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Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy

Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated... Hindawi Case Reports in Immunology Volume 2018, Article ID 4520294, 8 pages https://doi.org/10.1155/2018/4520294 Case Report Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy 1 1 1 Bolanle Gbadamosi , Daniel Ezekwudo , Bhadresh Nayak, 1 2 2 3 Zhou Yu , Sandra Gjorgova-Gjeorgjievski, Ming Xie, Colvin Robert , 1 1 Ishmael Jaiyesimi, and Marianne Huben Beaumont Hospital, Oakland University School of Medicine, Department of Hematology and Oncology, Royal Oak, MI, USA Beaumont Hospital, Oakland University School of Medicine, Department of Anatomic and Hematopathology, Royal Oak, MI, USA Beaumont Hospital, Oakland University School of Medicine, Department of Diagnostic Radiology and Molecular Imaging, Royal Oak, MI, USA Correspondence should be addressed to Bolanle Gbadamosi; bolanle.gbadamosi@beaumont.edu Received 10 October 2017; Accepted 27 December 2017; Published 12 February 2018 Academic Editor: Rajni Rani Copyright © 2018 Bolanle Gbadamosi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant melanoma is responsible for the majority of skin cancer deaths and is increasing in prevalence. Bone marrow (BM) involvement by melanoma is rare in the absence of widespread visceral disease. Here, we report the case of a 30-year-old female who presented to the hospital with back pain, low-grade fever, and easy bruising. She was found to be bicytopenic and in disseminated intravascular coagulopathy (DIC). Surprisingly, BM biopsy showed extensive involvement by metastatic malignant melanoma in the absence of visceral or brain metastasis. The unique presentati on of this case and the challenge of management of a potentially treatable cancer in a critically ill patient are discussed, alongside a review of published cases of metastatic melanoma in the BM and an exploration of currently available treatment options. eTh excellent response of our patient to combined immune checkpoint inhibitors has yet to be paralleled in the available literature. 1. Introduction literature and reported cases with metastatic melanoma in the BM. Malignant melanoma represents about one percent of all skin cancers, but it is responsible for the majority of all 2. Case Presentation skin cancer death. The average age of diagnosis of stage IV melanoma is 63 years, but there have been reports A 30-year-old healthy female with no past medical history in young adults, especially females, aged 20 to 39 years. presented to the emergency room with worsening fatigue, Historically, the 5-year survival rate of patients with stage IV easy bruising, low back pain, and low-grade fever. Physical metastatic melanoma is 15% to 20% [1]. Metastatic melanoma examination revealed normal vital signs, mild oozing of usually involves draining lymph nodes and adjacent skin blood from the gum, and a 3 cm right flank ecchymosis. first but eventually metastasizes to distant visceral sites. The Initial laboratory results showed severe thrombocytopenia, lung is most commonly involved followed by the brain, anemia, and coagulopathy (Table 1). Magnetic resonance liver, bone, and intestine [2]. Despite its predilection for imaging (MRI) of the thoracolumbar spine to evaluate low distant metastasis, BM involvement by melanoma is rare back pain showed pathologic process involving the marrow in the absence of widespread disease. We present a case of all visualized osseous structures (Figure 1) which prompted of malignant melanoma incidentally diagnosed aeft r a BM biopsy for bicytopenia and DIC in the absence of widespread a BM biopsy. Our differential diagnosis at the time included visceral metastasis, together with a systematic review of the acute leukemia, lymphoma, aplastic anemia, myelophthisic 2 Case Reports in Immunology Table 1: Laboratory result on admission. positive (Figure 2) but negative for CK7, TTF1, AE1/3, HepPar1, Glypican3, PAX8, HCG, CK5/6, P63, and OCT3/4, Laboratory test Patient Reference range thus excluding other solid malignancy. Conventional cyto- WBC 11.1 4–10× 10 /L genetic analysis of the bone marrow biopsy revealed an Hemoglobin 7.4 12–15 g/dL abnormal complex hypertriploid karyotype with 77–79 chro- MCV 90 80–100 fL mosomes in 18/20 metaphase cells. eTh composite karyo- Platelet 18 150–400× 10 /L type was designated as follows: 77–79⟨3n⟩XX, −X, add(2)(p21),+add(2)(q11.2),+4, add(5)(q11.2), +add(5)(q11.2), PT 29.3 9.3–12.4 seconds add(6)(q12), +7, +7, +8, +8, +9,−10,−11, +13, +15, +16,−19, INR 2.8 1–1.3 +20, +21, +22[cp18]/46, XX (2) (Figure 3). Metastatic mela- aPTT 44.0 23–30 seconds nomas oen ft present complex polyploid karyotypes such as D-dimer >5000 0–499 ng/ml the one identified in this study [3]. Molecular studies showed Fibrinogen <35 175–375 mg/dL the tumor positive for BRAF V600E and negative for NRAS Schistocyte 1-2 <1/hpf and c-kit. LDH 1719 100–238 U/L A na fi l diagnosis was made of metastatic melanoma of WBC: white blood cells; MCV: mean corpuscular volume; PT: prothrombin theBMpresentingwithDIC.Acompletemetastatic workup time; INR: international normalizing ratio; aPTT: activated partial thrombo- with CT of the chest, abdomen, and pelvis, as well brain plastin time; LDH: Lactate dehydrogenase. MRI, showed predominantly osseous and BM metastatic disease with no other visceral involvement. A full dermato- logic and ophthalmology examination showed a suspicious scalp lesion. Biopsy of the scalp lesion (Figure 4) revealed prominent intraepidermal atypical melanocytes with page- toidspread,aswellasthe presenceofwell-formedjunctional melanocytic nests, characteristic for malignant melanoma with superficial spreading pattern and stained positive for S-100 and SOX-10. eTh lesion was at least 2 mm deep (extending to the deep biopsy edges), Clark level IV with a mitotic rate of 2/mm ,andpossible partialregression. Lymph-vascular invasion, perineural invasion, or ulceration was not identified. Tumor cells had 10% PD-L1 expression on formalin-fixed-paraffin embedded tissue sections using the United States Food and Drug Administration (FDA) approved programmed death ligand 1 (PD-L1) Immunohis- tochemical (IHC) stain 28-8 pharmDx, a monoclonal rabbit anti-PD-L1 (Figure 5). The patient required a 10-day intensive care unit (ICU) admission for management of DIC that was complicated by multiple bleeding episodes. She received a total of 21 units of pooled cryoprecipitate, 15 units of apheresed platelet, 13 units of packed red blood cells, and 8 units of fresh frozen plasma. Systemic therapy with nivolumab, a programmed death 1 (PD-1) inhibitor, at a dose of 240 mg every 2 weeks, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor at a dose of 3 mg/kg every 3 weeks for 4 Figure 1: Sagittal T1 postcontrast image of the lumbar spine with cycles, was started immediately aer ft diagnosis. The therapy multiple rim-enhancing lesions as indicated by white arrows. choice was based on the results of the Checkmate 067 trial [4] that showed better objective response rate (ORR) in the nivolumab-plus-ipilimumab arm compared to nivolumab process from metastatic solid cancer, or a rare infec- alone and even better than ipilimumab alone; ORR was 72.1% tion. (95% CI, 59.9 to 82.3) in the nivolumab-plus-ipilimumab BM aspirate flow cytometry showed no immunopheno- group, 57.5% (95% CI, 45.9 to 68.5) in the nivolumab group, typic evidence of acute leukemia, lymphoma, or plasma cell and 21.3% (95% CI, 12.7 to 32.3) in the ipilimumab group. neoplasm.TheBMcorewashypercellularwith80% to Robert et al. reported ORR of 32.9% for pembrolizumab 90% cellularity and normal blast percentage. Hematoxylin in KEYNOTE 002. eTh patient had an excellent response and eosin staining revealed 60% involvement by a poorly to the combined immune-checkpoint inhibitors, becoming differentiated high-grade neoplasm with large pleomorphic transfusion-independent aer ft 2 treatment cycles followed by nuclei, mitosis, prominent nucleoli, and abundant vacuolated complete resolution of bicytopenia (Figure 6). cytoplasm; occasional multinucleated dark brown pigmented Despite anticipated toxicity with this combination regi- cells were also seen. The tumor cells were S100 and MART1 men, the patient has had no adverse eeff cts to date. As of Case Reports in Immunology 3 (a) (b) Figure 2: Immunohistochemical stain of bone marrow core biopsy with extensive involvement by poorly differentiated high-grade malignant neoplasm. Positive MART1 stain (a) and positive S100 stain (b). publishedcasepresented with DICasour patientdid.Mostof thepatientswerecriticallyillandonly5(17%)receivedsys- 12 34 5 temic chemotherapy. One (3%) patient was treated with pem- brolizumab with good response, another one (3%) patient, a 5-year-old boy treated with ipilimumab, died 4 months aer ft 6 7 8 9 10 11 12 diagnosis, and one patient treated with nivolumab died 3 months aer ft diagnosis. Overall, death within 6 months of 13 14 15 16 17 diagnosis was reported in 15 (52%) patients, 1 (3%) patient had a good response, and the outcome was unknown for 13 (45%) patients. Of the cases reviewed, none were treated 19 20 21 22 with combination immune-checkpoint inhibitors, as was the course of treatment for our patient. Figure 3: Cytogenetic analysis revealed a hypertriploid karyotype The pattern of metastasis in melanoma usually initially with multiple numerical and structural chromosome abnormalities. This cell demonstrates many, but not all, of the abnormalities desig- involves draining lymph nodes and adjacent skin then, distant nated in the composite karyotype, which was based on examination sites with the lung being the most common, followed by of twenty metaphase cells. Such complex karyotypes are common in thebrain,liver,bone,andintestine [2].Adultsolidcancers high-grade malignancies, including metastatic melanoma. with high propensity for BM metastasis include breast, lung, gastric, prostate, and Ewing sarcoma [32]. Metastasis of malignant melanoma to the BM is rare, especially at the time of diagnosis, and approximately 5% to 7% of BM metastatic this report, she has received a total of 20 doses of nivolumab melanoma occurs with widespread tumor dissemination [33]. and 4 doses of ipilimumab, also consistent with results in the AproportionofBMmetastasisofmalignant melanoma Checkmate 067 study, where the number of doses received occurs in the absence of an identifiable primary tumor, in in the nivolumab-plus-ipilimumab group ranged from 1 to 39 situations where it is generally believed that the primary [4]. tumor has regressed [34]. Melanoma generally demonstrates unique, well-charac- 3. Discussion terized receptor-ligand interactions during metastasis, as evi- An extensive literature search was conducted using PubMed, denced by the liver being the most common site of systemic metastasis of uveal melanoma; cutaneous melanoma is the Scopus, Embase, Web of Science, and Google Scholar using search terms of “metastatic melanoma,” “bone marrow,” most common cancer to metastasize to the submucosa of the and “disseminated intravascular coagulopathy.” Twenty-nine small intestine. Also, expressions of integrin Alpha-v beta-3 (avb3), integrin𝛼4𝛽1, and p75 Nerve Growth Factor Receptor casesofmetastaticmelanomaintheBMwerefound(Table 2). The median age at diagnosis was 55 (range: 5–81) years; the (NGF-R) by melanoma cells have been correlated with a tendency for lung, lymph node, or brain metastases, respec- primary lesions were cutaneous in 15 (52%) cases, ocular in 5 (17%) cases, anal mucosa in 1 (3%) case, tonsil in 1 (3%) tively [35–37]. There is no established receptor-ligand rela- case, and pleural in 1 (3%) case, and 6 (21%) cases had an tionship associated with malignant melanoma metastasizing to the BM. The mechanism of BM metastasis of malignant unknown primary lesion site. Presenting symptoms included fever, fatigue, bleeding, and back pain; only one previously melanoma can be linked to the concept of premetastatic niche 4 Case Reports in Immunology (a) (b) Figure 4: Immunohistochemical stain of the scalp lesion. Positive S-100 (a) 20x, SOX-10 (b) 20x. S-100 is a cytoplasmic stain, proving the malignant cells are originating from the neural crest derived tissue (melanocytes, glial cells, and Schwann cells). SOX-10 is a nuclear stain, confirming that the malignant cells are melanocytes. Figure 5: FDA-approved immunohistochemical stain for PD-L1, clone 28-8, (OPDIVO ) positive in 10.0% tumor cells with weak intensity. 18 200 16 15.9 15.1 14.5 160 12.5 11.8 11.2 10.8 9.9 8.9 7.4 6.2 20 22 0 0 0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50 (Weeks) (Weeks) (a) (b) Figure 6: Trend of hemoglobin (a) and platelet (b) lab values. Week 0:atdiagnosis.Treatmentwasinitiatedon Day 3 and patient was transfusion-independent by Week 8. Hemoglobin (g/dL) Platelets (bil/L) Case Reports in Immunology 5 Table 2: Reports of metastatic melanoma in the bone marrow, results of systematic review. Authors Age Presenting symptoms Primary Treatment Outcome Battle and Stasney [5] 60 Weight loss Ocular Supportive Death, 2 months Rubinstein [6] 47 Cord compression Occult Thiouracil Death, 2 months Franklin et al. [7] 67 Back pain Skin Supportive Death. Franklin et al. [7] 18 Fatigue Skin Not reported Unknown Brown et al. [8] 66 Malaise, weight loss Ocular Supportive Death, months Basile et al. [9] 63 Abnormal CBC Occult Chemotherapy Death, 6 months Villarrubia et al. [10] 57 Petechiae Skin Not reported Unknown Invernizzi and Pecci [11] 34 Fever Skin Not reported Unknown Chim and Trendell Smith [12] 67 Red eye Ocular Not reported Unknown Basu et al. [13] 74 Fatigue Anus Not reported Unknown Basu et al. [13] 35 Cord compression Tonsil Not reported Unknown Batsis and Barry [14] 75 Altered mental status Skin Supportive Death, 3 weeks Uesawa et al. [15] 67 Back pain Skin Not reported Unknown Jain et al. [16] 22 Epistaxis Occult Chemotherapy Unknown Bhandari et al. [17] 62 Fever, joint pain Ocular Supportive Unknown Downing et al. [18] 49 Low back pain Skin Not reported Unknown Hsiao and Chen [19] 76 Low back pain Ocular Supportive Death, 2 months Suzuki et al. [20] 77 Bleeding, DIC Occult Supportive Death, 1 week Bertolotti et al. [21] 55 Dyspnea Skin Supportive Death, days Velasco-Rodr´ıguez et al. [22] 75 Epistaxis Skin Chemotherapy Death, 2 months Serrier and Lesesve [23] 60 Dyspnea, back pain Skin Supportive Death, days Ferla et al. [24] 70 Fever, back pain Skin Supportive Death, 3 months Mirfazaelian et al. [25] 61 Abdominal pain Occult Not reported Unknown Kalodimos et al. [26] 81 Pancytopenia Skin Chemotherapy Unknown Volejnikova et al. [27] 5 Back pain, fever Skin Ipilimumab Death, 4 months Kassam and Shah [28] 79 Weight loss Occult Supportive Death, 2 weeks Fukumoto et al. [29] 26 Back pain Skin Nivolumab Death, 3 months Rosner et al. [30] 64 Fatigue, Fever Skin Pembrolizumab Good response Baniak et al. [31] 13 Pleural effusion Pleural Not reported Unknown (PMN), where Vascular Endothelial Growth Factor Receptor however, IL-2 use was limited by toxicity. Vaccine therapies 1- (VEGFR1-) positive BM-derived hematopoietic stem cells have been investigated in basic and clinical research both are mobilized by factors secreted from the melanoma, to form in adjuvant and in metastatic settings. Initial results from a PMN with a tumor-receptive environment in the BM prior phase II trials were promising; however, a phase III trial to the arrival of metastatic tumor cells. These PMN cells thus of CancerVax was prematurely stopped because of lack of dictate the metastatic pattern, directing melanoma cells to the efficacy [44–46]. BM [38]. In March 2011, ipilimumab, a human monoclonal anti- Therapeutic options for metastatic melanoma have body against the CTLA-4 receptor expressed on activated T- changed tremendously in the last 5 years following the cells, was approved for treatment of metastatic melanoma. approval of immune checkpoint inhibitors and targeted Treatment with ipilimumab showed a response rate (RR) of therapies against BRAF mutations. Chemotherapy remained 5% to 15% across clinical trials and overall survival benefit, the rfi st-line agent in the treatment of metastatic melanoma especially when combined with DTIC, though at the cost for about 4 decades [39–41]. of toxicity [47]. Pembrolizumab, a humanized anti-PD-1 The immunotherapy era for the treatment of metastatic antibody, received FDA approval for advanced melanoma in melanoma started with approval by FDA in 1998 of in- 2014basedonclinicaltrial resultswithanoutstanding RR terleukin-2 (IL-2), a cytokine that triggers production of of 38%andincreasedtolerabilityrelativetootherapproved lymphokine-activated killer (LAK) cells, which detect and medications. Melanoma cells highly express PD-L1 as an cause the death of cancer cells. Trials reported CR rates adaptive mechanism for protection against the immune sys- of approximately 7%, and partial remission (PR) rates of tem. PD-1 receptors are expressed on the surface of CD8+T- 10% [42, 43], with the best response in patients having soft cells and interact with corresponding ligands (PD-L1 and tissue and lung metastases. There was an associated durable PD-L2) expressed by the tumor cells, resulting in inhibitory response and survival benefit in a small group of patients; downstream signaling and cancer proliferation through the 6 Case Reports in Immunology evasion of immune-mediated death [48, 49]. When com- against NRAS, RAC1, ERK, and PI3K and c-KIT or PTEN. pared with ipilimumab, pembrolizumab showed signi-fi eTh role of percentage PDL-1 expression in the choice of cantly better progression-free survival (PFS), OS, and less immune checkpoint inhibitors, as well as the sequencing of high-grade toxicity in treatment-naive advanced melanoma therapy in patients with aberrant BRAF mutations, leaves patients [50]. Studies with nivolumab, another anti PD-1, intriguing questions to be answered. showed similar result. Combination immunotherapy, as received by our patient, 4. Conclusion hasbeeninvestigatedinmanyclinicaltrials. Phase1trialof combination nivolumab and ipilimumab in newly diagnosed Metastatic melanoma of the BM presenting with DIC in the advanced melanoma showed clinical activity with ORR of absence of widespread metastasis is rare but remains a differ- 40% and deep tumor regression in a large proportion of ential diagnosis in patients presenting with coagulopathy or cytopenia. Combination immunotherapy should be strongly patients, irrespective of absolute lymphocyte count or PDL- 1 expression [51]. This result was reproduced in Checkmate considered in patients with good performance status, as our 067, a 3-arm randomized phase III trial of ipilimumab alone, patient’s excellent response suggests high immunogenicity of the BM, consistent with evolving data on immune checkpoint ipilimumab plus nivolumab, or nivolumab alone, where results showed statistically signicfi antly longer PFS and OS inhibitors in hematologic malignancies. To our knowledge, with nivolumab plus ipilimumab or nivolumab alone than this is the rfi st case report of BM metastatic melanoma in with ipilimumab alone [4, 52]. The phase II Keynote 024 and DIC treated with combination nivolumab plus ipilimumab. Anti-PD1 Brain Collaboration (ABC) trials of nivolumab and Our systematic review confirmed the dismal prognosis of ipilimumab in combination also showed their effectiveness this patient cohort with standard chemotherapy or treatment and safety in melanoma with brain metastasis. In second- delay. Aggressive supportive care and prompt institution of line settings, ipilimumab alone had a better PFS compared immunotherapy can be lifesaving. to ipilimumab plus nivolumab, in patients with advanced melanoma after treatment failure on anti-PD-1 [53]. As Conflicts of Interest expected, nivolumab led to a better objective response and eTh authors declare that there are no conflicts of interest fewer toxic eeff cts than alternative chemotherapy in patients with advanced melanoma that progressed aer ft ipilimumab regarding the publication of this paper. or ipilimumab and a BRAF inhibitor [54]. Toxicity remains a major concern with combined immunotherapy as in our Acknowledgments patient. The most common adverse events reported in Check- mate 067 in the nivolumab-plus-ipilimumab group were diar- eTh authors thank Dr. Mark Micale for assistance with cyto- genetics images and interpretation and Dr. Michelle Young rhea (in 44.1% of patients), fatigue (in 35.1%), and pruritus (in 33.2%). One death due to neutropenia was reported for assistance with skin biopsy staining and interpretation. in the nivolumab alone group, but none were reported in the nivolumab-plus-ipilimumab group. 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Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy

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Copyright © 2018 Bolanle Gbadamosi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Case Reports in Immunology Volume 2018, Article ID 4520294, 8 pages https://doi.org/10.1155/2018/4520294 Case Report Effective Immunotherapy in Bone Marrow Metastatic Melanoma Presenting with Disseminated Intravascular Coagulopathy 1 1 1 Bolanle Gbadamosi , Daniel Ezekwudo , Bhadresh Nayak, 1 2 2 3 Zhou Yu , Sandra Gjorgova-Gjeorgjievski, Ming Xie, Colvin Robert , 1 1 Ishmael Jaiyesimi, and Marianne Huben Beaumont Hospital, Oakland University School of Medicine, Department of Hematology and Oncology, Royal Oak, MI, USA Beaumont Hospital, Oakland University School of Medicine, Department of Anatomic and Hematopathology, Royal Oak, MI, USA Beaumont Hospital, Oakland University School of Medicine, Department of Diagnostic Radiology and Molecular Imaging, Royal Oak, MI, USA Correspondence should be addressed to Bolanle Gbadamosi; bolanle.gbadamosi@beaumont.edu Received 10 October 2017; Accepted 27 December 2017; Published 12 February 2018 Academic Editor: Rajni Rani Copyright © 2018 Bolanle Gbadamosi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malignant melanoma is responsible for the majority of skin cancer deaths and is increasing in prevalence. Bone marrow (BM) involvement by melanoma is rare in the absence of widespread visceral disease. Here, we report the case of a 30-year-old female who presented to the hospital with back pain, low-grade fever, and easy bruising. She was found to be bicytopenic and in disseminated intravascular coagulopathy (DIC). Surprisingly, BM biopsy showed extensive involvement by metastatic malignant melanoma in the absence of visceral or brain metastasis. The unique presentati on of this case and the challenge of management of a potentially treatable cancer in a critically ill patient are discussed, alongside a review of published cases of metastatic melanoma in the BM and an exploration of currently available treatment options. eTh excellent response of our patient to combined immune checkpoint inhibitors has yet to be paralleled in the available literature. 1. Introduction literature and reported cases with metastatic melanoma in the BM. Malignant melanoma represents about one percent of all skin cancers, but it is responsible for the majority of all 2. Case Presentation skin cancer death. The average age of diagnosis of stage IV melanoma is 63 years, but there have been reports A 30-year-old healthy female with no past medical history in young adults, especially females, aged 20 to 39 years. presented to the emergency room with worsening fatigue, Historically, the 5-year survival rate of patients with stage IV easy bruising, low back pain, and low-grade fever. Physical metastatic melanoma is 15% to 20% [1]. Metastatic melanoma examination revealed normal vital signs, mild oozing of usually involves draining lymph nodes and adjacent skin blood from the gum, and a 3 cm right flank ecchymosis. first but eventually metastasizes to distant visceral sites. The Initial laboratory results showed severe thrombocytopenia, lung is most commonly involved followed by the brain, anemia, and coagulopathy (Table 1). Magnetic resonance liver, bone, and intestine [2]. Despite its predilection for imaging (MRI) of the thoracolumbar spine to evaluate low distant metastasis, BM involvement by melanoma is rare back pain showed pathologic process involving the marrow in the absence of widespread disease. We present a case of all visualized osseous structures (Figure 1) which prompted of malignant melanoma incidentally diagnosed aeft r a BM biopsy for bicytopenia and DIC in the absence of widespread a BM biopsy. Our differential diagnosis at the time included visceral metastasis, together with a systematic review of the acute leukemia, lymphoma, aplastic anemia, myelophthisic 2 Case Reports in Immunology Table 1: Laboratory result on admission. positive (Figure 2) but negative for CK7, TTF1, AE1/3, HepPar1, Glypican3, PAX8, HCG, CK5/6, P63, and OCT3/4, Laboratory test Patient Reference range thus excluding other solid malignancy. Conventional cyto- WBC 11.1 4–10× 10 /L genetic analysis of the bone marrow biopsy revealed an Hemoglobin 7.4 12–15 g/dL abnormal complex hypertriploid karyotype with 77–79 chro- MCV 90 80–100 fL mosomes in 18/20 metaphase cells. eTh composite karyo- Platelet 18 150–400× 10 /L type was designated as follows: 77–79⟨3n⟩XX, −X, add(2)(p21),+add(2)(q11.2),+4, add(5)(q11.2), +add(5)(q11.2), PT 29.3 9.3–12.4 seconds add(6)(q12), +7, +7, +8, +8, +9,−10,−11, +13, +15, +16,−19, INR 2.8 1–1.3 +20, +21, +22[cp18]/46, XX (2) (Figure 3). Metastatic mela- aPTT 44.0 23–30 seconds nomas oen ft present complex polyploid karyotypes such as D-dimer >5000 0–499 ng/ml the one identified in this study [3]. Molecular studies showed Fibrinogen <35 175–375 mg/dL the tumor positive for BRAF V600E and negative for NRAS Schistocyte 1-2 <1/hpf and c-kit. LDH 1719 100–238 U/L A na fi l diagnosis was made of metastatic melanoma of WBC: white blood cells; MCV: mean corpuscular volume; PT: prothrombin theBMpresentingwithDIC.Acompletemetastatic workup time; INR: international normalizing ratio; aPTT: activated partial thrombo- with CT of the chest, abdomen, and pelvis, as well brain plastin time; LDH: Lactate dehydrogenase. MRI, showed predominantly osseous and BM metastatic disease with no other visceral involvement. A full dermato- logic and ophthalmology examination showed a suspicious scalp lesion. Biopsy of the scalp lesion (Figure 4) revealed prominent intraepidermal atypical melanocytes with page- toidspread,aswellasthe presenceofwell-formedjunctional melanocytic nests, characteristic for malignant melanoma with superficial spreading pattern and stained positive for S-100 and SOX-10. eTh lesion was at least 2 mm deep (extending to the deep biopsy edges), Clark level IV with a mitotic rate of 2/mm ,andpossible partialregression. Lymph-vascular invasion, perineural invasion, or ulceration was not identified. Tumor cells had 10% PD-L1 expression on formalin-fixed-paraffin embedded tissue sections using the United States Food and Drug Administration (FDA) approved programmed death ligand 1 (PD-L1) Immunohis- tochemical (IHC) stain 28-8 pharmDx, a monoclonal rabbit anti-PD-L1 (Figure 5). The patient required a 10-day intensive care unit (ICU) admission for management of DIC that was complicated by multiple bleeding episodes. She received a total of 21 units of pooled cryoprecipitate, 15 units of apheresed platelet, 13 units of packed red blood cells, and 8 units of fresh frozen plasma. Systemic therapy with nivolumab, a programmed death 1 (PD-1) inhibitor, at a dose of 240 mg every 2 weeks, and ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor at a dose of 3 mg/kg every 3 weeks for 4 Figure 1: Sagittal T1 postcontrast image of the lumbar spine with cycles, was started immediately aer ft diagnosis. The therapy multiple rim-enhancing lesions as indicated by white arrows. choice was based on the results of the Checkmate 067 trial [4] that showed better objective response rate (ORR) in the nivolumab-plus-ipilimumab arm compared to nivolumab process from metastatic solid cancer, or a rare infec- alone and even better than ipilimumab alone; ORR was 72.1% tion. (95% CI, 59.9 to 82.3) in the nivolumab-plus-ipilimumab BM aspirate flow cytometry showed no immunopheno- group, 57.5% (95% CI, 45.9 to 68.5) in the nivolumab group, typic evidence of acute leukemia, lymphoma, or plasma cell and 21.3% (95% CI, 12.7 to 32.3) in the ipilimumab group. neoplasm.TheBMcorewashypercellularwith80% to Robert et al. reported ORR of 32.9% for pembrolizumab 90% cellularity and normal blast percentage. Hematoxylin in KEYNOTE 002. eTh patient had an excellent response and eosin staining revealed 60% involvement by a poorly to the combined immune-checkpoint inhibitors, becoming differentiated high-grade neoplasm with large pleomorphic transfusion-independent aer ft 2 treatment cycles followed by nuclei, mitosis, prominent nucleoli, and abundant vacuolated complete resolution of bicytopenia (Figure 6). cytoplasm; occasional multinucleated dark brown pigmented Despite anticipated toxicity with this combination regi- cells were also seen. The tumor cells were S100 and MART1 men, the patient has had no adverse eeff cts to date. As of Case Reports in Immunology 3 (a) (b) Figure 2: Immunohistochemical stain of bone marrow core biopsy with extensive involvement by poorly differentiated high-grade malignant neoplasm. Positive MART1 stain (a) and positive S100 stain (b). publishedcasepresented with DICasour patientdid.Mostof thepatientswerecriticallyillandonly5(17%)receivedsys- 12 34 5 temic chemotherapy. One (3%) patient was treated with pem- brolizumab with good response, another one (3%) patient, a 5-year-old boy treated with ipilimumab, died 4 months aer ft 6 7 8 9 10 11 12 diagnosis, and one patient treated with nivolumab died 3 months aer ft diagnosis. Overall, death within 6 months of 13 14 15 16 17 diagnosis was reported in 15 (52%) patients, 1 (3%) patient had a good response, and the outcome was unknown for 13 (45%) patients. Of the cases reviewed, none were treated 19 20 21 22 with combination immune-checkpoint inhibitors, as was the course of treatment for our patient. Figure 3: Cytogenetic analysis revealed a hypertriploid karyotype The pattern of metastasis in melanoma usually initially with multiple numerical and structural chromosome abnormalities. This cell demonstrates many, but not all, of the abnormalities desig- involves draining lymph nodes and adjacent skin then, distant nated in the composite karyotype, which was based on examination sites with the lung being the most common, followed by of twenty metaphase cells. Such complex karyotypes are common in thebrain,liver,bone,andintestine [2].Adultsolidcancers high-grade malignancies, including metastatic melanoma. with high propensity for BM metastasis include breast, lung, gastric, prostate, and Ewing sarcoma [32]. Metastasis of malignant melanoma to the BM is rare, especially at the time of diagnosis, and approximately 5% to 7% of BM metastatic this report, she has received a total of 20 doses of nivolumab melanoma occurs with widespread tumor dissemination [33]. and 4 doses of ipilimumab, also consistent with results in the AproportionofBMmetastasisofmalignant melanoma Checkmate 067 study, where the number of doses received occurs in the absence of an identifiable primary tumor, in in the nivolumab-plus-ipilimumab group ranged from 1 to 39 situations where it is generally believed that the primary [4]. tumor has regressed [34]. Melanoma generally demonstrates unique, well-charac- 3. Discussion terized receptor-ligand interactions during metastasis, as evi- An extensive literature search was conducted using PubMed, denced by the liver being the most common site of systemic metastasis of uveal melanoma; cutaneous melanoma is the Scopus, Embase, Web of Science, and Google Scholar using search terms of “metastatic melanoma,” “bone marrow,” most common cancer to metastasize to the submucosa of the and “disseminated intravascular coagulopathy.” Twenty-nine small intestine. Also, expressions of integrin Alpha-v beta-3 (avb3), integrin𝛼4𝛽1, and p75 Nerve Growth Factor Receptor casesofmetastaticmelanomaintheBMwerefound(Table 2). The median age at diagnosis was 55 (range: 5–81) years; the (NGF-R) by melanoma cells have been correlated with a tendency for lung, lymph node, or brain metastases, respec- primary lesions were cutaneous in 15 (52%) cases, ocular in 5 (17%) cases, anal mucosa in 1 (3%) case, tonsil in 1 (3%) tively [35–37]. There is no established receptor-ligand rela- case, and pleural in 1 (3%) case, and 6 (21%) cases had an tionship associated with malignant melanoma metastasizing to the BM. The mechanism of BM metastasis of malignant unknown primary lesion site. Presenting symptoms included fever, fatigue, bleeding, and back pain; only one previously melanoma can be linked to the concept of premetastatic niche 4 Case Reports in Immunology (a) (b) Figure 4: Immunohistochemical stain of the scalp lesion. Positive S-100 (a) 20x, SOX-10 (b) 20x. S-100 is a cytoplasmic stain, proving the malignant cells are originating from the neural crest derived tissue (melanocytes, glial cells, and Schwann cells). SOX-10 is a nuclear stain, confirming that the malignant cells are melanocytes. Figure 5: FDA-approved immunohistochemical stain for PD-L1, clone 28-8, (OPDIVO ) positive in 10.0% tumor cells with weak intensity. 18 200 16 15.9 15.1 14.5 160 12.5 11.8 11.2 10.8 9.9 8.9 7.4 6.2 20 22 0 0 0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50 (Weeks) (Weeks) (a) (b) Figure 6: Trend of hemoglobin (a) and platelet (b) lab values. Week 0:atdiagnosis.Treatmentwasinitiatedon Day 3 and patient was transfusion-independent by Week 8. Hemoglobin (g/dL) Platelets (bil/L) Case Reports in Immunology 5 Table 2: Reports of metastatic melanoma in the bone marrow, results of systematic review. Authors Age Presenting symptoms Primary Treatment Outcome Battle and Stasney [5] 60 Weight loss Ocular Supportive Death, 2 months Rubinstein [6] 47 Cord compression Occult Thiouracil Death, 2 months Franklin et al. [7] 67 Back pain Skin Supportive Death. Franklin et al. [7] 18 Fatigue Skin Not reported Unknown Brown et al. [8] 66 Malaise, weight loss Ocular Supportive Death, months Basile et al. [9] 63 Abnormal CBC Occult Chemotherapy Death, 6 months Villarrubia et al. [10] 57 Petechiae Skin Not reported Unknown Invernizzi and Pecci [11] 34 Fever Skin Not reported Unknown Chim and Trendell Smith [12] 67 Red eye Ocular Not reported Unknown Basu et al. [13] 74 Fatigue Anus Not reported Unknown Basu et al. [13] 35 Cord compression Tonsil Not reported Unknown Batsis and Barry [14] 75 Altered mental status Skin Supportive Death, 3 weeks Uesawa et al. [15] 67 Back pain Skin Not reported Unknown Jain et al. [16] 22 Epistaxis Occult Chemotherapy Unknown Bhandari et al. [17] 62 Fever, joint pain Ocular Supportive Unknown Downing et al. [18] 49 Low back pain Skin Not reported Unknown Hsiao and Chen [19] 76 Low back pain Ocular Supportive Death, 2 months Suzuki et al. [20] 77 Bleeding, DIC Occult Supportive Death, 1 week Bertolotti et al. [21] 55 Dyspnea Skin Supportive Death, days Velasco-Rodr´ıguez et al. [22] 75 Epistaxis Skin Chemotherapy Death, 2 months Serrier and Lesesve [23] 60 Dyspnea, back pain Skin Supportive Death, days Ferla et al. [24] 70 Fever, back pain Skin Supportive Death, 3 months Mirfazaelian et al. [25] 61 Abdominal pain Occult Not reported Unknown Kalodimos et al. [26] 81 Pancytopenia Skin Chemotherapy Unknown Volejnikova et al. [27] 5 Back pain, fever Skin Ipilimumab Death, 4 months Kassam and Shah [28] 79 Weight loss Occult Supportive Death, 2 weeks Fukumoto et al. [29] 26 Back pain Skin Nivolumab Death, 3 months Rosner et al. [30] 64 Fatigue, Fever Skin Pembrolizumab Good response Baniak et al. [31] 13 Pleural effusion Pleural Not reported Unknown (PMN), where Vascular Endothelial Growth Factor Receptor however, IL-2 use was limited by toxicity. Vaccine therapies 1- (VEGFR1-) positive BM-derived hematopoietic stem cells have been investigated in basic and clinical research both are mobilized by factors secreted from the melanoma, to form in adjuvant and in metastatic settings. Initial results from a PMN with a tumor-receptive environment in the BM prior phase II trials were promising; however, a phase III trial to the arrival of metastatic tumor cells. These PMN cells thus of CancerVax was prematurely stopped because of lack of dictate the metastatic pattern, directing melanoma cells to the efficacy [44–46]. BM [38]. In March 2011, ipilimumab, a human monoclonal anti- Therapeutic options for metastatic melanoma have body against the CTLA-4 receptor expressed on activated T- changed tremendously in the last 5 years following the cells, was approved for treatment of metastatic melanoma. approval of immune checkpoint inhibitors and targeted Treatment with ipilimumab showed a response rate (RR) of therapies against BRAF mutations. Chemotherapy remained 5% to 15% across clinical trials and overall survival benefit, the rfi st-line agent in the treatment of metastatic melanoma especially when combined with DTIC, though at the cost for about 4 decades [39–41]. of toxicity [47]. Pembrolizumab, a humanized anti-PD-1 The immunotherapy era for the treatment of metastatic antibody, received FDA approval for advanced melanoma in melanoma started with approval by FDA in 1998 of in- 2014basedonclinicaltrial resultswithanoutstanding RR terleukin-2 (IL-2), a cytokine that triggers production of of 38%andincreasedtolerabilityrelativetootherapproved lymphokine-activated killer (LAK) cells, which detect and medications. Melanoma cells highly express PD-L1 as an cause the death of cancer cells. Trials reported CR rates adaptive mechanism for protection against the immune sys- of approximately 7%, and partial remission (PR) rates of tem. PD-1 receptors are expressed on the surface of CD8+T- 10% [42, 43], with the best response in patients having soft cells and interact with corresponding ligands (PD-L1 and tissue and lung metastases. There was an associated durable PD-L2) expressed by the tumor cells, resulting in inhibitory response and survival benefit in a small group of patients; downstream signaling and cancer proliferation through the 6 Case Reports in Immunology evasion of immune-mediated death [48, 49]. When com- against NRAS, RAC1, ERK, and PI3K and c-KIT or PTEN. pared with ipilimumab, pembrolizumab showed signi-fi eTh role of percentage PDL-1 expression in the choice of cantly better progression-free survival (PFS), OS, and less immune checkpoint inhibitors, as well as the sequencing of high-grade toxicity in treatment-naive advanced melanoma therapy in patients with aberrant BRAF mutations, leaves patients [50]. Studies with nivolumab, another anti PD-1, intriguing questions to be answered. showed similar result. Combination immunotherapy, as received by our patient, 4. Conclusion hasbeeninvestigatedinmanyclinicaltrials. Phase1trialof combination nivolumab and ipilimumab in newly diagnosed Metastatic melanoma of the BM presenting with DIC in the advanced melanoma showed clinical activity with ORR of absence of widespread metastasis is rare but remains a differ- 40% and deep tumor regression in a large proportion of ential diagnosis in patients presenting with coagulopathy or cytopenia. Combination immunotherapy should be strongly patients, irrespective of absolute lymphocyte count or PDL- 1 expression [51]. This result was reproduced in Checkmate considered in patients with good performance status, as our 067, a 3-arm randomized phase III trial of ipilimumab alone, patient’s excellent response suggests high immunogenicity of the BM, consistent with evolving data on immune checkpoint ipilimumab plus nivolumab, or nivolumab alone, where results showed statistically signicfi antly longer PFS and OS inhibitors in hematologic malignancies. To our knowledge, with nivolumab plus ipilimumab or nivolumab alone than this is the rfi st case report of BM metastatic melanoma in with ipilimumab alone [4, 52]. The phase II Keynote 024 and DIC treated with combination nivolumab plus ipilimumab. Anti-PD1 Brain Collaboration (ABC) trials of nivolumab and Our systematic review confirmed the dismal prognosis of ipilimumab in combination also showed their effectiveness this patient cohort with standard chemotherapy or treatment and safety in melanoma with brain metastasis. In second- delay. Aggressive supportive care and prompt institution of line settings, ipilimumab alone had a better PFS compared immunotherapy can be lifesaving. to ipilimumab plus nivolumab, in patients with advanced melanoma after treatment failure on anti-PD-1 [53]. As Conflicts of Interest expected, nivolumab led to a better objective response and eTh authors declare that there are no conflicts of interest fewer toxic eeff cts than alternative chemotherapy in patients with advanced melanoma that progressed aer ft ipilimumab regarding the publication of this paper. or ipilimumab and a BRAF inhibitor [54]. Toxicity remains a major concern with combined immunotherapy as in our Acknowledgments patient. The most common adverse events reported in Check- mate 067 in the nivolumab-plus-ipilimumab group were diar- eTh authors thank Dr. Mark Micale for assistance with cyto- genetics images and interpretation and Dr. Michelle Young rhea (in 44.1% of patients), fatigue (in 35.1%), and pruritus (in 33.2%). One death due to neutropenia was reported for assistance with skin biopsy staining and interpretation. in the nivolumab alone group, but none were reported in the nivolumab-plus-ipilimumab group. 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