Reduced Corticosteroid Exposure Is Safe and Does Not Reduce Disease Control among Hodgkin Lymphoma Patients Treated with Escalated BEACOPP (eBEACOPP).

Background and Objectives: eBEACOPP is the most effective chemotherapy regimen for younger patients with early unfavorable (EU) and advanced-stage (AS) Hodgkin lymphoma (HL), albeit with significant toxicities. The 14-day/cycle prednisone course contributes to side effects, including osteoarticular events like avascular bone necrosis (AVN). Our center has been using eBEACOPP since 2009 for AS and 2014 for EU patients. In 2016, we reduced prednisone treatment to 7-10 days to lessen AVN risk. We analyzed the effects of this approach. Materials and Methods: We retrospectively collected data on patients who received at least two cycles of eBEACOPP for first-line HL treatment. Results: A total of 162 patients (33 EU, 129 AS) were included. Their median age was 31 (range 19-59 years), and 88 were males. A total of 94 patients received full corticosteroid courses, and 68 received reduced corticosteroid courses. The overall response rate (ORR) was 98%. Different corticosteroid dosings had no significant effect on ORR, febrile neutropenia episodes, or hospital admissions. After a median follow-up (mFU) of 58 months, the 5yPFS for the entire cohort was 98% vs. 95% for the standard course vs. the short corticosteroids course, respectively (p = 0.37), while the 5yOS was 98% vs. 99% for the standard course vs. short corticosteroids course, respectively (p = 0.87). In AS patients intended to be treated with six eBEACOPP cycles, 5yPFS and 5yOS were 100% vs. 97% and 100% vs. 99% for standard vs. short corticosteroid courses, respectively (p = 0.56 and p = 0.17). In EU patients, 5yPFS was 97% (standard) vs. 95% (short) (p = 0.98) and 5yOS 100% vs. 93.3% (p = 0.87). Osteoarticular events were numerically lower in patients receiving the shorter prednisone course, both in the whole cohort and in the subgroup of patients treated with six cycles of eBEACOPP, but this difference failed to reach statistical significance. Conclusions: eBEACOPP provides excellent and durable first-line disease control. Shortening the corticosteroid course does not compromise efficacy, potentially reducing toxicity. However, longer follow-ups and larger studies are needed for confirmation.

Aggressive B-cell non-Hodgkin lymphomas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Aggressive B-cell non-Hodgkin lymphomas are a heterogeneous group of diseases and our concepts are evolving as we learn more about their clinical, pathologic, molecular genetic features. Session IV of the 2020 EAHP Workshop covered aggressive, predominantly high-grade B-cell lymphomas, many that were difficult to classify. In this manuscript, we summarize the features of the submitted cases and highlight differential diagnostic difficulties. We specifically review issues related to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 and/or BCL6 rearrangements including TdT expression in these cases, HGBCL, not otherwise specified, large B-cell lymphomas with IRF4 rearrangement, high-grade/large B-cell lymphomas with 11q aberration, Burkitt lymphoma, and pleomorphic mantle cell lymphoma. Since the workshop, the 5th edition of the WHO Classification for Haematolymphoid Tumours (WHO-HAEM5) and International Consensus Classification (ICC) 2022 were published. We endeavor to use the updated terminology.

Melanoma Developing from an Intradermal Nevus: Report on Two Patients.

Dear Editor, Approximately 25-33% of cutaneous melanomas arise from nevi (1). Shitara et al. suggested that junctional and compound nevi are more likely give rise to melanoma than intradermal nevi, but this has not been definitively confirmed (2). Based on these results and our own clinical observation on rare malignant transformation in intradermal nevi, we present two patients with melanoma developing from an intradermal nevus. The first patient, a 63-year-old woman, presented with a suspicious lesion in 2017 on the upper back in the form of a dark brown macula juxtapositioned next to the dermal nevus (Figure 1, a). Dermoscopy of a flat part showed a dark-brown reticular, slightly structureless pattern (Figure 1, b). The patient was therefore referred to surgical excision. Histopathology of the elevated part showed aggregates of intradermal nevus cells of normal morphological characteristics. Atypical and irregularly sized melanocytes were observed in the flat part, infiltrating the entire depth of the epidermis and the upper parts of the papillary dermis. The diagnosis of malignant melanoma developing from a dermal nevus was established (Breslow 0.4 mm, pT1A) (Figure 1, c). The second patient, a 71-year-old man, presented in 2018 with a pendular non pigmented intradermal nevus on middle part of the back. The left-hand lateral side of the intradermal nevus showed a brown to dark-brown spot which measured 12 mm (Figure 2, a). A central blue white veil, atypical pigment network, and dots and globules of various sizes and shapes were observed on dermoscopy (Figure 2, b). The base of the nevus showed an asymmetric pigmentation. Because the lesion was highly suspicious of melanoma, an urgent excision was indicated. The histopathology of the elevated part (dermal nevus) showed a regular maturation of the nest of nevus cells in the dermis. The histopathology of the dark-brown macule showed proliferation of atypical melanocytes with well-marked nucleoli throughout the epidermis with the infiltration of the suprabasal epidermal layers and papillary dermis. The lesion was classified as melanoma with a partial regression (Breslow 1.3 mm, pT2A), arising in association with an acquired intradermal nevus (Figure 2, c). Case reports with melanoma developed from a small congenital or acquired dermal nevus are extremely rare in the literature. In all published cases, histopathology revealed a melanoma component situated below or laterally, next to the merging dermal nevus (3) and in one case next to and above the dermal component (4), which is very similar to our cases. In both of our cases, melanoma presented an epidermal component with atypical, large melanocytes next to or above the typical and small intradermal melanocytes of the Unna nevus. Despite the fact that the reported statistical occurrence of malignant transformation of every individual nevus is very low in the elderly population (>60 years of age), 1 in 33,000 (5), we believe our two presented cases show a striking similarity in the melanoma manifesting in the vicinity of a previously existing lesion, indicating nevus-associated melanoma (NAM). This letter presents an interesting finding of two cases, with a form of melanoma (NAM) that is statistically very rare in older patients but occurred twice within the span of a year within the same town and was diagnosed in the same hospital. Intradermal nevi are most commonly considered to be benign skin lesions. However, previous research and our two cases shows that intradermal nevi are not immune to malignant alteration. Based on these results, we suggest a detailed clinical and dermoscopic evaluation of each skin lesion, including intradermal nevi. Flat melanocytic parts in the vicinity of intradermal nevi should always raise suspicion and warrant excision with histopathological evaluation of the lesion so as to allow timely response to any malignant alteration.

The spectrum of nodular lymphocyte predominant Hodgkin lymphoma: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 4 of the 2021 European Association of Haematopathology/Society for Hematopathology Workshop focused on nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). First, the spectrum of immunophenotypic variations in NLPHL and the defining criteria for classic Hodgkin Lymphoma (CHL) were discussed. The added value of further immunophenotypic characterization of both tumor cells and microenvironment to support the differential diagnosis was presented. Next, unusual cases with combined growth patterns and evolution of morphological features over time were presented to explore the clinicopathological impact of presumed high-risk patterns. Based on a large collection of cases, the defining morphological, immunophenotypical, and gene expression features of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and THRLBCL-like NLPHL (pattern E) were reviewed to explore this challenging differential diagnosis and critically evaluate whether aggressive behavior and transformation of NLPHL can be predicted in practice.

Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed. The second half of the session focused on mediastinal and non-mediastinal gray zone lymphomas (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). Several cases illustrating the current challenges in separating this entity from PMBL/DLBCL and CHL were presented. There was discussion regarding the clinical and genetic differences between mediastinal and non-mediastinal GZLs. Rare cases of PMBL and GZL associated with EBV or follicular lymphoma were reviewed. Finally, several cases included in the session highlighted composite or sequential CHL and PMBL/DLBCL and/or GZL, highlighting challenges in separating such cases from GZL.

Lymphomas with plasmablastic features: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology.

Lymphomas with plasmablastic features are a heterogeneous group of aggressive and mostly uncommon neoplasms of varied aetiologies, presenting in immunocompetent individuals as well as in immunodeficiency, associated with EBV and Kaposi sarcoma virus infections, and some as progression from indolent B-cell lymphomas. They show overlapping diagnostic features and pose a differential diagnosis with other aggressive B-cell lymphomas that can downregulate the B-cell expression programme. The spectrum of rare reactive proliferations and all lymphomas defined by plasmablastic features, together with an expanding range of poorly characterised, uncommon conditions at the interface between reactive lymphoid proliferations and neoplasia submitted to the session V of the 20th European Association for Haematopathology/Society for Hematopathology lymphoma workshop are summarised and discussed in this paper.

Diffuse intestinal ulcerations: Diagnostic challenge in a patient with complicated celiac disease.

A 48-year-old female patient presented with longstanding unrecognized celiac disease (CD), a family history of CD, and a short duration of alarming symptoms. The diagnostic evaluation revealed the concomitant presence of small and large bowel ulcers raised a dilemma about differential diagnosis in her case. Pathologic examination of tissue specimens from the jejunal ulcer led to the diagnosis of enteropathy-associated T-cell lymphoma. In recent years, the availability of modern cross-sectional imaging and endoscopy modalities has dramatically improved the detection and characterization of small bowel lesions. Characterization of small bowel ulcers by endoscopy and radiology imaging in a patient with suspected complicated CD (CCD) needs to be made in conjunction with all clinical factors, as there is a wide overlap of the possible etiologic factors. Enteropathy-associated T-cell lymphoma is a highly aggressive T-cell lymphoma with a poor prognosis, since early diagnosis and appropriate treatment may be delayed due to nonspecific clinical and endoscopic presentation. Therefore, it is crucial to timely recognize patients with suspected CCD and properly navigate diagnostic imaging tools, acquire adequate biopsy, and perform immunophenotyping to set early diagnosis in patients with diffuse intestinal ulcers and CD.

CD4+/CD57+/CD69+ T lymphocytes and CD14+ dendritic cells accumulate in advanced follicular lymphoma.

Follicular lymphoma is the second most frequent non-Hodgkin's lymphoma, accounting for around 20 % of all lymphomas in Western countries. Initially, it behaves indolently, but in time becomes more aggressive and less susceptible to chemotherapy. Multiple features correlate with the survival of the patients and the progression of the disease, such as therapy with rituximab, tumour microenvironment and the intrafollicular proliferation index. Our research was focused on the association of specific components of tumour microenvironment and the tumour behaviour. The presence and the relative percentage of T lymphocytes, follicular dendritic cells, dendritic cells and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Our results show that T lymphocytes and dendritic cells affect tumour growth, possibly through interactions with tumour cells. Higher patients' ECOG score and the outcome of the disease are associated with the presence of CD14+ dendritic cells in tumour tissue, while the worse overall survival of patients is associated with the increased number of activated helper T lymphocytes that express marker of exhaustion CD57. Taken together, our results suggest that the efficiency of the immune response against follicular lymphoma depends on more than one type of immune cells. Also, we found that the phenotype of these cells, rather than just their number, affects the tumour behaviour and in consequence survival of the patients.

Correction to: Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas.

This erratum is meant to address the error in which the names of one of the authors of the manuscript, was incorrect. Author assumes full responsibility for this error.

The broad and challenging landscape of extranodal lymphoproliferations.

Two sessions in the workshop of the 19th meeting of the European Association for Haematopathology termed "challenging extranodal lymphoproliferations" and "extranodal non-site-specific lymphoproliferations", dealt with a series of heterogenous cases. These included lymphoproliferations of all cell lineages, from reactive lesions mimicking lymphomas through indolent lymphoid neoplasia and tumours with unclear biological behaviour to aggressive and transformed lymphomas. The themes addressed included cases with borderline features between hyperplastic and neoplastic lesions, the diagnostic spectrum of IgG4-related disease, T cell lymphoproliferations arising in extranodal sites with presumed indolent behaviour, diverse clinical presentations of intravascular large B cell lymphoma, diagnostic problems encountered with tumours displaying plasmablastic morphology, pitfalls concerning rare entities like adult T cell lymphoma/leukaemia (ATLL) and extranodal natural killer/T cell (NK/T) lymphomas, and unusual clinical presentations of various lymphomas. Altogether, within the frame of these two sessions, 75 cases remarkably differing in their clinical background, genetic features and overall need for a meticulous diagnostic approach were presented and discussed. In this paper, the salient points raised during the discussion of the cases, current diagnostic concepts and recommendations relevant to the diagnosis of these lymphoproliferations are described.

Update on lymphoproliferative disorders of the gastrointestinal tract: disease spectrum from indolent lymphoproliferations to aggressive lymphomas.

This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as STAT3-JAK2 fusion. In addition, novel clonal markers of disease, such as AXL and JAK3 somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with IRF4 translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e., CCND3-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.

Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.

The clinico-pathological spectrum of primary cutaneous lymphoma other than mycosis fungoides/Sezary syndrome.

The major aim of Session 1 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop was to collect examples of cutaneous lymphomas, excluding mycosis fungoides/Sezary syndrome, as defined in the current WHO classification of tumours of the haemetopoietic and lymphoid tissues. Overall 42 cases were submitted. These were considered in four main categories: primary cutaneous B cell lymphomas (12 cases), primary cutaneous T cell lymphomas/lymphoproliferations with CD8+/cytotoxic phenotype (12 cases), primary cutaneous CD30-positive lymphoproliferative disorders (15 cases) and primary cutaneous T cell lymphomas/leukaemias with CD4+ phenotype (4 cases). Using these cases as examples, we were able to present the full spectrum of cutaneous lymphoproliferations (excluding mycosis fungoides/Sezary syndrome), including examples of rare, provisional and new entities as listed in the 2017 update of the WHO classification. The findings are summarized in this report with emphasis on differential diagnostic considerations and the importance of clinico-pathological correlation for final subtyping. In presenting these findings we hope to raise awareness of this enigmatic group of neoplasms and to further our understanding of these rare disease entities.

High incidence of aseptic hip necrosis in Hodgkin lymphoma patients treated with escalated BEACOPP receiving methylprednisolone.

BACKGROUND: Escalated BEACOPP (eBEACOPP) is an effective but fairly toxic regimen for the treatment of Hodgkin lymphoma (HL). Avascular necrosis (AVN) of femoral head was previously reported to increase in patients treated with eBEACOPP, but so far, no systematic analysis of its frequency has been published. AIMS: To analyse the frequency and identify possible risk factors for AVN development in patients treated with eBEACOPP. METHODS: We identified 26 patients treated with eBEACOPP for newly diagnosed high-risk advanced-stage HL, 25 of whom were alive at the time of study. All patients were invited to participate in a cross-sectional study; 17 patients responded and were evaluated by magnetic resonance imaging and orthopaedic examination. RESULTS: Six patients (35.3%) were diagnosed with AVN after receiving eBEACOPP treatment. AVN was not correlated with age, gender, number of received eBEACOPP cycles, irradiation therapy or cumulative dose of steroids administered. There were significantly more cases of AVN in patients receiving methylprednisolone than prednisone (P = 0.01). CONCLUSION: The use of methylprednisolone was shown to be a risk factor for the development of AVN in patients treated with eBEACOPP and should not be the corticosteroid of choice in the treatment of patients with HL.

Folliculotropic Mycosis Fungoides Associated with Autoimmune Hepatitis.

Dear Editor, the association between lymphomas and autoimmune manifestations, as well as the prevalence of the cases of coexistent lymphomas and autoimmune conditions, has not been completely established (1-3). Since cutaneous T-cell lymphoma (CTCL) cases are rare, any hypothesis can only be based on case reports or small case series. We present the case of a male patient with folliculotropic mycosis fungoides (FMF) and synchronous autoimmune hepatitis (AIH) with extremely high levels of cancer antigen 19-9 (CA 19-9). The patient was under the supervision of a multidisciplinary team consisting of dermatologists, hepatologists, and hematologists. The patient died 15 months after the diagnoses of FMF and AIH were established and 3.5 years after the first skin changes. Based on our knowledge and search of medical databases, this is the first case of AIH in a patient with CTCL, i.e. with MF. A 53-year-old male patient was admitted to our Dermatology Clinic in September 2014 after being briefly treated with acitretin. During hospitalization, he was diagnosed with FMF, autoimmune hepatitis, and newly developed diabetes mellitus. At the time of hospital admission, about 70 percent of the surface of the skin was affected, infiltrated with numerous cysts on the face, neck, and upper thorax. The patient also presented with alopecia affecting most of the scalp, loss of eyebrows and eyelashes (Figure 1), and complained of intensive itching. The clinical presentation suggested the diagnosis of FMF, which was later confirmed based on histological (Figure 2) and immunohistochemical (Figure 3) findings. The histochemical staining method PAS-Alcian did not reveal mucin deposits. Immunohistochemical findings revealed tumor cells to show aberrant T-immunophenotypes - CD3+, CD2+, CD5-, CD7-, CD4+, CD8-, CD30-. Due to elevated serum conjugated bilirubin and extremely high levels of hepatocellular and cholestatic liver enzymes, the patient was transferred to the Gastroenterology Department. Diagnosis of AIH was established based on the liver biopsy (highly active autoimmune hepatitis) and the exclusion of viral etiology, drug-induced hepatotoxicity, and inherited metabolic disorders of the liver. CA 19-9 level was extremely high (4475.0; RR <37.0 µg/L). In March 2015, CA 19-9 decreased to 365.3. In April 2015, erythroderma and small isolated tumors on the trunk and extremities developed. The patient was treated with RE-PUVA and radio-therapy. In June 2015, due to systemic symptoms, the patient was started on PUVA with IFNα. In November 2015, erythroderma persisted together with larger and ulcerated tumors. The patient was treated at the Hematological Department with two cycles of cyclophosphamide, vincristine, doxorubicin, and methylprednisolone. From March 2015, the patient was continuously treated with ursodeoxycholic acid, prednisolone, azathioprine, analog insulin, and allopurinol. MSCT revealed lymphoma infiltrates in the liver, spleen, and peritoneum (gross tumors). The immunophenotypic analysis of the cells in ascites revealed atypical lymphocytes with convoluted nuclei - LCA+, CD3+, CD20-. The patient died in December 2015 due to sepsis with febrile neutropenia. Before death, he suffered from candidiasis and toxic liver damage due to fluconazole. FMF is an aggressive MF variant with infiltration of lymph nodes, visceral involvement at an earlier stage, and decreased life expectancy (4). Autoimmune hepatitis (AIH) is still an unclear progressive liver disease of unknown etiology which features hypergammaglobulinemia, detectable autoantibodies, and interface hepatitis (5). Being exposed to xenobiotic (acitretin) with consequent liver damage could lead to the formation of self-antigens to which the patient's immune system might have sensitized, and the autoimmune attack continued (6). Slightly elevated CA 19-9 levels in autoimmune hepatitis were reported by other authors (7-9). It should be noted that the liver involvement with atypical lymphocytes can be diffuse without any detectable nodules on a CT scan (4). Soluble liver antigen and liver-pancreas antibodies, together with CA 19-9, need to be implemented as routine diagnostic tools to rationalize the usage of tumor markers in day-to-day practice as well in diagnosis of AIH (10).

Role of MYC in B Cell Lymphomagenesis.

B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

[CROATIAN SOCIETY FOR MEDICAL ONCOLOGY CLINICAL GUIDELINES FOR DIAGNOSIS, TREATMENT AND FOLLOW-UP OF PATIENTS WITH MELANOMA]. / KLINICKE PREPORUKE HRVATSKOG DRUSTVA ZA INTERNISTICKU ONKOLOGIJU HLZ-A ZA DIJAGNOZU, LIJECENJE I PRACENJE BOLESNIKA/CA OBOLJELIH OD MELANOMA KOZE.

Melanoma in the Western world has an increasing incidence. One of the most important factor for the increase in incidence is sporadic, uncontrolled exposure to the sun. The basis for the treatment of primary melanoma is surgical treatment. Treatment of metastatic disease of melanoma in recent years experienced significant changes. BRAF and MEK inhibitors, immunotherapy with programmed cell-death immune checkpoint inhibitors (anti-PD-1-antibodies) are new options for the treatment of metastatic disease. A mulitidisiplinary team of Croatian Society for Medical Oncology provides recommendations for diagnosis, treatment and follow-up of melanoma primarily driven to the discovery of new drugs and therapeutic options, that change the prognosis of patients with metastatic melanoma.