroendocrine Carcinoma Research Articles

Merkel cell carcinoma: an update

Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine carcinoma associated with an adverse prognosis. In recent years, our understanding of MCC biology has markedly progressed. Since the discovery of the Merkel cell polyomavirus, it has become clear that MCC represents an ontogenetically dichotomous group of neoplasms with overlapping histopathology. Specifically, most MCCs arise secondary to viral oncogenesis, while a smaller subset is the direct result of UV-associated mutations. The distinction of these groups bears relevance in their immunohistochemical and molecular characterization, as well as in disease prognosis. Further recent developments relate to the landmark utilization of immunotherapeutics in MCC, providing optimistic options for the management of this aggressive disease. In this review, we discuss both fundamental and emerging concepts in MCC, with a particular focus on topics of practical relevance to the surgical or dermatopathologist.

Merkel cell carcinoma of an atypical presentation: A case report and literature review

Merkel cell carcinoma (MCC) is a primary cutaneous neuroendocrine carcinoma. It is a rare and aggressive tumor characterized by a high frequency of local recurrence, regional nodal metastasis, distant metastasis, and a low survival rate. Its diagnosis is challenging due to its rarity and it may be clinically mistaken for other skin cancers. It requires an incisional biopsy and confirmation by histology and immunohistochemical staining. This case illustrates an uncommon presentation of MCC in a 53-year-old young adult in an unexposed area of the right gluteal region. It is a rare cutaneous tumor that should be diagnosed and treated precociously given the aggressive nature of MCC and the limited therapeutic options for metastatic tumors. Herein, we urge physicians to suspect this diagnosis in front of any rapidly growing skin tumor, even in an unusual location, to provide the patient with appropriate treatment and improve the overall survival rate.

Merkel cell carcinoma of the eyelid and periocular region: A review.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma with a high mortality rate. It typically affects elderly Caucasians, with a slight predilection for males. It is associated with chronic sun exposure and/or immunosuppression. Almost half of all cases occur on the head or neck and an estimated 2.5%–10% arise on the eyelids or periocular skin. It ranks as the 5th most common malignant tumor at these sites, preceded in frequency by basal cell, squamous cell and sebaceous carcinoma, as well as melanoma. Its clinical presentation as a violaceous nodule/plaque lacks specificity, and it can be mistaken for cysts, chalazia or basal cell carcinomas. Sub-specialized histopathological and immunohistochemical evaluations are required for diagnosis. Clinical staging defines the extent of disease and governs management. This includes surgery and adjuvant radiotherapy for localized tumors and of late, immunotherapy for metastatic disease. Significant advances in our understanding of the dual etiopathogenesis (Merkel cell polyomavirus- and Ultraviolet radiation-induced) and the biology of the neoplasm have been achieved in recent years. Issuing from the tumor's known susceptibility to host immunity, a recent therapeutic breakthrough has occurred whereby immune checkpoint inhibition has been shown to mitigate advanced disease. These factors and the increased global incidence of the tumor have brought it to the forefront of medical attention. This review provides a clinically relevant update on MCC, with special reference to cases arising on the eyelid/periocular region.

Merkel cell carcinoma: A review.

Merkel cell carcinoma has been a focus of active scientific investigation in recent years and new information on the topic has emerged. Although uncommon, this primary cutaneous neuroendocrine carcinoma, usually involving the head/neck of elderly individuals, has a poor prognosis. Within the past two decades, an increase in the incidence of the tumor and the discovery of its link to the Merkel cell polyomavirus have focused medical attention on the lesion. The resulting studies have improved our understanding of the biology of the neoplasm and contributed to clinical care. Specifically, two pathogenic subsets of the tumor have come to light, the majority due to Merkel cell polyomavirus and the minority caused by ultraviolet radiation-induced genetic damage. This dichotomy carries prognostic implications favoring the former subset. In addition, having capitalized on the known susceptibility of the tumor to immune influences, investigators have recently discovered its responsiveness to immune checkpoint inhibition. This revelation has constituted a therapeutic milestone at the clinical level. Herein we provide an overview of the topic, outline updates in the field and place an emphasis on dermatopathologic aspects of Merkel cell carcinoma.

Danger is only skin deep: aggressive epidermal carcinomas. An overview of the diagnosis, demographics, molecular-genetics, staging, prognostic biomarkers, and therapeutic advances in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a high grade primary cutaneous neuroendocrine carcinoma and is among the most aggressive cutaneous malignancies. The rising incidence of MCC, together with its often rapidly aggressive course, underscore a critical need to recognize the histopathologic and the immunohistochemical features that inform its accurate diagnosis. In the current review, we summarize the current state of knowledge regarding the accurate diagnosis of MCC and the exclusion of other entities in the differential diagnosis. We provide a comprehensive review of genomic studies that identified the molecular-genetic drivers of MCC as well as a summary of studies identifying prognostic biomarkers that can facilitate risk stratification. Importantly, Merkel cell polyomavirus (MCPyV) appears to be causative in most cases of MCC and represents both a diagnostic and prognostic marker. Finally, as staging of MCC has undergone critical refinements with the introduction of the 8th Edition of the American Joint Committee on Cancer staging system, we provide an update on MCC staging. In particular, the prognostic significance of the sentinel lymph node (SLN) in MCC necessitates a systematic approach to its evaluation and diagnosis to ensure accurate and consistent risk stratification for patients, and we therefore provide a comprehensive overview of SLN evaluation in MCC. Finally, the intimate relationship between MCC and the integrity of the host immune system has led to paradigm-shifting therapeutic advances with the successful application of immune checkpoint blockade to treat patients with advanced disease, and we therefore summarize those studies and the correlative studies in which predictive biomarkers have been identified.

Neurofilament is superior to cytokeratin 20 in supporting cutaneous origin for neuroendocrine carcinoma.

Primary cutaneous neuroendocrine carcinoma, or Merkel cell carcinoma (MCC), cannot be distinguished morphologically from small-cell neuroendocrine carcinomas (SmCC) from other sites. Immunohistochemistry is required to confirm cutaneous origin, and is also used for detection of sentinel lymph node (SLN) metastases of MCC. Cytokeratin 20 (CK20) expression is commonly used for these purposes, but is negative in some MCC cases, and has unclear specificity. We evaluated immunohistochemistry for neurofilament and CK20 in MCC compared with SmCC from other sites. We evaluated neurofilament expression in 55 MCC specimens from 39 unique patients, including nine CK20-negative MCC tumours. Neurofilament expression was observed in 42 of 55 (76.4%) MCC cases, including seven of nine (77.8%) CK20-negative MCC cases. Neurofilament was expressed in nine of 12 (75%) Merkel cell polyomavirus-positive tumours and five of 10 (50%) virus-negative tumours. Compared to a standard immunohistochemical panel (cytokeratin cocktail and CK20), neurofilament was 87.5% sensitive for detecting SLN metastases. Neurofilament and CK20 expression was also assessed in 61 extracutaneous SmCC from 60 unique patients, with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2) and other sites (7). The specificity of neurofilament and CK20 for MCC versus non-cutaneous SmCC was 96.7% and 59.0%, respectively. Neurofilament has superior specificity to CK20 in distinguishing MCC from non-cutaneous SmCC. Neurofilament is frequently expressed in CK20- and virus-negative MCC tumours. Limitations of neurofilament immunohistochemistry include lower sensitivity than CK20 and subtle staining in some tumours. However, our findings indicate that neurofilament is useful for excluding non-cutaneous SmCC.

Merkel cell carcinoma in France: a registries-based, comprehensive epidemiological survey.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. Owing to its low incidence, epidemiological data are scarce and have never been analysed in France to identify the main epidemiological trends. Data from MCC patients diagnosed between 1998 and 2010 were obtained from 11 French cancer registries in the FRANCIM network. The main epidemiological characteristics of MCC were investigated between 2006 and 2010 because comprehensive data were only available for this period. The main focus was tumour incidence and mortality over time. Between 1998 and 2010, 562 cases of MCC were reported in the registries. From 2006 to 2010 (290 cases), European- and world-standardized incidence rates were 0.26 and 0.43 per 100,000 person-years in men and 0.24 and 0.38 per 100,000 person-years in women. MCC is more frequent in females in France (56.9%) with male/female ratio 1.1. Relative survival rates were 84%, 56% and 42% at one, three and 5 years, respectively. The incidence of MCC clearly increased over time in all areas under focus. The standardized incidence in France was comparable to the incidence observed in other countries for the same period, but French data are too recent to conclude on an increase in MCC incidence. Prognosis remains poor in all countries in which data are available.

Cytological, histopathological and immunohistochemical features of merkel cell carcinoma- A case report

Merkel cell carcinoma (MCC) is a rare, potentially aggressive primary cutaneous neuroendocrine carcinoma. MCC commonly occurs on sun-exposed skin in fair-skinned elderly individuals. It usually presents as a banal-appearing lesion, and the diagnosis is rarely suspected at the time of biopsy. We describe the cytomorphologic, histopathological, and immunohistochemical characteristics of MCC in a 76-year-old male patient presenting with rapidly evolving large red raised lesion over cheek for 1 month. Cytohistopathological evaluation suggested MCC. Immunohistochemistry revealed that the tumor cells were negative for leukocyte common antigen, S-100 protein, HMB45, and cytokeratin 20 and positive for neuron specific enolase. Because of the documented aggressiveness and rising incidence, early diagnosis of this rare tumor is necessary for the management of MCC.

Primary Cutaneous Neuroendocrine Carcinoma: Case with an Atypical Location

Primary Cutaneous Neuroendocrine Carcinoma: Case with an Atypical Location

Interaction between Merkel cell carcinoma and the immune system: Pathogenetic and therapeutic implications.

Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma. It usually appears on the face and neck of elderly Caucasian people as a flesh-colored, erythematous or violaceous dome-shaped, non-tender nodule with a smooth surface. In immunocompromised patients with T-cell dysfunction, such as patients with acquired immunodeficiency syndrome (AIDS) or solid organ transplant recipients, the incidence of this disease is markedly increased. This suggests a link between the development of MCC and the immune system. Merkel cell polyolmavirus (MCPyV) is clonally integrated into the majority of MCCs, suggesting its causative role in the pathogenesis of the majority of these tumors. Despite wide local excision, sentinel lymph node biopsy, and eventually, adjuvant radiation therapy, which remains the first-line treatment for MCC, the identification of MCPyV has opened novel therapeutic insights. Novel therapeutic strategies could be to inhibit MCPyV oncoproteins and to stimulate immune responses against virus-infected tumor cells by immunostimulatory cytokines, including interferons and interleukin-2.

Reduced H3K27me3 expression in Merkel cell polyoma virus-positive tumors

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.

Palliative radiotherapy for Merkel cell carcinoma: single-centre experience and review of the literature

AbstractBackground and purposeMerkel cell carcinoma is a rare and aggressive primary cutaneous neuroendocrine carcinoma with a high risk of loco-regional and distant metastasis. It is predominantly seen in the elderly, on the head and neck or extremities. Although treated primarily with surgery, some patients are too frail. A World Health Organization performance status of two or more with co-existing medical co-morbidities, or the site of the disease adjacent to a critical structure, can prevent surgical management. In this cohort of patients, primary palliative radiotherapy has been found to achieve excellent tumour regression and improve quality of life. A new palliative split-course hypofractionated regime has been used in North Middlesex University Hospital in this cohort of patients. The purpose of this case series was to provide supporting evidence on the efficacy of this dose and fractionation regime and review the literature for the palliative management of Merkel cell carcinoma.Materials and methodsIn total, four patients were treated with the palliative split-course hypofractionated regime. The regime consisted of an initial 20 Gray in 5 fractions over 1 week, a 2-week gap and then a further 20 Gray in 5 fractions over 1 week. Tolerability and response to treatment were evaluated by history and clinical examination.Results and conclusionThe split-course hypofractionated regime was well tolerated, achieved excellent tumour regression and improved quality of life in all four patients. Since then, a further three patients have been successfully treated with the above regime. This case series demonstrates the efficacy of this dose and fractionation in a select group of patients too frail for radical management and adds to the evidence base for the optimal palliative management of Merkel cell carcinoma.

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma

Cutaneous neuroendocrine (Merkel cell) carcinoma most often arises de novo in the background of a clonally integrated virus, the Merkel cell polyomavirus, and is notable for positive expression of retinoblastoma 1 (RB1) protein and low expression of p53 compared with the rare Merkel cell polyomavirus-negative Merkel cell carcinomas. Combined squamous and Merkel cell tumors are consistently negative for Merkel cell polyomavirus. Little is known about their immunophenotypic or molecular profile. Herein, we studied 10 combined cutaneous squamous cell and neuroendocrine carcinomas for immunohistochemical expression of p53, retinoblastoma 1 protein, neurofilament, p63, and cytokeratin 20 (CK20). We compared mutation profiles of five combined Merkel cell carcinomas and seven ‘pure’ Merkel cell carcinomas using targeted next-generation sequencing. Combined tumors were from the head, trunk, and leg of Caucasian males and one female aged 52–89. All cases were highly p53- and p63-positive and neurofilament-negative in the squamous component, whereas RB1-negative in both components. Eight out of 10 were p53-positive, 3/10 p63-positive, and 3/10 focally neurofilament-positive in the neuroendocrine component. Six out of 10 were CK20-positive in any part. By next-generation sequencing, combined tumors were highly mutated, with an average of 48 mutations per megabase compared with pure tumors, which showed 1.25 mutations per megabase. RB1 and p53 mutations were identified in all five combined tumors. Combined tumors represent an immunophenotypically and genetically distinct variant of primary cutaneous neuroendocrine carcinomas, notable for a highly mutated genetic profile, significant p53 expression and/or mutation, absent RB1 expression in the context of increased RB1 mutation, and minimal neurofilament expression.

Clinicopathological spectrum of a series of Merkel cell carcinomas diagnosed at a tertiary cancer referral center in India, with current concepts.

Merkel cell carcinoma (MCC) is a rare, clinically aggressive primary cutaneous neuroendocrine carcinoma. The present series describes clinicopathological features of 16 MCCs diagnosed at a tertiary cancer referral center. Sixteen MCCs occurred in 10 men and 6 women (M/F = 1.6:1), between the ages 37 and 74 years (mean, 58.3; median, 58.6), commonly in lower extremities (7) (43.7%) and head and neck sites (5) (31.2%), followed by upper extremities (3) (18.7%) and abdominal wall (1). Tumor size varied from 0.5 to 9.9 cm. Histopathologically, most tumors were composed of round to oval cells, mostly arranged diffusely with hyperchromatic nuclei, including "sudden" pleomorphism in some tumors. Variable features included coexisting Bowen disease (2/16), along with squamous, pseudoglandular, and rhabdomyoblastic dedifferentiation, all in a single tumor. Immunohistochemically, tumor cells were positive for at least a single epithelial marker in all 16 cases (100%) cases, including CK20, mostly paranuclear "dot-like" (12/13, 92.3%); CK (8/9, 88.8%), AE1/AE3 (3/3, 100%), and CK7 (1/6, 16.6%), along with neuroendocrine markers (16/16, 100%), including synaptophysin (11/13, 84.6%), chromogranin (12/15, 80%), and CD56 (4/4, 100%). Among other immunohistochemical markers, positive CKIT/CD117 was positive in 3 of 3 tumors. Surgical resection was performed in 11 (100%) of 11 cases, with adjuvant chemotherapy offered in a single case. Two cases with large-sized tumors, along with another case developed lymph node metastasis, including 1 who later developed pulmonary metastasis. Two patients were free of disease and 2 were alive with disease. Merkel cell carcinomas exhibit a diverse histopathological spectrum, including coexisting Bowen disease and, rarely, rhabdomyoblastic dedifferentiation, in some cases. Optimal immunohistochemical markers include CK20, synaptophysin, chromogranin, and CD56 for a timely diagnosis. Surgical resection is the treatment mainstay. Large-sized tumors and MCCs showing dedifferentiation portend a relatively more aggressive clinical course. Other recent developments in this tumor are discussed herewith.

Merkel cell carcinoma of the head and neck: emphasizing the risk of undertreatment.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. It occurs predominantly in the head and neck area and often behaves aggressively. In this single-institution retrospective observational cohort study, we describe the results of a treatment strategy that we developed over the past decades. Endpoints of this study were local, regional and distant control, disease-specific survival and overall survival. In total 47 patients with head and neck MCC, diagnosed in the Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AvL) between 1984 and 2012, were included in this study. Local tumor control was 82 % (95 % CI 71-95 %) at 5 years. Regional lymph node metastases were found at the moment of diagnosis in 13 cases (28 %). In the group of patients who were initially cN0, the 5-year regional control was 80 % (68-95 %). The 5-year metastasis-free interval probability was 80 % (68-94 %). The disease-specific survival (DSS) at 5 years was 70 % (56-86 %). An overall survival of 54 % (40-72 %) was found at 5-year follow-up and of 37 % (23-59 %) at 10-year follow-up. Univariable Cox regression analysis of many clinical and pathological variables did not identify any predictors for DSS. The MCC has a high propensity for locoregional and distant spread in the head and neck region. Undertreatment, especially of the lymph nodes in the neck, is a serious problem as regional (micro)metastasis are common even in T1 tumors. Future research will have to elucidate the role of the sentinel lymph node procedure versus the elective selective node dissection and standardized elective local and regional radiotherapy in the head and neck area.

Recurrent primary cutaneous mucinous carcinoma with neuroendocrine differentiation: case report and review of the literature

We report the case of a 60-year-old woman presenting with primary cutaneous mucinous carcinoma (PCMC) with neuroendocrine differentiation, revealed by neuroendocrine tumor lymph node metastasis 7 years before identification of the skin tumor. Only five cases of PCMC with neuroendocrine differentiation have been reported to date. The frequency of this neuroendocrine component may be underestimated, as it can require immunohistochemistry for identification, rather than being obvious on initial histopathologic examination. In the case presented here, the prominent neuroendocrine component displayed the morphological features of a well-differentiated neuroendocrine tumor with expression of common neuroendocrine markers, strong expression of estrogen and progesterone receptors and low Ki67 proliferation index (5%). This case shows that not all primary cutaneous neuroendocrine carcinomas are Merkel cell carcinomas (MCCs). In addition to rare primary cutaneous carcinoid tumors, the diagnosis of PCMC with neuroendocrine differentiation must be considered, particularly when confronted by a mucinous tumor or lymph node metastases of neuroendocrine carcinoma of unknown origin. On the basis of this case, identification of a neuroendocrine component in a PCMC might be an adverse prognostic indicator of recurrence or of lymph node metastasis and should support wider excision margins of the tumor.

Merkelzellkarzinom: eine Überprüfung und Aktualisierung über die Pathogenese, Diagnose und Therapieansätze

Merkel cell carcinoma (MCC) or primary cutaneous neuroendocrine carcinoma is a relatively uncommon form of skin cancer. It is an aggressive neoplasm with high tendency for local recurrence and lymph node and distant metastasis, whose incidence has been rising in the last 2 decades.A novel polyomavirus (MCPyV) has been found in a significant proportion of MCCs, and this finding significantly contributed to the understanding of its pathogenesis.It is fairly consensual at the current state of know-ledge that appropriate staging, including sentinel lymph node biopsy, is very important in order to plan adequate treatment. Treatment includes aggressive surgery of the primary tumour and lymph node basin, commonly combined with adjuvant radiotherapy. Chemotherapy is usually reserved for distant metastasis.In the present article, the authors review the current knowledge about MCC with special emphasis on the new pathogenetic findings and current recommendations regarding management.

Combined intraepidermal neuroendocrine (Merkel cell) and squamous cell carcinoma in situ with CM2B4 negativity and p53 overexpression*

Primary cutaneous neuroendocrine carcinoma, also known as Merkel cell carcinoma (MCC), usually presents as a dermal and/or subcutaneous tumor. Rarely, it is confined to the epidermis or adnexal epithelium [MCC in situ (MCCIS)]. Little is known about the spectrum of features and biology of MCCIS. Herein, we report a case of MCCIS arising on the cheek of a 77-year-old Caucasian male, which was associated with squamous cell carcinoma in situ. The tumor cells of both the neuroendocrine and squamous components prominently involved adnexal structures but did not invade the dermis. The tumor cells with neuroendocrine features were immunoreactive for cytokeratin-20, chromogranin and synaptophysin. They also expressed p53 but were non-reactive with the monoclonal antibody CM2B4. Lack of labeling for CM2B4 is in keeping with prior observations of combined squamous and MCC. Our findings support the concept of a distinct subtype of virus-independent cutaneous neuroendocrine carcinoma that differs from conventional MCC. The observed overexpression of p53 suggests that the development of this tumor type may be related to chronic ultraviolet damage.

Primary Cutaneous Neuroendocrine Carcinoma Within a Cystic Trichoblastoma: A Nonfortuitous Association?

Merkel cell (primary cutaneous neuroendocrine) carcinoma is a rare neoplasm of the skin. Its occurrence has been reported in association with other cutaneous neoplasms (Bowen disease, squamous cell carcinoma) in cases regarded as collision tumors. It has recently been described in association with cysts of the follicle apparatus. We present a unique case of rapidly growing nodular tumor on the left forearm of an 84-year-old woman, which proved to be a Merkel cell carcinoma located within a cystic trichoblastoma. The malignant component located in the center of the lesion had typical histopathological and immunohistochemical features of Merkel cell carcinoma. It was surrounded by an epithelial proliferation, made of K17-positive basaloid cells, whose aspects where those of trichoblastoma in a retiform pattern. Both lesions were intertwined, suggesting that the Merkel cell carcinoma had developed within a previously existing trichoblastoma and that it derived from the follicular Merkel cells present in the trichoblastoma. The unique features of this case, together with the reported cases of Merkel cell carcinoma arising within follicular lesions, and the fact that numerous Merkel cells are normally localized in the adult hair follicle, further support the hypothesis of a histogenetic link between normal follicular Merkel cells and Merkel cell carcinoma.

Prise en charge de 145 cas de carcinomes à cellules de Merkel

PurposeMerkel cell carcinoma (MCC)/primary cutaneous neuroendocrine carcinoma is a rare and aggressive malignant tumor. Optimal therapeutic strategy has not yet been established. Patients and methodsManagement of 145 patients from five centres was analysed. These data included ages, pathological stages, disease sites, histological and treatment details. Cause-specific (CSS) and overall survivals (OS) were analyzed by the Log-rank and Kaplan-Meier methods. ResultsMedian age was 78 years (47-95.2). We experienced 37 local, 37 regional and 15 distant relapses. In case of relapse, salvage therapy has been proposed whenever the general state of health condition of patient permitted it. ConclusionOur results for the treatment of relapse encourage multidisciplinary approach. Multicenter prospective trials are still needed to clarify and validate the optimal strategy.