To ascertain the histopathology of this lesion and give the guidance for formulating a therapeutic plan, an open biopsy was performed instead of core needle biopsy. The histopathology was consistent with a diagnosis of CHL. Enhanced CT of the neck, chest, and abdomen showed no evidence of involvement of the cervical, mediastinal, or retroperitoneal lymph nodes. Prognostic factors according to the adapted International Prognostic Score (IPS) were determined (Table 1). After discussing with hematologists and considering the patient's general condition, relative high IPS, high risk of pathologic fracture, and sciatic nerve compression symptoms, a treatment protocol of limb-salvage surgery using en bloc resection followed by modular hemipelvic prosthesis reconstruction and 6 cycles ABVD course chemotherapy (doxorubicin, 25 mg/m2, intravenous injection [iv] Day 1 and 15; bleomycin, 10,000 units/m2, iv Day 1 and 15; vinblastine, 6 mg/m2, iv Day 1 and 15; dacarbazine, 375 mg/m2, iv Day 1 and 15) with 2 cycles before surgery was performed for this patient.
The patient commenced another 4 cycles of chemotherapy with ABVD 1 month after surgery. Patient follow-up visits occurred frequently over the first year, at 1, 2, 3, 6, 9, and 12 months after discharge, and every 6 months thereafter. Imaging studies were focused on tumor recurrence and the stability of the prosthetic implant. By 6 months after surgery, the patient was capable of all activities of daily living needed for self-care. Up to now, 3 years after the treatment, there is no sign of cancer recurrence and metastasis. The patient had largely recuperated from the surgery with an ISOLS (International Society of Limb Salvage) score of 23.0. The prosthetic positioning is good, with no loosening, fracture, or dislocation (Fig. 5).
HL typically involves the lymphatic systems at 1 or more sites. Bony involvement in HL occurs through hematogenous spread or direct spread from the contiguous involved lymph node. WHO 2013 classification of bone tumor defined the primary NHL of bone as a neoplasm composed of malignant lymphoid cells, producing 1 or more masses within bone, without any supraregional lymph-node involvement or other extranodal lesions. After concluding the clinical and pathological characters of our case, the evidence supporting the diagnose of primary bone HL in our study are as follows: Bone involvement was the initial symptom and the CT showed lesion obviously spreading from ilium to sacral through sacroiliac joint, supporting the lesion coming from ilium. The typical necrosis nodular from the HE stain and the HRS cells in tumor demonstrated a typical immunohistochemical profile with CD30 and CD15 positive. Chest, neck, and abdomen radiological studies showed no involvement of lymph nodes in mediastinum, thoracic, and abdominal cavity. The lesion was predominant in bone with associated soft-tissue mass, without local positive adjacent lymph nodes, as the 3 enlarge lymph nodes in inguinal region were pathologically confirmed as reactive hyperplasia. No other extranodal lesions presented. But Dawson et al showed that primary extranodal HL should be diagnosed based on normal limits of the complete blood count and white cell differentiation. This was supported by Yang et al who presented a primary bone HL with a normal level of the complete blood count and differentiation. So, there are also 3 points that revealed a systemic disease of our case: first is the B symptom that the patient showed 3 months before being admitted to our hospital; Second, the high WBC count with relatively high neutrophils rate and low Hgb; lastly, the bone marrow aspiration revealed a hyperactive hyperplasia of karyocyte. Previous study showed stage IV included patients with multiple bone involvement without evidence of distant nodal or visceral disease. However, the adjacent multifocal lesions like ours and nonadjacent multifocal lesions suggested different disease stage, as adjacent multifocal lesions mostly come from local invasion but distant multifocal lesions revealed a hematogenous spread or direct spread from the contiguous involved lymph node. So, further work should focus on more details of this disease's diagnosis standard. As our patient had B symptom and the sacroiliac joint destruction (revealed 2 bone sites involvement), a finally diagnosis of unfavorable stage IV bone CHL (Ann Arbor staging criteria) was made.
HRS cells of HL are almost 100% positive for CD30 and 85% positive for CD15 on immunohistochemical staining. The differential diagnosis of CD30 positive neoplasms that show the similar clinical and pathologic features with CHL were primary mediastinal large B-cell lymphoma (PMBCL) and gray zone lymphoma. Hoeller et al found that BOB.1, CD79a, and cyclin E are applicable immunohistochemical markers that can help distinguishing CHL from PMBCL. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and CHL, was initially proposed in the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, which was afterward named gray zone lymphoma. There are mainly 2 type of gray zone lymphoma. One is similar to CHL in shape, but the immunophenotype of tumor cells was closer to DLBCL. Another was tumor morphology was similar to that of DLBCL, but immunophenotype of tumor cells was closer to CHL; CD30 and CD15 were diffuse positive whereas CD20 and PAX5 expression levels are down.[17,18]
It seems that primary bone HL most likely appears on spine or long bone, seldom occurs in pelvic (Table 2 ).[5,6,8,13,19–33] Nodular sclerosis CHL represents 70% of CHL in Europe and USA, and this figure in China is 32.6%. Almost 54% of nodular sclerosis CHL cases present with a huge soft mass. Fibrosis was another prominent feature in the nodular sclerosis case. So, primary bone HL may be one differential diagnosis of osseous tumor which is with a fibrous stromal component. For example, the initial diagnosis of Hodgkin disease was malignant fibrous histiocytoma in a recent study. The clinical manifestations and imaging are nonspecific with limitations to distinguish primary bone nodular sclerosis HL of pelvic involvement from other common primary pelvic sarcomas such as chondrosarcoma, Ewing sarcoma, osteosarcoma sarcoma, and malignant fibrous histiocytoma[37–41] (Table 3). Although the image features are sometimes similar, clinicopathologic characteristics and treatment options have obvious difference between CHL and other pelvic primary sarcomas.[9,40,42–44]
The IPS of our patient is 4, which indicates an unfavorable disease. IPS is the most widely accepted risk stratification model that can help to determine the clinical treatment as well as predict prognosis for stage III-IV cases. It utilizes 7 adverse prognostic factors and each of these factors can decrease the survival rate by 7% to 8%. According to the Memorial Sloan-Kettering Cancer Center experience, IPS ≥4 was a significant independent predictor of worse overall survival and progression-free survival for extensive or advanced HL. The patient in our study received a total of 6 cycles ABVD chemotherapy. The NCCN (2016) guidance for stage III-IV CHL patients revealed that ABVD or Stanford V for selected patients with IPS <3, or escalated-dose BEACOPP in selected patients <60 years with an IPS ≥4 are included as options for primary treatment for patients with stage III-IV disease.[46–49] Patients with 1 or multiple bone lesions usually respond well to combined-modality treatment, including chemotherapy and local radiotherapy. Up to now, 2 largest series patients with primary bone lymphoma studies demonstrated that patients with primary bone lymphoma treated with combined-modality versus single-modality therapy were found to have a superior outcome, with a significantly better survival.[50,51] Ding et al evaluated the antitumor activity of bortezomib in combination with IGEV (ifosfamide, gemcitabine, vinorelbine, and prednisone) chemotherapy in a young male with primary bone HL who achieved low response after ABVD and ECHOP chemotherapy. Complete response was achieved after 2 cycles. This event suggested that bortezomib in the therapy of young patient suffering from primary bone HL maybe effective and safe. For many HL patients who relapse following a response to initial chemotherapy, high-dose chemotherapy followed by an autologous stem cell transplantation is the standard care. In addition, small target drugs therapy showed promising outcome for relapsed HL cases in recent years. CD30 is expressed on the HRS cell and antibodies like brentuximab vedotin targeting this molecule have shown activity in vitro.[54,55] Recently reported clinical trials have shown that blocking interactions between the cell surface receptor programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 results in very high clinical-response rates. Other agents with promising activity for this patients group include histone deacetylase inhibitors, PI3K inhibitors, and immunomodulatory agents.[57,58]
Surgery resection and limb-salvage reconstruction are seldom performed for such a hematologic malignancy. In most contexts, surgery was strictly used for biopsy, especially when needle biopsy was limited to get a significant outcome for some special sites such as pulmonary. For bony HL, surgery was necessary for the treatment of actual or possible pathological fractures or spine cord and nerve comprehension.[52,59,60] Limb-salvage surgery in some special individuals got a satisfying clinical outcome. In a large series study, Khodamorad and colleagues suggested that combined-modality therapy for stage IE primary bone lymphoma resulted in good survival rate. In case of local recurrence, wide excision and limb-salvage reconstruction improved the clinical outcomes. Alper et al reported in a young male diagnosed with primary bone lymphoma located in distal femur, distal femoral resection prosthesis was performed to prevent the risk of fracture and the patient was in remission and continued to attend school. From the CT scan of our patient, we can see that the ilium, acetabular, and sacroiliac joint are severe destructed making the patient meet high risk of pathologic fracture. Furthermore, the patient showed a sciatic nerve comprehension symptom which was confirmed during surgery procedure. To sum up, as pelvic-ring is the central part of weight-bearing of our body and no other organs showing diseases involvement, tumor resection following limb-salvage reconstruction can get good local tumor control as well as preserve limb function to the greatest extent for our special individual.
The limb function of the patient recovered well so that she can take care of herself, study, and do some special works at 3-year follow-up. There are some key tips for such an extensive surgery to improve surgery success rate and limb function. First, the application of lower abdominal aortic balloon occlusion technique can effectively reduce an average blood loss of 1500 mL for pelvic sarcoma surgery, which typically shortens operative time to only 4 hours. Second, “no touch” resection of the tumor, with a surgical margin of normal tissue at least 1.0 cm wide from the tumor pseudocapsule are recommended to reduce risks of seeding of cancer cells into the circulation. Third, muscle and soft tissue in situ reconstruction was mainly designed to achieve sufficient soft tissue coverage and functional recuperation after the hemipelvic prosthetic reconstruction. Moreover, we adopted LARS (ligament advanced reinforcement system, R06 × 400/s, France) to reconstruct the hip capsule and supply the point of attachment for muscles and soft tissues during reconstruction in recent years. Fourth, functional exercise and the time to early ambulatory activity should be based on the extent of resection, the hip stability after reconstruction with the hemipelvic prostheses, and the reconstruction of the periacetabular muscles. The application of limb brace can reduce dislocation risk and help the patient for function exercise after surgery.
CHL initially presenting as pelvic involvement with such a huge tumor volume is indeed rare. The diagnosis of primary bone HL should be made by strict histological and clinical manifestation. Chemotherapy is still the main treatment option for bony HL patient. Limb-salvage surgical resection is required only when bony HL patient meets a high risk of pathological fracture like our case. Overall, limb-salvage surgery combining 6 cycles ABVD chemotherapy got a promising 3-year clinical outcome in our study for such a late stage unfavorable patient. Mastering the surgery indication and fully assessing different therapy options risk is necessary for such a challenging case.
. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. vol. 22013. World Health Organization; 2008.
. Guermazi A, Brice P, de Kerviler EE, et al. Extranodal Hodgkin disease
: spectrum of disease. RadioGraphics 2001;21:161–79.
. Zucca E. Extranodal lymphoma: a reappraisal. Ann Oncol 2008;19(suppl 4):iv77–80.
. Ma J, Wang Y, Zhao H, et al. Clinical characteristics of 26 patients with primary extranodal Hodgkin lymphoma. Int J Clin Exp Pathol 2014;7:5045–50.
. Binesh F, Mirjalili MR, Akhavan A, et al. Primary bony Hodgkin's lymphoma. BMJ Case Rep 2012;2012.
. Ostrowski ML, Inwards CY, Strickler JG, et al. Osseous Hodgkin disease
. Cancer 1999;85:1166–78.
. Gandhi JS, Mehta A, Sharma A, et al. Primary Hodgkin lymphoma of the ileum. J Cancer Res Ther 2010;6:342–3.
. Ha-ou-nou FZ, Benjilali L, Essaadouni L. Sacral pain as the initial symptom in primary Hodgkin's lymphoma of bone. J Cancer Res Ther 2013;9:511–3.
. Biswas A, Puri T, Goyal S, et al. Osseous Hodgkin's lymphoma-review of literature and report of an unusual case presenting as a large ulcerofungating sternal mass. Bone 2008;43:636–40.
. Enneking WF, Dunham WK. Resection and reconstruction for primary neoplasms involving the innominate bone. J Bone Joint Surg 1978;60:731–46.
. Fletcher CDM, Bridge JA, Hogendoorn P, et al. WHO/IARC Classification of Tumours of Soft Tissue and Bone, 4th ed. vol. 52013. World Health Organization; 2013.
. Dawson IM, Cornes JS, Morson BC. Primary malignant lymphoid tumours of the intestinal tract. Report of 37 cases with a study of factors influencing prognosis. Br J Surg 1961;49:80–9.
. Li Y, Wang XB, Tian XY, et al. Unusual primary osseous Hodgkin lymphoma in rib with associated soft tissue mass: a case report and review of literature. Diagn Pathol 2012;7:64.
. Matikas A, Briasoulis A, Tzannou I, et al. Primary bone lymphoma: a retrospective analysis of 22 patients treated in a single tertiary center. Acta Haematol 2013;130:291–6.
. Nam-Cha SH, Montes-Moreno S, Salcedo MT, et al. Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers. Mod Pathol 2009;22:1006–15.
. Hoeller S, Zihler D, Zlobec I, et al. BOB.1, CD79a and cyclin E are the most appropriate markers to discriminate classical Hodgkin's lymphoma from primary mediastinal large B-cell lymphoma. Histopathology 2010;56:217–28.
. Rentas Torres Y, Rodriguez-Lopez JL, Valentin M, et al. Difficult diagnosis between B cell lymphoma and classical Hodgkin's lymphoma. Boletin de la Asociacion Medica de Puerto Rico 2015;107:98–101.
. Evens AM, Kanakry JA, Sehn LH, et al. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol 2015;90:778–83.
. Spencer J, Dresser R. Lymphoblastoma (Hodgkin's and sarcoma type) of bone. N Engl J Med 1936;214:877–9.
. Kooreman PJ, Haex AJC. Hodgkin's disease of the skeleton. Acta Med Scand 1943;115:177–96.
. Gold RH, Mirra JM. Case report 101. Primary Hodgkin disease
of humerus. Skeletal Radiol 1979;4:233–5.
. Chan KW, Rosen G, Miller DR, et al. Hodgkin's diseases in adolescents presenting as a primary bone lesion. A report of four cases and review of literature. Am J Pediatr Hematol Oncol 1982;4:11–7.
. MacCormick R, Covert A, Gross M. Primary bony involvement in Hodgkin's disease. Can Med Assoc J [Journal de l’Association medicale canadienne] 1989;140:1059–60.
. Cowie F, Benghiat A, Holgate C. Primary Hodgkin's disease of bone. Clin Oncol 1991;3:233–5.
. Fried G, Ben Arieh Y, Haim N, et al. Primary Hodgkin's disease of the bone. Med Pediatr Oncol 1995;24:204–7.
. Citow JS, Rini B, Wollmann R, et al. Isolated, primary extranodal Hodgkin's disease of the spine: case report. Neurosurgery 2001;49:453–6.
. Nguyen BD, Roarke MC. Multicentric primary spinal Hodgkin's lymphoma: PET/CT and MR imaging. Clin Nucl Med 2005;30:702–3.
. Gebert C, Hardes J, Ahrens H, et al. Primary multifocal osseous Hodgkin disease
: a case report and review of the literature. J Cancer Res Clin Oncol 2005;131:163–8.
. Langley CR, Garrett SJ, Urand J, et al. Primary multifocal osseous Hodgkin's lymphoma. World J Surg Oncol 2008;6:34.
. Samadian M, Vahidi S, Khormaee F, et al. Isolated, primary spinal epidural Hodgkin's disease in a child. Pediatr Neurol 2009;40:480–2.
. Nikolica G, Badnjar Z, Cadjenovic T, et al. Primary extra nodal Hodgkin disease
: bone presentation. Pol J Radiol 2014;79:91–3.
. Uehara M, Takahashi J, Hirabayashi H, et al. Hodgkin's disease of the thoracic vertebrae. Spine J 2013;13:e59–63.
. Luo W, Zhang F, Sun J, et al. Unusual primary osseous Hodgkin's lymphoma: a case report. Oncol Lett 2015;9:677–80.
. Sun J, Yang Q, Lu Z, et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. Am J Clin Pathol 2012;138:429–34.
. Colby TV, Hoppe RT, Warnke RA. Hodgkin's disease: a clinicopathologic study of 659 cases. Cancer 1982;49:1848–58.
. Ozdemirli M, Mankin HJ, Aisenberg AC, et al. Hodgkin's disease presenting as a solitary bone tumor. A report of four cases and review of the literature. Cancer 1996;77:79–88.
. Laitinen M, Parry M, Albergo JI, et al. Outcome of pelvic bone sarcomas in children. J Pediatr Orthop 2016.
. Guder WK, Hardes J, Gosheger G, et al. Osteosarcoma and chondrosarcoma of the pelvis
and lower extremities. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 2015;86:993–1003.
. Rajiah P, Ilaslan H, Sundaram M. Imaging of sarcomas of pelvic bones. Semin Ultrasound CT MR 2011;32:433–41.
. Park SK, Lee IS, Cho KH, et al. Osteosarcoma of pelvic bones: imaging features. Clin Imaging 2017;41:59–64.
. Flores M, Caram A, Derrick E, et al. Ewing sarcoma of the pelvis
with an atypical radiographic appearance: a mimicker of non-malignant etiologies. Cureus 2016;8:e787.
. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776–90.
. Jawad MU, Haleem AA, Scully SP. Malignant sarcoma of the pelvic bones: treatment outcomes and prognostic factors vary by histopathology. Cancer 2011;117:1529–41.
. Outani H, Hamada K, Imura Y, et al. Comparison of clinical and functional outcome between surgical treatment and carbon ion radiotherapy for pelvic chondrosarcoma. Int J Clin Oncol 2016;21:186–93.
. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998;339:1506–14.
. Edwards-Bennett SM, Jacks LM, Moskowitz CH, et al. Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol 2010;21:574–81.
. Engert A, Haverkamp H, Kobe C, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 2012;379:1791–9.
. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol 2013;31:684–91.
. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol 2003;21:607–14.
. Beal K, Allen L, Yahalom J. Primary bone lymphoma: treatment results and prognostic factors with long-term follow-up of 82 patients. Cancer 2006;106:2652–6.
. Tao R, Allen PK, Rodriguez A, et al. Benefit of consolidative radiation therapy for primary bone diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys 2015;92:122–9.
. Ding L, Wang HX, Xue M, et al. Bortezomib in combination with IGEV chemotherapy regimen for a primary refractory Hodgkin's lymphoma of bone. Leuk Res 2009;33:e170–2.
. Ansell SM. Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016;91:434–42.
. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010;363:1812–21.
. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol 2012;30:2183–9.
. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015;372:311–9.
. Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol 2012;30:2197–203.
. Meadows SA, Vega F, Kashishian A, et al. PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signalling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012;119:1897–900.
. Liu YC, Gau JP, Yu YB, et al. Prognostic factors and treatment efficacy in patients with primary diffuse large B-cell lymphoma of the bone: single institute experience over 11 years. Int Med 2014;53:95–101.
. Cirakli A, Elli M, Dabak N, et al. Evaluation of primary bone lymphoma and the importance of positron emission tomography. Acta Orthop Traumatol Turc 2014;48:371–8.
. Jamshidi K, Jabalameli M, Hoseini MG, et al. Stage IE Primary Bone Lymphoma: Limb Salvage for Local Recurrence. Arch Bone Joint Surg 2015;3:39–44.
. Luo Y, Duan H, Liu W, et al. Clinical evaluation for lower abdominal aorta balloon occluding in the pelvic and sacral tumor resection. J Surg Oncol 2013;108:148–51.
. Guo W, Li D, Tang X, et al. Reconstruction with modular hemipelvic prostheses for periacetabular tumor. Clin Orthop Relat Res 2007;461:180–8.
. Zhou Y, Duan H, Liu Y, et al. Outcome after pelvic sarcoma resection and reconstruction with a modular hemipelvic prostheses. Int Orthop 2011;35:1839–46.