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Unusual presentation of diffuse large B-cell lymphoma involving the calcaneus: A case report

Open AccessPublished:October 23, 2021DOI:https://doi.org/10.1016/j.fastrc.2021.100102

      Abstract

      Lymphoma involves malignancy of the lymphatic system which includes the spleen, thymus, bone marrow and lymph nodes. Diffuse large B-cell lymphoma (DLBCL) is an aggressive, rapidly-growing type of non-Hodgkin lymphoma (NHL). We present a case of an 18-year-old male who initially presented with right hindfoot pain and swelling. Initial radiographs revealed no osseous pathology that correlated with the area of pain and swelling. Magnetic resonance imaging (MRI) was obtained which revealed a large soft tissue mass surrounding the calcaneus with cortical erosion and complete marrow replacement of the calcaneus. Due to concern for malignancy, the patient underwent a fluoroscopic-guided biopsy of the calcaneus. The pathology report revealed large atypical lymphoid infiltrates that were positive for B-cell molecular markers, CD20 and PAX5, consistent with the diagnosis of B-cell lymphoma. Initial positron emission tomography (PET) scan demonstrated hypermetabolism at the right foot, right popliteal fossa and right inguinal region which was consistent with Diffuse Large B-cell lymphoma, Grade 3B, Stage I or II. The patient underwent 6 cycles of chemotherapy. The patient's pain and swelling to the hindfoot had completely resolved and the patient remains in remission.

      Keywords

      Introduction

      Lymphoma usually occurs when cells, specifically lymphocytes, grow uncontrollably within the lymphatic system, specifically in the lymph nodes. Lymphoma can be divided broadly into Hodgkin's Lymphoma (HL) and non-Hodgkin's lymphoma (NHL) with NHL being more common. Diffuse large B-cell lymphoma (DLBCL) is an aggressive, rapidly-growing type of NHL. DLCBL is the most common subtype and constitutes approximately 30% of all NHLs.
      • Airaghi L
      • Greco I
      • Carrabba M
      • Barcella M
      • Baldini IM
      • Bonara P
      • Goldaniga M
      • Baldini L
      Unusual presentation of large B cell lymphoma: a case report and review of literature.
      ,
      • Moller MB
      • Pedersen NT
      • Christensen BE
      Diffuse large B-cell lymphoma: clinical implications of extranodal versus nodal presentation – a population-based study of 1575 cases.
      ,
      • Paone G
      • Itti E
      • Haioun C
      • Gaulard P
      • Depuis J
      • Lin C
      • Meignan M
      Bone marrow involvement in difusse large B-cell lymphoma: correlation between FDG-PET uptake and type of cellular infiltrate.
      DLBCL can affect patients of all ages; however, most patients are over the age of 60 at diagnosis and are predominantly male (55%).
      • Gouveia GR
      • Siqueira SA
      • Pereria J
      Pathophysiology and molecular aspects of diffuse large B-cell lymphoma.
      ,
      • Gatter K
      • Pezzella F
      Diffuse large B-cell lymphoma.
      ,
      • Blume P
      • Charlot-Hicks F
      • Mohammed S
      Case Report and Review of Primary Bone Diffuse Large B-Cell Lymphoma Involving the Calcaneus.
      DLBCL can begin in the lymph nodes or in extranodal sites such as the central nervous system, gastrointestinal tract, liver, bone or basically any organ of the body.
      • Airaghi L
      • Greco I
      • Carrabba M
      • Barcella M
      • Baldini IM
      • Bonara P
      • Goldaniga M
      • Baldini L
      Unusual presentation of large B cell lymphoma: a case report and review of literature.
      ,
      • Gouveia GR
      • Siqueira SA
      • Pereria J
      Pathophysiology and molecular aspects of diffuse large B-cell lymphoma.
      ,
      • Katusiime C
      • Kambugu A
      A rare entity extranodal diffuse large B cell lymphoma of the lower limb calf in an HIV-infected young adult on highly active antiretroviral therapy.
      Often DLBCL has an extranodal presentation rather than presenting with a symptomatic rapidly enlarging mass due to enlarged lymph nodes.
      • Airaghi L
      • Greco I
      • Carrabba M
      • Barcella M
      • Baldini IM
      • Bonara P
      • Goldaniga M
      • Baldini L
      Unusual presentation of large B cell lymphoma: a case report and review of literature.
      ,
      • Moller MB
      • Pedersen NT
      • Christensen BE
      Diffuse large B-cell lymphoma: clinical implications of extranodal versus nodal presentation – a population-based study of 1575 cases.
      There are many non-specific symptoms associated with DLBCL that vary from mild general pain to soft tissue swelling, sometimes with systemic symptoms also known as B symptoms (fever, night sweats and unintentional weight loss). According to Park et al, bones that are involved with DLBCL include the femur (27%), pelvis (15%), tibia/fibula (13%), humerus (12%), spine (9%), mandible (2%), radius/ulna (1%), scapula (1%), skull (1%) and bones of the hands and feet were uncommonly involved.
      • Park I
      • Kang S
      Distal appendicular skeletal involvement of diffuse large B cell lymphoma on technetium-99m methylenediphosphonate bone scintigraphy and 18F-fluorodeoxyglucose positron emission tomography/computed tomography: a case report.
      Lymphoma can infiltrate any organ in the body including bone with bone marrow involvement present in approximately 50% to 80% of patients with low grade NHL and 25% to 40% of those with high-grade NHL.
      • Qiu L
      • Chen Y
      • Huang Z
      • Zhu Y
      • Wen Q
      Diffuse large B cell lymphoma infiltrating limb bones with a few lymphadenopathy revealed on whole-body 18F-FDG PET/CT.
      ,
      • Campo E
      • Swerdlow SH
      • Harris NL
      • Pileri S
      • Stein H
      • Jaffe ES
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      Although NHL is a common type of lymphoma in adults, it is a relatively uncommon pedal neoplasm.
      • Mendeszoon MJ
      • Wire KR
      Diffuse large B-cell lymphoma of the ankle, a case study of surgical intervention and outcome.
      In this report, we present a case of an 18 year old male who was diagnosed with diffuse large B-cell lymphoma with an initial extranodal presentation. With the aid of MRI, the painful hindfoot was further evaluated and was highly suspicious for malignancy. Therefore, surgical biopsies were obtained with final pathological diagnosis of DLBCL.

      Case report

      An 18-year-old male who was referred to the senior author with an 8 month history of right hindfoot swelling and pain with walking and standing. He denied any injuries or previous trauma to the right lower extremity. The patient denied any constitutional symptoms including unintentional weight loss, night sweats or fever. The patient did admit to decrease in appetite. His medical history and surgical history were unremarkable. He had no known drug allergies and was not taking any medication. His family history was not significant for cancer. He denied using any tobacco products, illicit drugs or alcohol.
      Physical examination of his right foot revealed normal, full, pain-free range of motion of the metatarsophalangeal, ankle and subtalar joints. No crepitus was noted at the subtalar or ankle joints. Pain was noted on direct palpation of the lateral calcaneal wall, peroneal tendons and slight pain was noted at the sinus tarsi region. Moderate non-pitting edema, erythema and ecchymoses was noted to the lateral aspect of the right hindfoot (Fig. 1). Neurovascular examination was within normal limits.
      Fig. 1
      Fig. 1Nonpitting edema with ecchymoses noted to the lateral aspect of the hindfoot.
      The radiographic examination consisted of multiple views of the foot and ankle, which revealed no osseous pathology that correlated with the area of pain and swelling. No radiographic evidence of osteolysis or sclerotic lesions of the calcaneus. No acute fractures were seen. The ankle joint appeared stable, with no cortical erosion, periosteal reaction or cortical wall break. MRI of the right hindfoot revealed a large soft tissue mass surrounding the calcaneus that encased the flexor hallucis longus tendon and extended into the quadratus plantae muscle. There was cortical erosion of the calcaneus at the peroneal tubercle, lateral and superior aspects of the calcaneal tuberosity and complete marrow replacement of the calcaneus (Fig. 2).
      Fig. 2
      Fig. 2A, T1 weighted image demonstrating surrounding soft tissue mass. B, T1 weighted image demonstrating complete marrow replacement of the calcaneus. C, T2 weighted image demonstrates cystic areas within the calcaneus and cortical wall erosion.
      The patient was brought into the operating room and placed on the operating room table in the supine position. Anesthesia was administered and the right lower extremity was prepped and draped in the usual aseptic manner. A palpable soft tissue mass was noted on the lateral aspect of the right hindfoot superior to the calcaneus along the peroneal tendons measuring 8.0 cm x 6.0 cm as outlined intra-operatively (Fig. 3). A trephine was used to obtain bone from the calcaneus for the biopsy at the level of cystic changes which was confirmed with intra-operative fluoroscopy (Fig. 4). The specimens, including bone and soft tissue, were sent for evaluation, both microbiology and pathology.
      Fig. 3
      Fig. 3Palpable soft tissue mass outlined on the lateral hindfoot extending along the peroneal tendons. Bone biopsy site (arrow).
      Fig. 4
      Fig. 4A, Trephine was used to retrieve a small sample of calcaneus and sent to microbiology and pathology for evaluation. B, Trephined sample of calcaneus that was sent for evaluation.
      Cultures including acid fast stain and Grocott methenamine silver (GMS) stain for fungal elements were negative. Histologic slides showed large atypical lymphoid infiltrate with necrotic cellular debris (Fig. 5A). Immunophenotyping and histochemical stains were positive for B-cell molecular markers including CD20 and PAX5 but were CD99 negative (Fig. 5B,C,D). Fluorescence in situ hybridization (FISH), a molecular cytogenetic test used to distinguish DLBCL from other lymphomas was negative. All these findings led to a diagnosis that was highly suspicious for B-cell lymphoma. The patient was referred to orthopedic oncology who evaluated the patient and referred the patient to medical oncology. Initial staging PET scan demonstrated hypermetabolism at the right foot, right popliteal fossa and right inguinal region which was consistent with Diffuse Large B-cell lymphoma, Grade 3B, Stage I or II. Fertility preservation was completed and then he began 6 cycles of chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin and vincristine, known as R-CHOP. After 6 cycles, repeat PET scan demonstrated complete response to therapy with no evidence of disease. At his followup appointment 12 months since diagnosis, new radiographs of the right foot were obtained which demonstrated no osseous pathology as seen in Figure 6. Clinically, the right foot was within normal limits with no edema or ecchymoses present (Fig. 7). Patient is currently in remission, denies any pain to the right lower extremity and has returned to all activities.
      Fig. 5
      Fig. 5A, H&E stain with neoplastic B cells. B, CD20 positive. CD 20 is a membrane-embedded surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. C, PAX5 positive. PAX5 is a transcription factor that encodes the B-cell lineage specific activator protein that is expressed at early, but not late stages of B-cell differentiation. D, CD99 positive. Transmembrane protein that plays a role in actin cytoskeleton arrangement.
      Fig. 6
      Fig. 6A, Anteroposterior foot view and B, lateral ankle view of patient at 12 months postoperatively highlighting no cortical erosion.
      Fig. 7
      Fig. 7Right hindfoot 12 months since diagnosis of Diffuse Large B-Cell Lymphoma. No edema or ecchymoses noted.

      Discussion

      Lymphoma is not uncommon and musculoskeletal symptoms may be the key to an early diagnosis. Lymphoma is a category of cancers that affects the lymphatic system. The two main kinds of lymphoma are Hodgkin's Lymphoma which spreads in an organized manner from one group of lymph nodes to another, and non-Hodgkin's lymphoma which spreads through the lymphatic system in a non-organized manner.
      • Campo E
      • Swerdlow SH
      • Harris NL
      • Pileri S
      • Stein H
      • Jaffe ES
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      DLBCL, the most common type of NHL, varies clinically and current treatment protocols involve combinations of immunotherapy and chemotherapy.
      • Mendeszoon MJ
      • Wire KR
      Diffuse large B-cell lymphoma of the ankle, a case study of surgical intervention and outcome.
      ,
      • Schneider C
      • Pasqualucci L
      • Dalla-Favera R
      Molecular Pathogenesis of Diffuse Large B-cell Lymphoma.
      Once a neoplasm has been identified it is important to perform a thorough history and physical examination with a focus on constitutional symptoms as well as identify if any other locations are involved.
      • Blume P
      • Charlot-Hicks F
      • Mohammed S
      Case Report and Review of Primary Bone Diffuse Large B-Cell Lymphoma Involving the Calcaneus.
      Depending on the location, size, appearance of the neoplasm and growth rate, treatment protocols will vary and often involves a multi-disciplinary team of medical oncology, radiation oncology, surgery, radiology and pathology.
      Radiographic features of lymphoma involving osseous structures are variable and sometimes can appear normal, lytic or sclerotic. If visible on radiographs they can produce a “moth-eaten” appearance.
      • Blume P
      • Charlot-Hicks F
      • Mohammed S
      Case Report and Review of Primary Bone Diffuse Large B-Cell Lymphoma Involving the Calcaneus.
      ,
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      There is often a surrounding soft-tissue mass and sometimes there is a cortical break that can lead to pathological fractures. Other imaging modalities can be very useful such as bone scan or MRI as lymphoma involving bones can have a normal or very subtle appearance on radiographs.
      • Blume P
      • Charlot-Hicks F
      • Mohammed S
      Case Report and Review of Primary Bone Diffuse Large B-Cell Lymphoma Involving the Calcaneus.
      ,
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      As with the presented case, further imaging for symptomatic patients with normal radiographs is required to diagnose marrow disease.
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      MRI plays an important role in the diagnosis of lymphoma involving the bones, showing high sensitivity for marrow replacement.
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      When the bone marrow is replaced by a tumor it will show low intensity on T1-weighted images and high intensity on T2-weighted images.
      • Blume P
      • Charlot-Hicks F
      • Mohammed S
      Case Report and Review of Primary Bone Diffuse Large B-Cell Lymphoma Involving the Calcaneus.
      ,
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      PET scans also play an integral role in the initial staging of lymphoma, detecting other sites that may not be seen on other imaging modalities as well as treatment response. PET scan has an advantage over CT/MRI because of its ability to decipher between active, viable tumor and necrotic tumor that have responded well to treatment.
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      The etiology of lymphoma is not fully understood but there have been links to lymphoma to certain viral infections, for example, human immunodeficiency virus (HIV) and Epstein Barr virus.
      • Campo E
      • Swerdlow SH
      • Harris NL
      • Pileri S
      • Stein H
      • Jaffe ES
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      Two molecular subtypes of DLBCL have been accepted including the germinal center B-cell (GCB) type and the activated B-cell form (ABC) which are associated with specific genetic alterations, different molecular signaling pathways and different clinical outcomes.
      • Campo E
      • Swerdlow SH
      • Harris NL
      • Pileri S
      • Stein H
      • Jaffe ES
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      According to Schneider et al., most DLBCLs derive from germinal center B-cells which are secondary lymphoid tissues.
      • Schneider C
      • Pasqualucci L
      • Dalla-Favera R
      Molecular Pathogenesis of Diffuse Large B-cell Lymphoma.
      These germinal centers (GC) have proliferating B-cells that develop into plasma cells that produce antibodies and memory B cells that provide protection from infections with re-invading organisms.
      • Schneider C
      • Pasqualucci L
      • Dalla-Favera R
      Molecular Pathogenesis of Diffuse Large B-cell Lymphoma.
      Certain genetic variations that have been found in DLBCL include chromosomal translocations, sporadic somatic mutations and copy number alterations, denoted by deletions or amplifications.
      • Schneider C
      • Pasqualucci L
      • Dalla-Favera R
      Molecular Pathogenesis of Diffuse Large B-cell Lymphoma.
      Additional subtypes of DLBCL has been recognized by the World Health Organization (WHO) which includes EBV-positive DLBCL and DLBCL associated with chronic inflammation.
      • Campo E
      • Swerdlow SH
      • Harris NL
      • Pileri S
      • Stein H
      • Jaffe ES
      The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.
      The skeletal system is an uncommon site of lymphoma involvement and DLBCL is rarely found in the foot and ankle. When lymphoma occurs within the musculoskeletal system it likely represents secondary haematologic spread.
      • Lim CY
      • Ong KO
      Imaging of musculoskeletal lymphoma.
      With this particular case presentation, as would be true for any type of cancer, it is imperative to obtain further diagnostic imaging with persistent symptoms, obtain a biopsy for definitive diagnosis and treatment should use a multidisciplinary approach.

      Informed patient consent

      Complete informed consent was obtained from the patient for the publication of this study and accompanying images.

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