Table of Contents

Original ArticlesOptimal Management of Acute Lymphoblastic Leukemia (ALL) in Adult Patients During the Novel Coronavirus Disease 2019 (COVID-19) Pandemic ...........................................................................................................................07Ahmad Alhuraiji, Saleem Eldadah, Feras Alfraih, Ramesh Pandita, Ahmad Absi, Amr Hanbali, Mahmoud Aljurf, Riad El Fakih

Combined Intraoperative Radiotherapy (IORT) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with Cytoreduction Surgery (CRS) as a Novel Approach in the Management of Resectable Pancreatic Cancer ....................................19Ayman Zaki Azzam, Tarek Mahmoud Amin

Peritoneal Carcinomatosis of Colorectal origin in Cyclosporine Immunosuppressed Rats .....................................................................27Elie Rassy, George Hilal, Viviane Track-Smayra, Joseph Kattan, Riad Sarkis, Aline Khazzaka

A Comparative Study of Uninterrupted Treatment by Radiotherapy versus Standard Gap Correction after Interruptions in Oropharyngeal Cancer .............................................................................................................................................31Satya Narayan, Neeti Sharma, Sweta Soni, Rajkumar Niwan

The Frequency and Specific Features of Rare Epidermal Growth Factor Receptor Mutations in Moroccan Patients with Lung Adenocarcinoma whose Tumors harbor positive EGFR mutations ..........................................................40Hind El Yacoubi, Mohamed Lemine Sow, Meryem El Ghouti, Fouad Kettani, Lamia Gamra, Amina Mestari, Lamia Jabri, Ibrahim Elghissassi, Hassan Errihani

Dosimetric Evaluation and Comparison Between Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) Plan in Head and Neck Cancers ..............................................................................45Murugaiyan Nagarajan, Ramesh Banu, Balraj Sathya, Thangavel Sundaram, Thirumalai Palanichamy Chellapandian

Mode of Presentation of Laryngeal Cancer: A Single Radiotherapy Institute Experience in Iraq ............................................................51Shkar Othman Arif, Yousif Ibrahem Al Chalabi, Hiwa Asaad Abdul Kareem, Karzan Marif Murad, Jalil Salih Ali, Sazgar Star Majeed, Shwan Ali Mohammed, Nyan Othman Saeed, Bamo Mohammed Muhsin, Ayah Said, Layth Mula-Hussain

Factors Affecting Survival in Glioblastoma: A 10-year Single-Center Experience from Saudi Arabia ...................................................58Abdullah Azab, Nasser Alsayegh, Omar Kashkari, Suliman Hanbazazah, Yazid Maghrabi, Fahad Alghamdi, Rolina Al-Wassia, Saleh S. Baeesa

Prognostic Impact of Alpha Fetoprotein at Diagnosis on Overall Survival of Single Small Hepatocellular Carcinomas ........................64N. Lahmidani, FZ. Hamdoun, M. Lahlali, H. Abid, M El Yousfi, DA .Benajah, M. El Abkari, SA. Ibrahimi

Clinical Outcomes of Head and Neck Cancer Patients Treated with Palliative Oral Metronomic Chemotherapy at a Tertiary Cancer Center in Kerala, India .......................................................................................................................68Vinin NV, Geetha Muttath, Joneetha Jones, Kalpita Shringarpure, Karthickeyan Duraisamy, Vanitha Priya Deenathayalan, Priya Rathi

Case ReportPrimary Squamous Cell Carcinoma of the Trachea: Two Cases Report ....................................................................................................75Amany Hussein, Khaled Al-Saleh, Mustafa El-Sherify, Hamdy Sakr, Jitendra Shete, Marwa Nazeeh

Bilateral Vocal Cord Immobility After Chemoradiotherapy For Nasopharyngeal Carcinoma ...................................................................80Selvamalar Vengathajalam, Thevagi Maruthamuthu, Nik Fariza Husna Nik Hassan, Irfan Mohamad

Toxic Leukoencephalopathy: An unusual Presentation by 5-Fluorouracil Infusion .................................................................................84Virendra Kumar Meena, Punnet Pareek, Satya Narayan, Sweta Soni

Transformation of Grade I Follicular Lymphoma to Anaplastic Large Cell Lymphoma CD30+ ALK1 - with Complete Response to Brentuximab Vedotin and High-Dose Methotrexate ................................................................................87Mubarak Al-Mansour, Hatim Al-Maghraby, Bader Shirah

Conference Highlights/Scientific Contributions• News Notes .............................................................................................................................................................................................91

• Scientific events in the GCC and the Arab World for 2020 ...................................................................................................................95

87

Abstract

Lymphomas are a heterogeneous group of diseases that encompass malignant disorders of B-cells, T-cells, or natural killer cells. B-cell lymphomas represent approximately 80-85% of cases. Transformation of B-cell lymphomas from a low grade to a higher grade within the same lineage is a well-described phenomenon. The most common and well-known transformation is from follicular lymphoma to diffuse large B-cell lymphoma. However, the transformation of B-cell lymphomas to T-cell lymphomas is extremely rare. In this article, we report a case of grade I follicular lymphoma (B-cell

lymphoma) that transformed into anaplastic large cell lymphoma CD30+ ALK1- (T-cell lymphoma). This article reported a case with a unique particular combination of morphology and immunophenotype in the same patient. In addition, we report a remarkable response with complete remission following treatment with Brentuximab vedotin (anti-CD30 antibody-drug conjugate) and high-dose methotrexate. The patient achieved this durable response despite the aggressive presentation.

Keywords: Transformation; Follicular Lymphoma; Anaplastic Large Cell Lymphoma; CD30+; Brentuximab Vedotin.

Case Report

Transformation of Grade I Follicular Lymphoma to Anaplastic Large Cell Lymphoma CD30+ ALK1- with

Complete Response to Brentuximab Vedotin and High-Dose Methotrexate

Mubarak Al-Mansour1*, Hatim Al-Maghraby2, Bader Shirah3

1 Department of Oncology, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.

2 Department of Pathology and Lab Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia. 3 King Abdullah International Medical Research Center / King Saud bin Abdulaziz University for

Health Sciences, Jeddah, Saudi Arabia.

IntroductionLymphomas are a heterogeneous group of diseases

that encompass malignant disorders of B-cells, T-cells, or natural killer cells1. B-cell lymphomas represent approximately 80-85% of cases2. Transformation of B-cell lymphomas from a low grade to a higher grade within the same lineage is a well-described phenomenon3. The most common and well-known transformation is from follicular lymphoma to diffuse large B-cell lymphoma4. However, the transformation of B-cell lymphomas to T-cell lymphomas is extremely rare5. In this article, we report a case of grade I follicular lymphoma (B-cell lymphoma) that transformed into anaplastic large cell lymphoma CD30+ ALK1- (T-cell lymphoma). In addition, we report an excellent response and outcome after treatment with Brentuximab vedotin (anti-CD30 antibody-drug conjugate).

Case ReportA 40-year-old male presented to the medical oncology

clinic with a one-year history of right submandibular swelling and no B symptoms or other symptoms. On examination, performance status was 1, and he had a bulky right submandibular mass about 10 cm with no other

Corresponding author: Mubarak Al-Mansour, Associate Dean, Academic and Student Affairs,

College of Medicine-Jeddah, King Saud bin Abdulaziz University for Health Sciences. Section Head,

Medical Oncology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah, Saudi Arabia.

Contact No.: 00966562202206. Address: Saudi Arabia, Jeddah, P.O. Box: 9515, Jeddah,

21423. Email: Mansourmu@ngha.med.sa

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palpable lymphadenopathy and no abdominal masses or organomegaly. CT scan of neck, chest, abdomen, and pelvis showed a large solid mass lesion with necrotic areas, isodense to neck muscles on right side of neck measuring 5 x 4.6 x 5cm extending from the level of mandibular angle downward to the supraclavicular region. In addition, there were bilateral submandibular and submental lymph node enlargement of a 1 cm. Left neck lymph node excisional biopsy showed lymph node with effaced architecture and nodules of centrocytic cells with small cleaved nuclei and few centroblasts (<5/HPF). Immunohistochemistry showed LCA ++, L26 ++, CD3 -, CD10 ++, CD34 -, Bcl2 ++, Bcl6 ++, Ki67 (20%) (Figure 1). Immunophenotyping by flow cytometry showed 43% B-cells expressing CD19, CD10(dim), CD20, and Sig-kappa light chain. Bone marrow biopsy revealed no evidence of lymphoma. He was treated with three cycles of cyclophosphamide, vincristine, prednisolone, and rituximab (CVP-R) then three cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) followed by local radiotherapy.

Five years later, He had a relapsed follicular lymphoma when he presented with enlarged right inguinal lymph node, and CT scan revealed enlarged right inguinal and right external iliac lymph node in keeping with disease relapse. Left neck lymph node excisional biopsy showed the same features of the previous lymph node biopsy. The

final diagnosis was relapsed follicular lymphoma grade I. Bone marrow biopsy revealed no evidence of lymphoma. He was treated with four cycles of bendamustine and rituximab, which was complicated by prolonged thrombocytopenia. Bendamustine was stopped, and he continued on maintenance rituximab every three months for two years. In addition, he received radiation therapy to the inguinal lymph node.

Three years later, he presented with multiple painful skin lesions with significant weight loss and night sweating. On examination, multiple variable sized, well-defined, erythematous, pinkish plaques with a smooth surface in the right thigh and right inguinal enlarged lymph node. Blood work revealed thrombocytopenia at 4 (normal 150-450), white blood cells 3 (normal 4-11), hemoglobin 12.2 (normal 13-18), and elevated lactate dehydrogenase at 1558 (normal 100-217). CT scan showed multiple mediastinal, axillary, retroperitoneal, liver, and splenic lesions as well as pleural based nodularities. In addition, there was interval development of bilateral cervical lymphadenopathy with interval development of bilateral frontal meningeal-based lymphomatous masses, suggestive of secondary CNS involvement. MRI of the brain showed bifrontal dural lymphomatous lesions and diffuse calvarial bone involvement (Figure 2). Punch biopsy from the skin of right thigh showed skin with diffuse

Figure 1: Histopathology sections from the lymph node showing (A) effacement of lymph node architecture by back-to-back monomorphic neoplastic follicles, H&E, x50, (B) follicles consisting of centrocytres and centroblasts. Centroblasts are <5 centroblasts/hpf counted in 10 follicles, H&E, x200, (C) diffuse positivity for BCL2 immunohistochemistry in neoplastic follicles, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x200, and (D) diffuse positivity for CD10 immunohistochemistry in neoplastic follicles, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x200.

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dermal infiltration by lymphoid cells, sparing the Grenz zone infiltrating deep into subcutaneous fat and formed of cells having large pleomorphic nuclei with prominent nucleoli with frequent mitosis and single cell necrosis. Immunohistochemistry showed CK -, LCA ++, CD20 -, CD3 -, CD5 -, CD10 -, CD30 ++, Ki67 95%, Bcl2 -, Bcl6 -, ALK1 – (Figure 3). These results were consistent with the diagnosis of cutaneous anaplastic CD30+, ALK1- large cell lymphoma. Bone marrow showed no evidence of lymphoma infiltration. Left cervical lymph node biopsy confirmed T-cell lymphoma, CD30+ Ki 67 95%. Immunohistochemistry showed K -, LCA ++, CD20 -, CD3

++, CD5 -, CD10 -, Bcl2 -, Bcl6 -, Ki67 95%, Cyclin -, CD43 +, CD30+, ALK- (Figure 4). The final diagnosis was stage IV anaplastic large cell lymphoma ALK-negative with CNS and cutaneous involvement. He was treated with brentuximab vedotin (1.2 mg/m2) alternating with high dose methotrexate (3.5 g/m2) on D10 of brentuximab vedotin. He tolerated five cycles of brentuximab vedotin and eight cycles of high-dose methotrexate. Brentuximab vedotin was held due to grade 3 peripheral sensory neuropathy where he required pregabalin and morphine with adequate control of his symptoms.

A follow-up brain CT showed resolution of the subcutaneous and dural-based masses. A follow-up CT scan of neck, chest, abdomen, and pelvis showed stable exam on multiple occasions. He achieved complete remission and remained in remission for more than two years. Peripheral sensory neuropathy decreased to grade 2.

DiscussionSeveral theories may explain the mechanisms which

underlie the transformation of a B-cell lymphoma to T-cell lymphoma6. The first theory is that both lymphomas arise from the malignant transformation of a stem cell that is able to differentiate along B and T-lineages. Another theory is that the lymphomas may result from a shared genetic predisposition such as mutations that activate an

Figure 2: MRI of the brain showing bifrontal dural lymphomatous lesions with smooth enhancement, the largest in the right side measuring 2.1 x 1.2 cm. In addition, there was a diffuse calvarial bone involvement.

Figure 3: Histopathology sections of skin biopsy showing (A) infiltration by sheets of large atypical neoplastic cells with vesicular nuclei, prominent nucleoli, and moderate to scant amphophilic cytoplasm. Frequent mitosis and apoptosis are present. H&E, x400, (B) diffuse positivity for CD3 immunohistochemistry in neoplastic cells, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x400, and (C) diffuse membranous and cytoplasmic positivity for CD30 immunohistochemistry in neoplastic cells, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x400.

Figure 4: Histopathology sections of the lymph node biopsy showing (A) infiltration by sheets of large atypical neoplastic cells with vesicular nuclei, prominent nucleoli, and moderate to scant amphophilic cytoplasm. Frequent mitosis and apoptosis are present. H&E, x400, (B) diffuse positivity for CD30 immunohistochemistry in neoplastic cells, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x400, and (C) diffuse membranous and cytoplasmic positivity for CD30 immunohistochemistry in neoplastic cells, ABC- immunohistochemistry, Ventana Medical Systems, Tucson, AZ, x400.

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oncogene or inactivate a tumor suppressor gene. The third theory is related to exposure to a common carcinogen that has the capacity to independently transform B-cell and T-cell progenitors. The fourth theory associated the development of a second lymphoma due to factors secreted by the initial neoplastic cell population that stimulate other lymphocyte subpopulations to proliferate. Another possibility is that the second lymphoma may be therapy-related. Finally, the development of multiple lymphomas may reflect an underlying immune deficiency state since patients with immune deficiencies are at an increased risk for the development of lymphomas such as EBV-associated lymphoma7.

The distinction between histologic progression and a second de novo lymphoma may not be possible in some situations such as in our case. There is a possibility that the two lymphomas are unrelated and coincidental. Since follicular lymphomas usually have an indolent clinical course, the patients may simply survive for a period that is long enough for another unrelated lymphoid malignancy to develop. In our case, it is possible that the T-cell lymphoma that developed after three years from the relapsed B-cell lymphoma represents a histological transformation across lineages or be a de novo lymphoma occurring coincidentally in the same patient.

Brentuximab vedotin is an antibody-drug conjugate that is comprised of an anti-CD30 monoclonal antibody conjugated by a highly potent anti-microtubule agent (monomethyl auristatin E)8. The United States Food and Drug Administration first approved brentuximab vedotin on August 19, 2011, for two types of lymphomas; Hodgkin lymphoma and anaplastic large cell lymphoma. On November 16, 2018, the approval was expanded to include previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas9. In a recent study by Horwitz et al., brentuximab vedotin was combined with CHP (cyclophosphamide, doxorubicin, and prednisone) in CD30+ peripheral T cell lymphomas including anaplastic large cell lymphoma ALK-negative, and it showed progression-free survival and overall survival compared to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)10. To our knowledge, the tolerability and the durability of response to the brentuximab vedotin and high-dose methotrexate regimen have not been reported previously.

Brentuximab vedotin showed unprecedented success and expanded the spectrum of targeted therapy since it has outstanding efficacy and acceptable toxicity. The most significant side effect of the medication is peripheral neuropathy, which is dose-dependent and cumulative11. Our patient responded to Brentuximab vedotin therapy and achieved complete remission with no recurrence

for more than two years. However, he developed grade 3 peripheral sensory neuropathy in lower limbs.

ConclusionThis article reported a case with a unique particular

combination of morphology and immunophenotype in the same patient. In addition, we report a remarkable response with complete remission following treatment with Brentuximab vedotin and high-dose methotrexate. The patient achieved this durable response despite the aggressive presentation.

Conflict of Interest: The authors declare that they have no conflicts of interest.

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