[Esophageal Lichen Planus - An Underdiagnosed Disease]. / Der Lichen planus des Ösophagus ­ Eine unterschätzte Erkrankung.

An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middleaged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.

[Esophageal Lichen Planus - an Underdiagnosed Disease]. / Der Lichen planus des Ösophagus ­ Eine unterschätzte Erkrankung.

An involvement of the esophagus in patients with lichen planus was described for the first time in 1982. Ever since, it has been seen as a rarity. However, studies over the last 10 years have shown a higher prevalence than expected. It may even be supposed that esophageal lichen planus (ELP) is more common than eosinophilic esophagitis. ELP mostly affects middle-aged women. The principal symptom is dysphagia. Endoscopically, ELP is characterized by denudation and tearing of the mucosa, trachealization and hyperkeratosis and esophageal stenosis may occur in patients with long courses of the disease. Histologic findings including mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis (civatte bodies) and dyskeratosis are crucial. Direct immunofluorescence shows fibrinogen deposits along the basement membrane zone. So far, there is no well-established therapy but a treatment with topic steroids is effective in 2/3 of the patients. Common therapy of lichen planus of the skin seems to be ineffective for treatment of ELP. Symptomatic esophageal stenosis should be endoscopically dilated. ELP joins the group of "new" immunologic diseases of the esophagus.

Trigger-dependent differences determine therapeutic outcome in murine primary hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a hyperinflammatory syndrome affecting patients with genetic cytotoxicity defects. Perforin-deficient (PKO) mice recapitulate the full clinical picture of FHL after infection with lymphocytic choriomeningitis virus (LCMV). Hyperactivated CD8+ T cells and IFN-γ have been identified as the key drivers of FHL and represent targets for therapeutic interventions. However, the response of patients is variable. This could be due to trigger-dependent differences in pathogenesis, which is difficult to address in FHL patients, since the trigger frequently escapes detection. We established an alternative FHL model using intravenous infection of PKO mice with murine CMV (MCMV)Smith . PKO mice developed acute FHL after both infections and fulfilled HLH diagnostic criteria accompanied by excessive IFN-γ production by disease-inducing T cells, that enrich in the BM. However, direct comparison of the two infection models disclosed trigger-dependence of FHL progression and revealed a higher contribution of CD4 T cells and NK cells to IFN-γ production after MCMV infection. Importantly, therapeutic intervention by IFN-γ neutralization or CD8+ T-cell depletion had less benefit in MCMV-triggered FHL compared to LCMV-triggered FHL, likely due to MCMV-induced cytopathology. Thus, the context of the specific triggering viral infection can impact the success of targeted immunotherapeutic HLH control.

γδ T-cell Receptors Derived from Breast Cancer-Infiltrating T Lymphocytes Mediate Antitumor Reactivity.

γδ T cells in human solid tumors remain poorly defined. Here, we describe molecular and functional analyses of T-cell receptors (TCR) from tumor-infiltrating γδ T lymphocytes (γδ TIL) that were in direct contact with tumor cells in breast cancer lesions from archival material. We observed that the majority of γδ TILs harbored a proinflammatory phenotype and only a minority associated with the expression of IL17. We characterized TCRγ or TCRδ chains of γδ TILs and observed a higher proportion of Vδ2+ T cells compared with other tumor types. By reconstructing matched Vδ2- TCRγ and TCRδ pairs derived from single-cell sequencing, our data suggest that γδ TILs could be active against breast cancer and other tumor types. The reactivity pattern against tumor cells depended on both the TCRγ and TCRδ chains and was independent of additional costimulation through other innate immune receptors. We conclude that γδ TILs can mediate tumor reactivity through their individual γδ TCR pairs and that engineered T cells expressing TCRγ and δ chains derived from γδ TILs display potent antitumor reactivity against different cancer cell types and, thus, may be a valuable tool for engineering immune cells for adoptive cell therapies.

Fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab.

Vedolizumab (VDZ) inhibits α4ß7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non-responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients.

Continuous T cell receptor signals maintain a functional regulatory T cell pool.

Regulatory T (Treg) cells maintain immune homeostasis and prevent inflammatory and autoimmune responses. During development, thymocytes bearing a moderately self-reactive T cell receptor (TCR) can be selected to become Treg cells. Several observations suggest that also in the periphery mature Treg cells continuously receive self-reactive TCR signals. However, the importance of this inherent autoreactivity for Treg cell biology remains poorly defined. To address this open question, we genetically ablated the TCR of mature Treg cells in vivo. These experiments revealed that TCR-induced Treg lineage-defining Foxp3 expression and gene hypomethylation were uncoupled from TCR input in mature Treg cells. However, Treg cell homeostasis, cell-type-specific gene expression and suppressive function critically depend on continuous triggering of their TCR.

S. mansoni bolsters anti-viral immunity in the murine respiratory tract.

The human intestinal parasite Schistosoma mansoni causes a chronic disease, schistosomiasis or bilharzia. According to the current literature, the parasite induces vigorous immune responses that are controlled by Th2 helper cells at the expense of Th1 helper cells. The latter cell type is, however, indispensable for anti-viral immune responses. Remarkably, there is no reliable literature among 230 million patients worldwide describing defective anti-viral immune responses in the upper respiratory tract, for instance against influenza A virus or against respiratory syncitial virus (RSV). We therefore re-examined the immune response to a human isolate of S. mansoni and challenged mice in the chronic phase of schistosomiasis with influenza A virus, or with pneumonia virus of mice (PVM), a mouse virus to model RSV infections. We found that mice with chronic schistosomiasis had significant, systemic immune responses induced by Th1, Th2, and Th17 helper cells. High serum levels of TNF-α, IFN-γ, IL-5, IL-13, IL-2, IL-17, and GM-CSF were found after mating and oviposition. The lungs of diseased mice showed low-grade inflammation, with goblet cell hyperplasia and excessive mucus secretion, which was alleviated by treatment with an anti-TNF-α agent (Etanercept). Mice with chronic schistosomiasis were to a relative, but significant extent protected from a secondary viral respiratory challenge. The protection correlated with the onset of oviposition and TNF-α-mediated goblet cell hyperplasia and mucus secretion, suggesting that these mechanisms are involved in enhanced immune protection to respiratory viruses during chronic murine schistosomiasis. Indeed, also in a model of allergic airway inflammation mice were protected from a viral respiratory challenge with PVM.

The Nlrp3 inflammasome regulates acute graft-versus-host disease.

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome-mediated IL-1ß production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1ß or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro-IL-1ß cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1ß originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1ß were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication.

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100.

Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvß3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.

Treatment option of bendamustine in combination with rituximab in elderly and frail patients with aggressive B-non-Hodgkin lymphoma: rational, efficacy, and tolerance.

We analyzed the safety and efficacy of rituximab plus bendamustine (R-B) in elderly and frail patients with aggressive B-non-Hodgkin lymphoma (a-B-NHL). Few reports have as yet reported on R-B in a-B-NHL, albeit its value for indolent lymphoma vs. R-CHOP has impressively been shown. We assessed 20 consecutive patients with a-B-NHL receiving R-B as first-line or relapse treatment after (R)-CHOP in our department. Besides patient- and lymphoma-specific characteristics, comorbidity indices were determined. The median patient age was 72 years (51-86), the median Karnofsky performance status was 55 % (40-90 %), and according to the international prognostic index, 15 had high-intermediate or high-risk disease. The comorbidity indices revealed a median Kaplan-Feinstein index of 3 (range 1-3), Charlson comorbidity index of 4 (range 0-9), hematopoietic cell transplantation-specific comorbidity index of 3 (range 0-11), and Freiburg comorbidity index of 2 (range 0-2). Moreover, eight patients had echocardiographic and laboratory signs of cardiac insufficiency, all leading to R-B rather than R-CHOP treatment. The overall response rate was 55 %, with complete response and partial response rates of 20 and 35 %, respectively. In our frail and elderly patient cohort, R-B therapy was well-tolerated. Median progression free survival and overall survival were 8.3 months (95 % confidence interval [CI], 2.8--not reached [n.r.]) and 19.4 months (95 % CI, 4.6--n.r.), respectively. We conclude that R-B is a feasible and safe therapy option in a-B-NHL patients not qualifying for R-CHOP but needs to be further assessed in larger subsequent trials, these currently being under way.

Acute hepatitis after autologous stem cell transplantation and rapid progression to liver cirrhosis.

A 51-year-old woman was diagnosed with a diffuse cerebral large cell lymphoma. During the period of a combined chemotherapy followed by autologous stem cell transplantation with multiple blood donations, an acute hepatitis without hepatitis C antibodies was diagnosed. Liver biopsy showed steatohepatitis, initially thought to be related to chemotherapy. Sixteen months after the transplantation, liver cirrhosis appeared with circulatory bypass. Retrospectively, testing of serum samples showed a hepatitis C infection. Infection with the hepatitis C virus (HCV) from a blood donation was excluded through retrospective testing for HCV-RNA of blood donors. Finally, the cause of infection remained elusive. Hepatitis serology is not a reliable test under immunosuppressive therapy. The course of progression to liver cirrhosis in the presented short period of 22 months after HCV infection is remarkable and has - to our knowledge - not been reported in literature before.

Standards and impact of hematopathology in myelodysplastic syndromes (MDS).

The diagnosis, classification, and prognostication of patients with myelodysplastic syndromes (MDS) are usually based on clinical parameters, analysis of peripheral blood and bone marrow smears, and cytogenetic determinants. However, a thorough histologic and immunohistochemical examination of the bone marrow is often required for a final diagnosis and exact classification in these patients. Notably, histology and immunohistology may reveal dysplasia in megakaryocytes or other bone marrow lineages and/or the presence of clusters of CD34-positive precursor cells. In other cases, histology may reveal an unrelated or co-existing hematopoietic neoplasm, or may support the conclusion the patient is suffering from acute myeloid leukemia rather than MDS. Moreover, histologic investigations and immunohistology may reveal an increase in tryptase-positive cells, a coexisting systemic mastocytosis, or bone marrow fibrosis, which is of prognostic significance. To discuss diagnostic algorithms, terminologies, parameters, and specific issues in the hematopathologic evaluation of MDS, a Working Conference involving a consortium of US and EU experts, was organized in June 2010. The outcomes of the conference and resulting recommendations provided by the faculty, are reported in this article. These guidelines should assist in the diagnosis, classification, and prognostication in MDS in daily practice as well as in clinical trials.

Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis.

As current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnostic impact of dynamic contrast enhanced (DCE)-volumetric computed tomography (VCT) (descriptive analysis), DCE-MRI (two-compartment model) and diffusion weighted imaging (DWI) for monitoring anti-angiogenic therapy effects of the VEGF antibody bevacizumab in breast cancer bone metastases in rats was studied. Nude rats (n=8 animals treated with bevacizumab and n=9 untreated control rats) with site-specific osteolytic bone metastasis of the hind leg were imaged with a 1.5T clinical MRI-scanner in an animal coil as well as in a volumetric CT-scanner at days 30, 40, 50 and 60 after inoculation of MDA-MB-231 human breast cancer cells. From these data, osteolytic lesion size (OLS), peak enhancement (PE), area under the curve (AUC), amplitude (A), exchange rate constant (k(ep)) and apparent diffusion coefficient (ADC) were determined in bone metastases. Prior to changes in OLS (p< or =0.05 at days 50 and 60) there was already a significant decrease in PE, AUC and A (p< or =0.05 at days 40-60) in treated animals compared to controls. However, for k(ep) and ADC there were no significant differences between the groups at any time point (p>0.05 at days 40-60). In conclusion, anti-angiogenic treatment response in osteolytic breast cancer bone metastases can be assessed early with surrogate markers of vascularization, while DWI appears to be insensitive.

Superiority of magnetic resonance imaging over conventional radiographs in multiple myeloma.

BACKGROUND: Bone lesions in multiple myeloma (MM) are screened with radiological skeletal survey (RSS) due to its widespread availability. Although bone lesions can be missed by RSS, more sensitive radiological surveys are not as yet recommended for routine use due to the low availability of the methodology and economical considerations. CASE REPORT: We report on a 68-year-old male with IgG kappa stage IIIA MM presenting with skeletal pain, fatigue and osteolytic lesions. Since the patient refrained from more intensive therapy, including autologous stem cell transplantation (auto-SCT), he was treated with vertebral irradiation and included in an institutionally guided study which randomized melphalan, prednisone (MP)-lenalidomide (MPR) to MP alone. Although he initially responded, his bone pain reoccurred after three MP cycles. The repeated RSS showed minor, if any changes. Therefore, an MRI was added which revealed extensive osteolyses and extramedullary disease. Justified by these results it was possible to convince the patient that a more intensive therapy approach, including auto-SCT, local irradiation and thalidomide maintenance, was appropriate. CONCLUSION: This case calls for an earlier integration of MRI and/or PET/CT scanning in MM, even if RSS remains unchanged, especially if initial bone disease is substantial and/or MM-related symptoms recur. The time course of information and linked decision-making point towards the future significance of an intensified integration of imaging methodologies in the classification and disease management of MM.

Role of T cells in virus control and disease after infection with pneumonia virus of mice.

Infection of mice with pneumonia virus of mice (PVM) is used as a natural host experimental model for studying the pathogenesis of infection with the closely related human respiratory syncytial virus. We analyzed the contribution of T cells to virus control and pathology after PVM infection. Control of a sublethal infection with PVM strain 15 in C57BL/6 mice was accompanied by a 100-fold increase in pulmonary cytotoxic T lymphocytes, 20% of which were specific for PVM. T-cell-deficient mice failed to eliminate PVM and became virus carriers in the absence of the clinical or histopathological signs of pneumonia that occurred after infection of control mice. Mice with limited T-cell numbers did not achieve virus control without weight loss, indicating that T-cell-mediated virus control was closely linked to immunopathology. Both CD4 and CD8 T cells independently contributed to virus elimination and disease. Virus control and disease were similar in the absence of perforin, gamma interferon, or tumor necrosis factor alpha. Interestingly, disease and mortality after lethal high-dose PVM infection were independent of T cells. These data illustrate a key role for T cells in control of PVM infection and demonstrate that both T-cell-dependent and -independent pathways contribute to disease in a viral dose-dependent fashion.

Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors.

To better understand the molecular pathogenesis of neuroendocrine tumors (NET), we investigated the molecular and clinical characteristics of malignant poorly differentiated colorectal NET and compared these findings with sporadic CRC and well-differentiated benign and malignant fore-/midgut NET. Tumors were analyzed and correlated for microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). NET were scored for proliferation using Ki-67. A total of 34 malignant poorly differentiated colorectal NET, 38 well-differentiated benign and malignant fore-/midgut-NET and 150 sporadic colorectal cancers (CRC) with known MSI status were investigated. Among the sporadic CRC, CIMP was significantly correlated with MSI-high (MSI-H) (p < 0.001). Of the 34 colorectal NET, 0/1 of the MSI-H, 3/5 (60%) of the MSI-L and 13/19 (68%) of the MSS tumors were CIMP+ (p = 0.17). Of the fore-/midgut-NET, none was MSI-H. 20/34 (59%) colorectal NET vs. 11/38 (29%) fore-/midgut-NET were CIMP+ (p = 0.01). The Ki-67 index was significantly higher in poorly differentiated colorectal NET compared to the less malignant fore-/midgut-NET (p < 0.0001). Besides the location in the colon, Ki-67 predicted poor outcome in NET (p < 0.0001). CIMP status did not affect survival. In NET, p16 methylation predicted a poor outcome (p = 0.0004). We conclude that molecular pathogenesis in sporadic CRC and poorly differentiated colorectal NET is different despite some similarities. Main differences between malignant well-differentiated and poorly differentiated NET are the Ki-67 proliferation rate and differential methylation in tumor-associated genes. Predictors of a poor outcome in patients with NET are poor differentiation, a high Ki-67 index and p16 methylation.

Bevacizumab inhibits breast cancer-induced osteolysis, surrounding soft tissue metastasis, and angiogenesis in rats as visualized by VCT and MRI.

The aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer bone metastasis and to monitor osteolysis, soft tissue tumor, and angiogenesis in bone metastasis noninvasively by volumetric computed tomography (VCT) and magnetic resonance imaging (MRI). After inoculation of MDA-MB-231 human breast cancer cells into nude rats, bone metastasis was monitored with contrast-enhanced VCT and MRI from day 30 to day 70 after tumor cell inoculation, respectively. Thereby, animals of the treatment group (10 mg/kg bevacizumab IV weekly, n = 15) were compared with sham-treated animals (n = 17). Treatment with bevacizumab resulted in a significant difference versus control in osteolytic as well as soft tissue lesion sizes (days 50 to 70 and 40 to 70 after tumor cell inoculation, respectively; P < .05). This observation was paralleled with significantly reduced vascularization in the treatment group as shown by reduced increase in relative signal intensity in dynamic contrast-enhanced MRI from days 40 to 70 (P < .05). Contrast-enhanced VCT and histology confirmed decreased angiogenesis as well as new bone formation after application of bevacizumab. In conclusion, bevacizumab significantly inhibited osteolysis, surrounding soft tissue tumor growth, and angiogenesis in an experimental model of breast cancer bone metastasis as visualized by VCT and MRI.

Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer.

Granulocytic sarcoma mimicking a synchronous second primary neoplasm (SPN) constitutes a diagnostic and therapeutic challenge particularly in elderly patients. We report on a 75-year-old female presenting with a Core-binding Factor (CBF) AML of M4eo subtype. The patient also had jaundice, highly elevated bilirubin, lipase, alkaline phosphatase (AP), CA 19-9, and a pancreatic mass highly suspicious of infiltrating pancreatic carcinoma. However, a biopsy demonstrated granulocytic sarcoma. Since the patient had no comorbidities and had been in excellent performance status until the diagnosis of AML, induction chemotherapy was initiated, with subsequent normalization of bilirubin, CA 19-9, lipase and AP. Complete hematologic remission of AML was attained and the pancreatic mass could not be detected anymore. Retrospective analysis of the c-kit protooncogene did not disclose activating mutations of exons 8 or 17. Following one consolidation treatment, the patient remained in excellent health until relapse occurred 7 months later and she succumbed to AML. In conclusion, AML can rarely mimic the clinical picture of pancreatic cancer. The initially good response of this CBF leukemia highlights the principal usefulness of aggressive induction chemotherapy also in older AML patients, if they are carefully selected not only according to biological risk factors such as cytogenetics, but also to "host factors" (good performance status, lack of comorbidities, etc.).

An unusual case of Merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin mainly found in elderly white patients. Due to its poor prognosis with distant metastases in up to 33% and local recurrence in 25-33% and a 5 year disease-specific survival of 64% (1-2) its early diagnosis and appropriate treatment is mandatory. METHODS: The study is an exceptional clinical case of a patient with a large inoperable MCC unable to be treated according to treatment guidelines due to her old age. We review the literature addressing treatment options. RESULTS: The patient was treated with palliative definitive radiotherapy to her large MCC of the left lower leg. She showed a rapid clinical response to four palliative radiation doses of 7 Gy each, necrosis of tumor mass and persistent clearing at a follow-up of 32 weeks. Our patient was very unusual in terms of her extensive MCC and her rapid and complete response to palliative radiotherapy lasting for 6 months at present. CONCLUSIONS: As MCC is an aggressive tumor, best survival is achieved with early diagnosis in a localized stage and prompt adequate surgery and further stage-adjusted treatment. Thus, the differential diagnosis of MCC should not be dismissed in a reddish nodule on the leg, and every excision should be submitted to pathology. In accordance with the literature we demonstrate here that definitive radiotherapy is an effective treatment option for inoperable MCC, which in this individual patient produced necrosis of the extensive tumor mass after only four palliative doses.