Conjunctival melanoma (CM) is an exceptionally rare tumor, with a propensity for local and distant recurrence, with the lungs, skin, liver, and brain being the most common sites of metastasis. Recent progress in systemic treatments, with checkpoint inhibitors and targeted therapies blocking BRAF and MEK, has redefined the standard of care of advanced unresectable and metastatic melanoma. Although most trials did not include patients with conjunctival melanoma, its close molecular and genetic relationship to cutaneous melanoma might suggest a similar response to these novel agents. The authors describe two uncommon cases of metastatic conjunctival melanomas with distinct genetic profiles and, as such, submitted to different systemic treatments.

A paraneoplastic leukemoid reaction is a rare condition of extreme leucocytosis in patients with solid malignancies. The differential diagnosis is often a true challenge. We present a case of a 56-year old woman with a history of stage IIIA malignant melanoma resected in 2004 that was diagnosed in May 2013 with BRAF V600E-mutated metastatic disease (left arm mass, lungs and adrenal glands). The laboratory findings revealed leucocytosis with granulocytosis that increased progressively to values up to 120.0 × 10(9)/L. After a diagnostic work-up, a diagnosis of a paraneoplastic leukemoid reaction was established. We report the response of leucocytosis to radiation and BRAF inhibitor therapy, albeit short-lived. To the best of our knowledge, this is the first case report of a paraneoplastic leukemoid reaction in metastatic melanoma with characterisation of BRAF V600 mutation status. It remains unclear whether the aggressive tumour phenotype is related to the leukemoid reaction and whether this is related to the BRAF mutation.

Anorectal melanoma is an uncommon cancer with a poor prognosis. We aim to describe the clinical presentation, treatment and outcome of patients with anorectal melanoma in our center. Retrospective study of patients with anorectal melanoma treated between 2000 and 2011 at a cancer center in Lisbon. Ten patients were identified, eight females and two males, with median age 70.5 years (32-79). Symptoms at presentation were rectal bleeding (8), anal pain (4) and discomfort (3). Tumor location was anal (6), rectal (3) and anorectal transition (2). Seven patients had surgery: abdomino-pelvic resection (5) and local resection (2). Among the two patients who underwent local resection, one was an incidental finding in a hemorrhoidectomy specimen. This patient had further adjuvant chemotherapy (dacarbazine). Three patients had distant metastasis at diagnosis, one had chemotherapy and two had best supportive care. Six of the seven operated patients relapsed in a median time of 5.4 months: distant metastasis (4), local recurrence (1), both (1). The two local relapse patients had surgical widening of resection margins (1) and radiotherapy (2). One-year survival was 30 %; 3-year survival was 20 %. Anorectal melanoma has a poor prognosis due to advanced disease at presentation and aggressive course, with relapse in almost all operated patients. Treatment guidelines have not been established due to the lack of randomized studies. However, recent studies show that sphincter-sparing surgical procedures along with low dose intensity radiotherapy seem to achieve a local control similar to abdomino-pelvic resection. No systemic therapy is considered standard of care for advanced disease, and regimens are extrapolated from cutaneous melanoma experience.

Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil). Method A retrospective cohort of melanoma patients was established, comprising adult patients diagnosed with malignant melanoma treated with immunotherapy or targeted therapy. Exposure was characterized by nature, time and intensity of exposure. To account for different exposure periods, person-time was used as unit of analysis. Main outcomes measure Occurrence of AEs. Results Data from 111 patients included in the cohort indicates the majority received immunotherapy regimens (CTLA-4, anti-PD-1 and combination therapy; (n = 70; 63.1%), among which anti-PD-1 were the predominant treatment. Pembrolizumab was the most frequently prescribed drug (n = 30; 45.7%). Three hundred and seventy-one AEs were extracted. The incidence of AEs was lower in the anti-PD-1 mAc group (54 AEs per 1000 person.months) and the number of AEs/patient was also lower (3.1 ± 2.0). Grade 3 to 4 AEs occurred in 15.3% (n = 17) of the cohort, being more common in the targeted therapy group. Forty-two (11.6%) of the extracted AEs were not described in the Summary of Product Characteristics of the drugs under study. Conclusion This study suggests various known and unknown AEs of immunotherapy and targeted therapy may be identified using the Cancer Registry database. These events should be considered as signals worth further investigation for assessment of causality as the underreporting of AEs in cancer may have potential implications for the patient's quality of life.

Merkel cell carcinoma is a rare and aggressive cutaneous tumor, and the use of checkpoint inhibitors immunotherapy is a recent indication in its metastatic setting, both first and second line. However, the widespread use of immunotherapy is associated with an increase of acute and late immune-mediated adverse events. We present a case of an elderly fit patient with metastatic Merkel cell carcinoma treated with pembrolizumab who developed diabetic ketoacidosis, a severe immune-mediated adverse event. A multidisciplinary approach was crucial to overcome the life-threatening event. Even with early treatment stop, the patient had a significant and durable response to the treatment for 15 months. Meanwhile, a progressive pancerebellar syndrome emerged, possible due to a paraneoplastic syndrome with a negative onco-neuronal antibody panel, although an autoimmune etiology associated with immunotherapy could not be excluded. Unfortunately, the situation was irreversible and refractory to immunomodulatory treatment. Despite the unpredictable toxicity, it is important to note the efficacy profile, with a progression-free survival of 15 months, which is higher than the one reported in reference clinical trials in this setting.