Research Paper
E-ISSN NO : 2455-295X | VOLUME : 3 | ISSUE : 11 | NOV 2017
OCULAR MALIGNANT MELANOMA BRAF V600E MUTATION, TREATED WITH TARGETED MOLECULAR TREATMENT, WITH MULTIPLE METASTASIS - CASE REPORT CRISTINA MARIA MARGINEAN 1 | M.S. POPESCU 2 | M. VLADAIA 3 | DIANA RODICA TUDORASCU 1 | F. PETRESCU 1 1 UNIVERSITY
OF MEDICINE AND PHARMACY OF CRAIOVA, ROMANIA. DEPARTMENT OF INTERNAL MEDICINE, COUNTY CLINICAL EMERGENCY HOSPITAL OF CRAIOVA, ROMANIA. 3 PHD STUDENTS / DOCTORAL SCHOOL, UNIVERSITY OF MEDICINE AND PHARMACY OF CRAIOVA, ROMANIA. 2
ABSTRACT Malignant melanoma is a rare disease but also the most common primary ocular neoplasia. The origin is represented by melanocytar cells wich serve the function of producing melanine that determines the eye color. Uveal malignant melanoma is associated with increased risk of secondary metastasis. Choroid melanoma has the least favorable prognosis. The diagnosis is most often accidental durring a rutine checkup, usually the patient is asymptomatic, the only signs that can be present are local pain and visual imparement. We will present the case of a 31 year old male, diagnosed with uveal malignant melanoma of the left eye, by histopathologic examination and immunohistochemistry investigation of the biopsy piece. The patient is under treatment with Dabrafenib, Tramatinib and targeted palliative photon radiotherapy, with unfavorable evolution and multiple metastasis. Keywords: Malignant Melanoma, Uveal, BRAF V600E Mutation, Metastasis, Targeted Molecular Treatment.
Case report We are presenting the case of a 31 year old patient in the oncology ward survailance that is admitted into the hospital for bone pain, difuse abdominal pain, weight loss (10kg in two months), dyspnea, headakes and fatigue. The patient’s personal history reveals surgical removal of the left eye on 21st of March 2017 for uveal melanoma. The physical exam reveals a patien with altered state of health, underweight, pale skin and mucosae, surgical scars on both hands, ( 1st and 3rd finger on the right hand; 2nd and 3rd finger on the left) during childhood, accentuated pulmonary murmur, BP= 110/60mmHb, HR= 78bpm, difuse abdominal pain, agitated state, left eye prosthesis.
Abdominal CT: multiple secondary
lesions found on both kidneys; surrounding lymphadenopathies. Pancreas tail lesion measuring 2cm, intraperitoneal lesions, multiple metastatic nodules in the retroperitoneal fatty tissue and subcutaneous. Minimal peritoneal fluid.
Histopathological examination of the left eye Diagnosis: Uveal melanoma with epithelioid cells, extended necrosis (pT3 )
Macroscopic examination: reveals anteroposterior
Head, chest and abdomen CT March 20th 2017
axis measuring 2,5cm, cranio-caudal and transvers diameters measuring 2cm. Opaque pupila, transparent chornea. After incision the interior is almost entirely occupied by a white formation with a black center, 2cm in diameter. Only the insertion of the optic nerve is visible.
Head CT: no secondary intraparenchimal lesions.
Microscopic examination: all tissue samples show
Pathological thickening of the base and posterior wall of the left Meckel cavity, solid lesion of the posterior-lateral wall of the rear ocular chamber, suggestive of choroid melanoma, posterior chamber content is hyperdens and heteroegeneous.
neoplasic prolipheration with the tumor measuring 20mm; optic nerve infiltration; multiple neoplasic embolies present in the posterior vessels of the sclera; choroid infiltration; lymphocyte infiltration; necrosis present; neo formed vessels within the tumor.
Chest CT: multiple secondary locations in both lungs,
Immunohistochemistry investigation revealed mutation and significant BRAF expression.
most in the basal anteromedial segment of the left inferior lobe, lateral to the base segment of the right inferior lobe, top of the inferior left lobe. Multiple lymphadenopathies, partialy nechrotic in the mediastinum prevascular area, near of the left atrium, retroesophagial, lymphadenopatic conglomerate on the left side of the diaphragm. No pleural or pericardic fluid. Multiple metastasis in the left ventricule around the apex and the lateral wall.
BAP1
BRAF, NRAS, KIT mutation tests revealed BRAF codone 600 mutation ( p.V600E) present. NRAS codon12; 13, 58-59-61; 117-146 all negative and KIT exon 9; 11; 13; 17; 18 also negative for mutation tests.
Cardiac MRI March 28th 2017 Confirms the presence of solid mediastinium lesions compatible with metastasis with the following locations:
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E-ISSN NO : 2455-295X | VOLUME : 3 | ISSUE : 11 | NOV 2017
superior vena cava near its atrial origin measuring 31mm; inferior vena cava near its atrial origin measuring 21mm; in the free area of the septal wall 3 confluent lesions measuring 27mm in diameter, in front of the descending thoracic aorta. Multiple metastasis in the pulmonary parenchima, No pleural or pericardic fluid, ventricular kinetics is conserved ( left ventricule ejection fraction of 64%, right ventricule ejection fraction of 52% ).
Transthoracic ecocardiogram April
13th
2017
Measurements: aorta 31mm diameter, diastolic left ventricular diameter 49mm, interventrucular wall thickness 11mm, systolic left ventricular diameter 29mm, posterior wall of the left ventricule 11mm, left ventricule ejection fraction of 65%. To the side of the apex a mass measuring 21mm adherent to the lateral wall of the endocardium protruding into the cavity presently with no hemodynamic relevance and another mass 9/11mm round and immobile. No signs of pulmonary hypertension. No fluid in the pericardium.
Positive diagnosis by anamnesis, CT scans of the
cranium, thorax, abdomen and pelvis, transthoracic ecocardiograme, cardiac MRI, histopathologic examination and immunohistochemistry investigation of biopsies: Malignant melanoma of the left eye, surgicaly removed, BRAF V600E mutation, treated with targeted molecular treatment - Dabrafenib and Trametinib pT3 stage. Cerebral, pulmonary, pericardium, cardiac, diaphragmatic, peritoneal, retroperitoneal, right adrenal gland, left and right kidneys, liver, pancreas, soft tissue and bone metastasis. Intracranial hypertension syndrome. Moderate secondary anaemia.
The malignant melanoma and metastasis are documented and don’t require differential diagnosis, the moderate anaemia can be a side effect of treatment and intracranial hypertension a consequence of cerebral metastasis. CT evaluation after 5 months showed cerebral metastasis , increase in volume of previous lymphadenopathies, new metastasis formed and increase in size of preexistent ones in early CT evaluation.
Head, chest and abdomen CT August 5th 2017 Head CT: hyperdense cerebral formations ( that have
characteristics suggesting metastasis ), osteolysis of the temporal bone and invasion of the right cavernous sinus.
Chest CT: nodous formation located in the posterior
segment of the inferior right pulmonary lobe with signs specific for metastasis. Mediastinal lymphadenopathies, some partialy necrotic. Secondary formation above the left scapula beneath the trapezius muscle. Metastasis in the pericardium measuring from 1,6 cm to 9,5 cm, the largest one located at the apex, infiltrating the diaphragm and left pleura, extending to the abdomen and infiltrating the gastric fornix. Multiple formations found in the left ventricule and right atrium. Osteolysis of the left humerus head ( possible metastasis).
Abdomen CT: multiple formations in the peritoneum
with diffuse outline located around the stomach, liver and kidneys. Pancreas with a 4,7cm formation located at the tail segment that infiltrates the spleen and superior pole of the left kidney. Secondary formation of the right adrenal gland measuring 17mm. metastasis of the left and right kidneys measuring 20mm and 14mm. Minimum peritoneal fluid.
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Fig 1: Head, Chest and Abdomen CT images - August 5th 2017 Discussions: Malignant melanoma is a rare disease that
affects the uveal tract components. The incidence of ocular melanoma is higher among males, according to recent studies. [1,2] Signs and symptoms are few and minimal, most cases are diagnosed at random during an ophthalmological rutin examination. As the tumor grows signs of visual problems can begin to manifest ( blurry vision, decreased visual acuity due to retina detachement), pupillary distortions, local pain. [1] Malignant melanomas prognosis depends on a series of factors that associates with increasing risk of metastasis, such as: cell type; size of the tumor; tumors location; presence of an orange pigment at the surface of the tumor; extraocular extension; lymphocyte infiltration and extent of damage to the choroid; and expression of certain genetic mutations. [3] BRAF V600E is extremely rare in the case of posterior
uveal melanoma, GNAQ/GNA11 is more often encountered; BAP1 mutation is high correlated with the prognosis of the disease. [4] Treatment is established depending on the size of the tumor and results of the histiopathologic examination as well as type and stage of evolution, secondary effects of therapeutic procedures, underlying diseases. The progress in radiotherapy has significantly reduced the number of surgicaly treated patients; nowadays this option is reserved only for severe cases. The most common practice is the use of brachytherapy where plates made of Iod 125, Paladium 103 are applied to the outer surface of the sclera for a few days and are removed afterwards. The surgical options include iridectomy and iridocilectomy. [5,6] In the case of ocular malignant melanoma the cancerous cell disseminate throw the blood stream or to nearby tissue. The most often affected organ is the liver in 80-90% of cases. Other metastasis form in the lungs, bones, subcutaneous; only half of the patients will develop
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metastasis. The chance of survival after the liver metastasis is formed depends on a few factors like: the extent of systemic dissemination of cancer cells, free interval of disease, underlying disease.[7]
3.Jager MJ, Dogrusöz M, Woodman SE. Uveal Melanoma: Identifying Immunological and Chemotherapeutic Targets to Treat Metastases. Asia Pac J Ophthalmol (Phila). 2017 Mar-Apr;6(2):179-185
Specific to this case are the young age of the patient, the rapid progression in size of preexisting metastasis and development of new metastasis, targeted BRAF V600E mutation treatment ( Dabrafenib, rare mutation in cases of uveal melanoma associated with MEK inhibitors ( Trametinib ) and external photon radiotherapy. Despite optimal dose treatment the patient didn’t respond well and new lymphadenopathies and metastasis have formed including cerebral metastasis, the previous metastasis grew in size, with rapid altering of the vital prognosis. [6]
4.Shields CL, Say EAT, Hasanreisoglu M, Saktanasate J, Lawson BM, Landy JE, Badami AU, Sivalingam MD, Hauschild AJ, House RJ, Daitch ZE, Mashayekhi A, Shields JA, Ganguly A. Personalized Prognosis of Uveal Melanoma Based on Cytogenetic Profile in 1059 Patients over an 8-Year Period: The 2017 Harry S. Gradle Lecture. Ophthalmology. 2017 Oct;124(10):1523-1531
REFERENCES 1. Parul Singh and Abhishek Singh. Choroidal melanoma Oman Journal Of Ophtalmology Jan-Apr 5 2012 Jan-Apr; 5(1): 3–9 2. Spqndi Emiroglu R. ; Dulger E.; Aykan U. Near East University. Uveal Melanoma after multiple primary skin cancers, Ophthalmology, Nicosia, Cyprus. Congress of the European Society Of Ophthalmology (SOE) 6-9 June 2015 Viena, Austria – pag 174
5.Chen Y, Hu Y; Photodynamic Therapy For An Iris Metastasis From Pulmonary Adenocarcinoma. 2017 Oct 28. pii: S1572-1000(17)30382-4 6.Francis JH, Kim J, Lin A, Folberg R, Iyer S, Abramson DH. Growth of Uveal Melanoma following Intravitreal Bevacizumab. Ocul Oncol Pathol. 2017 Jul;3(2):117-121. 7.Hachiya M, Satoh K, Takami S, Uetake S, Arihiro S, Hokari A, Ishikawa T, Takagi I, Tajiri H, Saruta M. A case of metastatic uveal melanoma of the liver and digestive tract Nihon Shokakibyo Gakkai Zasshi. 2017;114(11):1978-1986.
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