Hodgkin disease rarely presents as an osseous lesion, and the majority of patients are found at staging to have concurrent disease in lymph nodes. Many cases of osseous Hodgkin disease have been misdiagnosed on initial biopsy.
Hodgkin disease rarely presents as an osseous lesion, and the majority of patients are found at staging to have concurrent disease in lymph nodes. Many cases of osseous Hodgkin disease have been misdiagnosed on initial biopsy.
All cases of Hodgkin disease diagnosed by open bone biopsy at the Mayo Clinic were identified. These included patients with primary osseous tumors, those presenting with multiple sites of involvement (with osseous lesions), and those with recurrence in bone. Recut sections were subjected to immunohistochemical stains to confirm the diagnosis. Clinical data and follow-up information were obtained from patients' charts.
Twenty-five patients (15 males and 10 females with an average age of 37 years) with osseous Hodgkin disease were identified during the years 1927–1996. Three patients had solitary, osseous tumors and two had primary, multifocal, osseous Hodgkin disease without involvement of nonosseous sites. Twelve patients who presented with lesions in osseous sites also had nonosseous tumors detected at staging, and 8 patients had recurrent Hodgkin disease that presented in bone. The majority of patients with primary and recurrent tumors presented only with bone pain; >50% of patients with concurrent osseous and nonosseous disease also had B-type symptoms. Nearly all lesions were in the axial and proximal appendicular skeleton. Radiographic features included osteosclerotic, osteolytic, and mixed lytic/sclerotic patterns. Cortical destruction, periosteal new bone formation, and soft tissue masses were present in 50% of cases. The histologic diagnosis of osseous Hodgkin disease occasionally was problematic; osteomyelitis was the most frequent misdiagnosis. Immunohistochemical stains revealed expression of CD15 and CD30 in neoplastic cells (which were negative for CD45 and B-cell and T-cell antigens) in all but two cases. Involved lymph nodes typically exhibited nodular sclerosis Hodgkin disease. Three patients with primary solitary osseous Hodgkin disease received radiation treatment only; at last follow-up 2 patients were alive at 22 months and 10 years, respectively. Patients with concurrent osseous and nonosseous tumors exhibited a 60% overall survival rate, but at last follow-up all 4 patients diagnosed after 1986 still were alive; those with Hodgkin disease that recurred as osseous lesions had a 60% survival rate at 8 years, but only 1 of the 5 patients diagnosed since 1984 had died of disease.
Osseous Hodgkin disease typically presents with bone pain, and the majority of patients have concurrent nonosseous lesions detected at staging. Radiographic features of osseous Hodgkin disease vary but indicate an aggressive malignant process. The histologic diagnosis may be problematic; immunohistochemical stains aid in establishing the diagnosis of Hodgkin disease in bone. Survival of patients with osseous Hodgkin disease has been found to be good for the last 10 years. Cancer 1999;85:1166–78. © 1999 American Cancer Society.
Lymphomas of bone are uncommon, comprising only 8% of primary malignant bone tumors.1 Most malignant lymphomas of bone are diffuse non-Hodgkin lymphomas of B-cell type.2–7 A previous study of 422 malignant lymphomas of bone included 13 cases of Hodgkin disease and no cases of primary solitary osseous Hodgkin disease.5 Although radiologically detectable osseous lesions are present in Hodgkin disease in 10–20% of cases,8–13 presentation with an osseous lesion is distinctly uncommon, with only about 20 cases reported in the literature. In most of these cases, associated lymph node involvement has been detected at staging or surgery. The histologic diagnosis of osseous Hodgkin disease is often problematic, but it is facilitated by immunohistochemical studies. We present a series of 25 cases of osseous Hodgkin disease, 17 of which presented initially as osseous lesions (including 5 primary osseous tumors), from clinical, radiologic, and pathologic perspectives.
For this study, only patients with bone lesions biopsied at the Mayo Clinic and with medical records and slides available for review were included. Medical records were reviewed for staging, treatment, and follow-up information with approval from the Institutional Review Board of the Mayo Foundation (M.O., T.E.W.). Original slides from all lymphomas of bone were reviewed (M.O.) and those with Hodgkin disease were selected for study. All cases of osseous Hodgkin disease were reviewed by four authors (M.O., C.Y.I., J.G.S., and K.K.U.). Histologic sections were prepared from 10% formalin or B-5 fixed, paraffin embedded tissue, and stained with hematoxylin and eosin. Immunohistochemical staining was performed on recut sections using an avidin-biotin technique with diaminobenzidine, employing microwave technology for antigen retrieval.14 The antibodies used were against CD3, CD30, CD45, and L26 (DAKO, Carpinteria, CA) and CD15 (Boehringer Mannheim, Indianapolis, IN). For the diagnoses of primary osseous Hodgkin disease and primary multifocal osseous Hodgkin disease, we required that only osseous lesions be present at the time of diagnosis and staging, and for at least the following 6 months of follow-up, as in a previous study of lymphomas of bone.5
From representative slides of over 500 malignant lymphomas of bone, 33 cases of Hodgkin disease were found. Two cases from 1918 and 1926 were eliminated due to histologic features and immunohistochemical studies not supportive of this diagnosis. From the remaining 31 cases, 25 had medical records available for review. The skeletal distribution of the lesions and patient ages at presentation are illustrated in Figure 1. There were 38 lesions in 25 patients (15 males and 10 females; age range, 11–73 years). Twenty-seven lesions occurred in the axial skeleton; most others involved the proximal appendicular bones. Patients were subdivided into four groups, with clinical features, treatment, and follow-up data shown in Tables 1–4. Since 1980, bilateral bone marrow biopsies have been performed in staging Hodgkin disease. Radiologic studies were available for review in 16 patients with 21 lesions (Table 5). Concurrent nonosseous disease was of nodular sclerosis type in 11 of 12 classifiable cases, a slightly higher percentage of this subtype than that recently noted in Hodgkin disease overall. (Of 662 patients with Hodgkin disease who were seen at the Mayo Clinic from January 1988 through August 1997, 494 [75%] had nodular sclerosis type.)
|1 1960||73/F||Right hip pain||Right femur||Radiation||Multiple recurrences (3 and 4 yrs), inguinal lymph nodes, spleen, mediastinum, thoracic and lumbar spine, pelvic bones; treated with chemo, DOD (4 yrs)|
|2 1968||34/M||Left distal arm pain||Left humerus||Radiation||AWD (10 yrs), then LTFU|
|3 1995||61/F||Left thoracolumbar pain||T11||Resection and radiation||AWD (22 mos)|
|1 1927||42/M||Right flank pain, pain in abdomen, shoulders||T4–T8||Radiation||Alive (10 mos), then LTFU|
|2 1958||53/M||Left shoulder pain||Left humerus, left ilium||Radiation||DOD (4 mos)|
|Case||Year||Age/gender||Signs and symptoms||Bone site(s)||Other site(s)||Treatment||Status|
|1||1934||58/M||Chest mass||Manubrium||Anterior chest wall soft tissueb||Radiation||DOD (date unknown)|
|2||1953||50/M||Chest pain||Sternum||Bilateral axillary lymph nodes||Radiation||DOD (9 mos)|
|3||1967||30/M||Left leg pain, night sweats, fever||Left tibia||Bilateral cervical lymph nodes||Radiation, Chemo||Multiple recurrences (9 mos–6 yrs) in ribs, right tibia, vertebrae, lung, treated with radiation and chemo; DOD (6 yrs)|
|4||1971||37/F||Draining sinuses right axilla, right axillary lymphadenopathy, fever||Right scapula||Right axillary lymph nodesb||Chemo||DOD (9 mos)|
|5||1980||21/M||Back pain, hip pain, weight loss, night sweats, fever||Left iliac crest,a right sacrum||Paraaortic and pancreatic lymph nodes, T3, T10, L4||Chemo||AWD (16 yrs)|
|6||1983||32/M||Right thigh pain, left supraclavicular lymphadenopathy, night sweats||Right femur||Left supraclavicular lymph node,b mediastinum||Chemo||Multiple recurrences (diagnosed elsewhere, unknown sites), bone marrow transplant; DOD (6 yrs)|
|7||1986||29/F||Low back pain, fever||Right acetabulum,a right humerus||Mediastinum, right supraclavicular lymph nodeb||Chemo||LTFU|
|8||1986||41/M||Rib, chest pain||Right ribs||Right chest wall, intercostal muscle||Chemo||Recurrences in right chest wall (3 and 5 yrs); alive (5 yrs), then LTFU|
|9||1986||41/M||Upper back pain, night sweats, fever||T10||Lung,b T4, T6, L1; cervical, inguinal, paraaortic lymph nodes, spleen||Chemo||Recurrence in left cervical lymph nodes, bone marrow transplant (2 yrs); AWD (10 yrs)|
|10||1991||13/F||Chronic back pain, fever||L1, L4a||Mediastinum, lungb||Chemo||Recurrence (1 yr) in spleen and supraclavicular lymph nodes, bone marrow transplant; AWD (5 yrs)|
|11||1993||51/F||Right leg pain||Right ilium||Mediastinum||Chemo||AWD (3 yrs)|
|12||1996||11/M||Left leg pain, fever||Left ilium||Cervical lymph nodes,b mediastinum, liver, left ischium, right femur||Chemo||Alive (1 yr) after multiple cycles of chemo with residual right paratracheal/anterior mediastinal mass; will possibly receive radiation|
|Case||Year||Age/gender||Signs and symptoms||Bone site(s)||Original site/year||Initial treatment||Treatmentb||Statusc|
|1||1964||20/M||Unknown||Left sternuma and claviclea||Cervical lymph node, 1962||Unknown||Radiation||Multiple recurrences L1–L3 (2, 6, 7 yrs), all treated with chemo and radiation. DOD (7 yrs) with cryptococcal meningitis|
|2||1965||50/F||Pain, right thigh||Right femur||Nasopharynx, 1962||Unknown||Radiation||AWD (12 yrs), then LTFU|
|3||1967||22/M||Spinal cord compression||T7a–T11a||Cervical, axillary, inguinal lymph nodes, mediastinum, 1964||Chemo and radiation||Chemo and radiation||DOD (20 mos)|
|4||1984||31/M||Back pain||Right ilium,a L2||Right scalene, paraaortic lymph nodes, liver, spleen, 1983||Chemo||Chemo and radiation||LTFU|
|5||1985||46/F||Pain, numbness of right lower extremities||L5, sacrum,a coccyx||Left cervical lymph nodes, 1984||Radiation||Chemo||AWD (8 yrs)|
|6||1988||27/F||Hip pain||Right proximal femur||Cervical, supraclavicular lymph nodes, mediastinum, 1987||Chemo and radiation||Chemo and radiation||Recurrence in left femur (1 yr), bone marrow transplant (2 yrs); AWD (8 yrs)|
|7||1990||21/F||Back pain||Right proximal femur; ilium,a left ischium||Mediastinum, 1988||Chemo and radiation||Chemo||Will have bone marrow transplant elsewhere; LTFU|
|8||1991||36/M||Back pain, leg pain||L2,a left femur||Cervical, axillary, inguinal lymph nodes, 1978||Chemo and radiation||Chemo||DOD (1 yr)|
|Radiographic features||Group 1b n = 2||Group 2c n = 14||Group 3d n = 5||Total|
|Pattern of bone destruction|
|Mixed (lytic and sclerotic)||0||6||3||9|
|Negative conventional X-ray||0||1||1||2|
|Soft tissue mass||2||6||2||10|
Features of three patients with primary osseous Hodgkin disease are listed in Table 1. Case 1, from 1960, had only a limited work up, with a negative chest radiograph but without bone marrow biopsies, bone survey, or lymphangiography. The erythrocyte sedimentation rate was elevated at 47 mm/hour (n = 0–22 mm/hour). Chemotherapy at that time consisted only of intravenous nitrogen mustard. In Case 2, staging included a negative lymphangiogram and bone survey. In Case 3, two nondiagnostic fine-needle aspiration biopsies were obtained, 1 and 2 months before a diagnosis of Hodgkin disease was rendered on examination of the resected vertebra. The results of bone survey, bone scan, bilateral iliac bone marrow biopsies, and computed tomography (CT) of the chest, abdomen, and pelvis were negative, and the patient was treated with 40 gray after surgery.
Two patients presented with primary multifocal osseous Hodgkin disease (without nonosseous disease) (Table 2). Diagnosed in 1927 and 1958, these patients had very limited evaluations, compared with current standards. In Case 2, initial biopsies performed elsewhere, 18 months before presentation to the Mayo Clinic, were diagnosed as eosinophilic granuloma of both osseous sites.
The largest group of patients in our study presented with osseous lesions but were found at staging to have nonosseous Hodgkin disease, or presented with such within 6 months of the osseous tumor diagnosis (Table 3). There were four Stage II lesions, two Stage III lesions, and six Stage IV lesions.15 Biopsies from three of these patients were initially misdiagnosed as osteomyelitis. Case 5 had biopsies that were interpreted as osteomyelitis on frozen section, but the diagnosis was amended the following day. In Case 9, a diagnosis of osteomyelitis was made initially elsewhere. After 1 year of antibiotic treatment, during which time B symptoms continued and additional lesions developed in many sites, biopsies revealed Hodgkin disease, which was treated with MOPP/ABVD (mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine, dacarbazine). Case 12 was originally diagnosed as osteomyelitis of the left ilium. Two months later, cervical lymphadenopathy developed, and biopsies of these lymph nodes revealed nodular sclerosis Hodgkin disease. One patient (Case 8) presented 15 years after presentation with a diffuse large cell lymphoma of the left axillary region and scapula.
Eight patients had recurrent Hodgkin disease, which presented in osseous sites, more than 6 months after the original diagnoses of nonosseous Hodgkin lymphoma (Table 4). The original cases included two Stage I lesions, three Stage II lesions, and three Stage III lesions.15 Of those classifiable, there were four cases of nodular sclerosis and one of mixed cellularity subtype. One patient (Case 8) who initially presented with Hodgkin disease involving multiple lymph nodes developed cutaneous T-cell lymphoma and T-cell lymphoma of an axillary lymph node in 1983; an anaplastic plasmacytoma in a cervical lymph node in 1987; and recurrent Hodgkin disease, syncytial variant of nodular sclerosis, in a cervical lymph node in 1988, prior to developing recurrent Hodgkin disease in bone.
Radiographs of 15 patients were available for review; features are shown in Table 5. Studies included conventional radiography (18 lesions), CT (10 lesions), nuclear scintigraphy (9 lesions), and magnetic resonance imaging (MRI) (5 lesions). Lesions were located in the axial and proximal appendicular skeleton; two-thirds were axial. The five appendicular lesions were present in the proximal regions of long bones; two also showed epiphyseal involvement.
The radiographic features of osseous Hodgkin disease were variable, with osteolysis in 24% of cases (Figs. 2 and 3), osteosclerosis in 24% (Fig. 4), and an admixture of osteolysis and osteosclerosis in 45% (Figs. 5 and 6). Lesional margins were ill-defined, and there was frequent cortical destruction, periosteal reaction, and extension of tumor into surrounding soft tissue. Two lesions were detectable only with MRI (Fig. 7). CT was beneficial for assessing periosteal reaction and cortical destruction. Bone scans invariably showed increased activity at the sites of osseous Hodgkin disease. The radiographic differential diagnosis included primary sarcomas of bone, non-Hodgkin lymphomas and leukemia, osteomyelitis, and metastatic lesions.
In our study, there were no radiographic features that distinguished between groups when cases of primary solitary osseous Hodgkin disease were compared to those with multiple sites of involvement at presentation or osseous recurrence. However, it is noteworthy that two of three pathologic fractures occurred in patients with primary solitary osseous Hodgkin disease (Table 1, Cases 2 and 3), and both of these were lytic lesions with cortical destruction and soft tissue masses. Mineralization was not detected in either bone or soft tissue components, and classic “ivory vertebrae” were not present.
Histologically, osseous Hodgkin disease was typically present as an infiltrate between intact bone trabeculae, similar to non-Hodgkin lymphoma involving bone (Fig. 8). In some cases, bone formation was noted in cortical regions or around bone trabeculae (Fig. 9), corresponding to the periosteal reactions and osteosclerosis noted on radiographs. The infiltrate consisted of lymphocytes, eosinophils, plasma cells, and histiocytes, with atypical mononuclear cells and Reed–Sternberg cells (Fig. 10). The latter were identified in every case. Fibrosis, necrosis, and acute inflammatory cells were present to varying degrees. Only 1 case (Fig. 11; Table 3, Case 6) exhibited features diagnostic of a specific subtype of Hodgkin disease (nodular sclerosis), identical to those in a left supraclavicular lymph node. Well-formed granulomata, such as those present in fungal or mycobacterial infection, or sarcoidosis, were not present in any case.
Immunohistochemical stains for CD15 and CD30 were positive in neoplastic cells (Fig. 12), with corresponding nonimmunoreactivity for B- and T-cell markers and CD45 in all but 2 cases. In one case, sufficient material was not available in paraffin blocks for additional studies. In the second, histologic features were typical of Hodgkin disease, but the atypical cells of Reed–Sternberg type lacked immunoreactivity to CD15, CD30, CD45, and B- and T-cell markers. Molecular genetic studies revealed no clonal rearrangements of immunoglobulin genes or T-cell receptor genes. In this case, Hodgkin disease was diagnosed on the basis of the histomorphologic features in conjunction with these findings.
The most frequent misdiagnosis was acute osteomyelitis. This diagnosis was suggested by large areas of necrosis with prominent polymorphonuclear cell infiltration (Fig. 13), alternating with areas of fibrosis and chronic inflammation. Reed–Sternberg cells were sparsely present, however, and immunohistochemical results were identical to those noted above. In two cases, eosinophils were very prominent (Fig. 14), but Reed–Sternberg cells were also present, and there were no Langerhans cells.
Hodgkin disease usually presents clinically with painless lymphadenopathy, most typically in the cervical region. Although radiologically detectable bone involvement is not unusual in advanced cases of Hodgkin lymphoma, osseous lesions are seldom the primary manifestations of this disease. In a previous study of 422 malignant lymphomas of bone, there were only 13 cases of Hodgkin disease,5 none of which was a primary lesion, as defined in our study. Hodgkin disease involving osseous sites must also be distinguished from involvement of the bone marrow by Hodgkin disease, which occurs in approximately 5–10% of patients.16–21 Unlike cases with bone marrow involvement, however, Hodgkin disease with clinically symptomatic osseous involvement has been associated with prognoses similar to, or slightly better than, those with lymph node disease alone.22, 23
In our study, of 17 patients who presented with osseous lesions, 3 had primary solitary osseous tumors. Four cases of primary solitary osseous Hodgkin disease have been previously reported in the English-language literature.23–26 Two were reported before 1944, however, and thus were inadequately staged by current standards.23, 24 Gold and Mirra25 reported a case of primary humeral Hodgkin disease in a woman age 25 years who survived for 4 1/2 years after receiving radiation only. The survival of their patient, and of two primary solitary cases reported herein, after only radiation to the osseous sites, attests to the true primary nature of these rare lesions.27 This point is important, because Hodgkin disease involving osseous sites has sometimes been considered to portend an unfavorable prognosis, or even to represent Stage IV disease.
Three previously reported cases of primary Hodgkin disease involving multifocal osseous sites were treated with chemotherapy, with or without radiation.28–30 As in our examples of primary multifocal osseous Hodgkin disease, 2 of these cases29, 30 had limited follow-up (less than 6 months); 1 survived without recurrence for 3 years.28
Radiographic evidence of bone involvement has been noted in 10–15% of cases of Hodgkin disease;13 these lesions are not typically biopsied. Although these lesions are distinct from those in the current study with regard to clinical presentation, Parker et al.31 reported a distribution of lesions similar to that in our study, with a predilection for the axial and proximal appendicular skeleton. Of interest, all except one of our cases presented in adults in bones containing hematopoietic marrow. Osseous Hodgkin disease presenting in the sternum, sometimes with an associated soft tissue mass, has been reported as an unusual presentation of this tumor,32–34 and three of our cases had sternal and/or manubrial involvement.
The radiologic features of osseous Hodgkin disease have been described as osteosclerotic, osteolytic, or mixed osteosclerotic/osteolytic.9, 35–37 Lytic lesions were sometimes interpreted as representative of hematogenous spread, and sclerotic lesions as direct extensions of disease from contiguous lymph nodes.16, 36 However, two of our three primary solitary cases were lytic, and the cases that presented with osseous recurrence were not distinct radiologically. Furthermore, although regional lymph nodes may be involved in cases of osseous Hodgkin disease, less than half of the cases in our study that presented with both osseous and nonosseous disease had lymph node disease that might be considered contiguous with osseous foci.
The histologic diagnosis of osseous Hodgkin disease may be very problematic, undoubtedly related to the rarity of presentation of Hodgkin disease in bone. All four cases reported by Ozdemirli et al.37 were described as diagnostic problems. Osteomyelitis is a particularly difficult differential diagnostic entity, as the clinical and radiologic features of this and osseous Hodgkin disease may be quite similar. Necrosis and extensive polymorphonuclear cell infiltration (similar to that sometimes noted in Hodgkin disease in lymph nodes) were present in two of our cases initially misdiagnosed as osteomyelitis. In these cases, the patient had concurrent lymphadenopathy, or developed such within 6 months.
The misdiagnosis of eosinophilic granuloma has been noted previously in Hodgkin disease,38, 39 and in 1 case the 15-month delay in diagnosis was stated to have resulted in the death of that patient.39 In a study by Chan et al.,40 of four adolescent patients who presented with “primary” bone lesions (all of whom had lymph node disease at diagnosis), eosinophilic granuloma was initially suspected or favored in all cases, based on histologic studies. Eosinophilic granuloma may be associated with fever, and the sites of presentation of this entity may overlap with those of osseous Hodgkin disease. Radiographically, however, eosinophilic granuloma usually shows well-delineated osteolytic lesions, a feature which is helpful in distinguishing this from osseous Hodgkin disease.
Most cases of osseous non-Hodgkin lymphoma are B-cell neoplasms with a significant large-cell component. Non-Hodgkin osseous lymphoma may be associated with fibrosis or sclerosis. In a previous study, fibrosis with spindling of cells contributed significantly to diagnostic dilemmas in 2% of lymphomas of bone.5 Fibrosis was part of the reactive background in most of our cases of osseous Hodgkin disease, but was not a prominent feature (except in the nodular sclerosis case). In a recent study,37 however, the initial diagnosis in one case was malignant fibrous histiocytoma. Thus, it appears that Hodgkin disease should be included in the differential diagnosis of osseous lesions with cellular spindling or a fibrous stromal component.
In summary, patients who present with apparent solitary osseous Hodgkin disease almost always harbor nonosseous disease that becomes manifest with staging studies. Osseous Hodgkin disease presents with bone pain; many patients have B-type symptoms. Lymph nodes typically demonstrate nodular sclerosis Hodgkin disease. The radiographic features of osseous Hodgkin disease are nonspecific but indicate a destructive malignant process with osteosclerosis and/or osteolysis. Hodgkin disease should be included in the histologic differential diagnosis of bone lesions in cases in which osteomyelitis, eosinophilic granuloma, or a lesion with cellular spindling or a fibrous component is considered. Immunohistochemical stains are very helpful in the diagnosis of osseous Hodgkin disease. Primary, solitary osseous Hodgkin disease is extremely rare; a few cases have been cured with radiation therapy. With current chemotherapeutic regimens, the long term prognosis of patients with osseous Hodgkin disease appears good. The presence of osseous lesions in Hodgkin disease, at either presentation or recurrence, should not be interpreted to imply a worse prognosis than Hodgkin disease without involvement of osseous sites.