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.
After 2 cycles ABVD chemotherapy in department of hematology, the limb-salvage surgery was performed until the patient got a relatively good condition. A standard iliofemoral approach was used, according to the classification of pelvic resections by Enneking and Dunham. A lower abdominal aortic balloon occlusion was used during the resection procedure. Type I-II-IV left pelvic resection and total hip arthroplasty were performed to achieve clear margins. During the operation, a soft-tissue mass with a maximum volume of 26.0 × 16.5 × 9.0 cm was visualized. It was bounded by the rear of the sacrum, and extended down to the femoral head, with involvement of lumbar muscle, the gluteus medius, and part of the S1 nerve root. During the procedure, a modular hemipelvic replacement system (Chun Li Zheng Da Co. Beijing, China) was implanted to reconstruct the left hemipelvis (Fig. 3). Three enlarged lymph nodes in the left inguinal region were dissected for biopsy. Finally, the muscles and soft tissues were sutured into the femoral prosthesis stem and acetabulum with 2–0 nonabsorbable sutures (Ethibond* Excel, Polyester Suture, Green Braided, Johnson & Johnson, New Jersey) to complete the in situ restoration and functional reconstruction. The surgery lasted 4.5 hours and blood loss was approximately 1500 mL for the entire procedure.
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.
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