Hematolymphoid Neoplasms of Bone

Clinical Features

Almost all patients present with pain in the involved bone, sometimes with swelling or palpable mass, and usually without systemic symptoms. PLB with pathologic fracture can occur ( Fig. 19.1 ) and is most common in the weight-bearing long bones of the lower extremities. Vertebral involvement can lead to spinal cord or nerve root compression in the setting of a fracture or epidural extension.

PLB affects both the axial skeleton and the appendicular skeleton. The bones of the lower half of the body are more often involved than are those of the upper half. The femur is most often involved, followed by the spine, pelvis, tibia, humerus, skull, jaw, and ribs. The scapula, other long bones (ulna, radius, fibula), and clavicle are less often affected. Involvement of the hands and feet is rare. Localized, monostotic, unifocal involvement is more common than is multifocal or polyostotic disease. A few cases are multifocal within a single bone. Polyostotic disease is more common among children.

Radiologic Findings

PLB is typically a poorly demarcated, permeative, lytic lesion, occasionally with a mixed lytic and sclerotic appearance. Rarely, the lesion is entirely sclerotic. Extension into the soft tissue is common. There may be an associated periosteal reaction. Pathologic fracture is seen in a minority of cases ( Fig. 19.1 ).

Pathologic Features

Diffuse large B-cell lymphoma

Microscopic findings

DLBCL, by far the most common type of PLB, is composed of large atypical cells with irregular nuclei, multilobated nuclei, centroblasts with round to oval nuclei, vesicular chromatin, and peripheral nucleoli, immunoblasts with prominent central nucleoli, elongate spindle cells, or bizarre cells. Crush artifact is common. Many admixed small lymphocytes and histiocytes and areas of fibrosis may be present. Reactive woven bone is often present at the periphery of the lesion. Fracture callus consistent with pathologic fracture may be seen ( Fig. 19.2 ).

Ancillary Studies

Prognosis and Treatment

Optimal radiation therapy to the primary site effectively prevents local relapse but does not prevent distant relapse. A combination of anthracycline-based chemotherapy and radiation is usually recommended to increase the chance of cure for adult patients. Chemotherapy alone is preferred for children, as the outcome is good and decreases the risk of secondary sarcomas compared to radiated bone.

Primary DLBCL of bone has a better prognosis than do most other malignancies arising in bone and most extra-osseous DLBCL. Up to 90% of optimally treated patients achieve complete remission. In some series, the 5-year survival is over 80%, and as high as 90% for patients under age 60. Gene expression profiling exhibiting the DLBCL-GC-CC origin correlates with a favorable prognosis: in general, DLBCL-GC-CC has a better prognosis than does DLBCL-GC-CB.

Relapses occur in a minority of DLBCL patients; they may involve the primary site, other bones, regional lymph nodes, other lymph nodes and, infrequently, other sites, including the lungs, bone marrow, and central nervous system (CNS). A variety of clinical and pathological features affect the prognosis of DLBCL of bone. An unfavorable outcome is associated with a higher stage, polyostotic disease, soft tissue extension, vertebral or pelvic primary, older age, pathologic fracture at presentation, elevated serum LDH, and neoplastic cells that are centroblasts, immunoblasts, or pleomorphic. A superior outcome is associated with age <60 years, lymphoma arising in a long bone, lymphoma composed of large irregular cells or multilobated cells, GCB phenotype, and complete response with initial therapy.

Differential Diagnosis

The clinical and radiographic features of primary lymphoma of bone (PLB) are not specific. The differential diagnosis includes osteomyelitis, plasmacytoma, myeloid sarcoma, Langerhans cell histiocytosis, Ewing sarcoma, and other small round cell neoplasms. Multiple lesions can suggest plasma cell myeloma and metastases. Rendering the correct diagnosis may be difficult because of associated crush artifact, excessive decalcification, small biopsy size, sampling artifact, and admixture of many reactive cells. PLB can be misinterpreted as a reactive process such as chronic osteomyelitis or as a simple fracture if reactive cells and/or fracture callus predominates or if neoplastic cells are sparse or poorly preserved.

Neoplastic cells of some PLB are elongate and resemble spindle cells, or grow in nests or cords, so that sarcoma and metastatic carcinoma enter the differential diagnosis. PLB can be associated with reactive woven bone formation and mimic osteosarcoma. Plasmacytoma composed of immature plasma cells can mimic DLBCL arising in bone, but plasmacytomas are diffusely CD138+, typically lack B-cell associated antigens CD20 and Pax5, and often express strong monotypic cytoplasmic immunoglobulin light chain on paraffin sections, while DLBCL is typically B-antigen positive, negative for CD138, and negative or occasionally weakly positive for light chains. Individuals with plasmacytomas may have diffuse bone marrow involvement by plasma cell myeloma and a serum paraprotein, in contrast to most patients with DLBCL. Large lymphoid cells typically have slightly larger nuclei, with either more vesicular or more coarsely clumped chromatin, and less delicate nuclear membranes than those of myeloid sarcoma. Differentiation into recognizable maturing myeloid elements, when present, helps to identify a neoplasm as myeloid sarcoma. Myeloid sarcomas with a component of immature monocytes with irregular nuclei can resemble DLBCL with large cleaved or multilobated cells. Lymphoma may also raise the consideration of a small round cell tumor, but Ewing sarcoma has cytoplasmic glycogen, a more cohesive growth pattern, and less pleomorphic nuclei. Neuroblastoma is characterized by pear- or carrot-shaped tumor cells that may be loosely cohesive and with denser chromatin than lymphoma; they may form rosettes.

Differential diagnosis of lymphoblastic lymphoma includes DLBCL, myeloid sarcoma, and Ewing sarcoma. Cases with CD20 expression may be mistaken for DLBCL. Lymphoblastic lymphoma negative for CD45 may be mistaken for Ewing sarcoma or other small round cell tumors. The primitive nuclei may suggest myeloid sarcoma. The characteristic hallmark cells of ALK+ ALCL have relatively abundant eosinophilic cytoplasm and can resemble immature myeloid cells, leading to a misdiagnosis of myeloid sarcoma. Hodgkin lymphoma presenting with involvement of bone can mimic acute or chronic osteomyelitis, depending on the composition of the reactive population, especially if the large neoplastic cells are sparse.

The differential diagnosis of PLB also includes secondary involvement of bone by lymphoma, which is more common than is PLB and is more likely to involve the axial than the appendicular skeleton. A wide variety of types of lymphoma can affect the bones secondarily.

Clinical Features

SPB affects men more often than it does women, with a male:female ratio that varies among series, but is approximately 2:1 overall. The patients are mostly middle-aged and older adults with a median age of 55 to 60 years. Young adults are occasionally affected. The patients typically present with localized pain, sometimes accompanied by fracture. They commonly have a serum or urine M component, most often IgG followed by IgA, and infrequently light chain only. The axial skeleton is affected more often than is the appendicular skeleton; the bones most often affected are the vertebrae, pelvis, ribs, skull, and long bones. Vertebral SPB with fracture can be associated with spinal cord compression. The complex interaction between the neoplastic cells and the microenvironment leads to osteoblastic inhibition and osteoclastic activation resulting in bone loss.

Radiologic Features

SPB takes the form of a lytic bone lesion; osseous lesions may be multiple in cases of plasma cell myeloma. In evaluating the patient for additional bony abnormalities, MRI and PET/CT are more sensitive than are plain radiographs alone ( Fig. 19.4 ).

Pathologic Features

Microscopic Findings

Neoplastic plasma cells in SPB grow in sheets, displacing the normal elements and disrupting the bony trabeculae; evidence of fracture is seen in some cases. The morphology of neoplastic cells can vary among cases. Some are composed of normal-appearing plasma cells with clock-faced chromatin and eccentrically placed cytoplasm; some have small lymphocyte-like plasma cells; many others are composed of atypical, enlarged plasma cells with occasional distinct nucleoli and abundant cytoplasm; and a few have plasmablast morphology with large nuclei, vesicular chromatin and prominent centrally placed nucleoli. Rare cases have anaplastic morphology ( Fig. 19.5 ).

Ancillary Studies

Differential Diagnosis

Plasma cell neoplasms with lymphocyte-like morphology can mimic lymphoplasmacytic lymphoma. Cases with anaplastic morphology can mimic a non-hematologic neoplasm. Chronic osteomyelitis may contain many plasma cells, but they are typically small and mature, and express polytypic immunoglobulin. See also the differential diagnosis of lymphoma of bone, above.

Prognosis and Treatment

Radiation provides effective local control for the vast majority of SPB. The local recurrence rate is high without radiation. Radiation does not prevent progression to plasma cell myeloma, however. The treatment of plasma cell myeloma has evolved substantially over the years. The treatment options include chemotherapy, immunomodulatory therapy (e.g., thalidomide, lenalidomide), proteasome inhibitors (e.g., bortezomib), bisphosphonates to decrease bone loss, and high-dose chemotherapy with stem cell transplantation.

Approximately two-thirds of SPB patients progress to plasma cell myeloma within 3 years; this is significantly more likely among patients with SPB with minimal bone marrow involvement (“plasmacytoma plus”) than in those with no clonal plasma cells on bone marrow biopsy. SPB >5 cm has been associated with recurrence or local progression of disease, higher risk of progression to myeloma, and poorer overall survival (OS). Older age and the persistence of the serum M component after treatment, consistent with persistent occult disease, are associated with a higher risk of progression to myeloma. Elevated β 2-microglobulin is associated with a poorer OS. One-third of SPB patients have long survival (>10 years) without progression to myeloma.

Among those with plasma cell myeloma, an unfavorable outcome is associated with older age (>60 or 70 years in different series), poor performance status, and plasmablastic morphology. Genetic features have a strong impact on prognosis. The abnormalities associated with standard risk include translocations of CCND1 and CCND3 and hyperdiploidy; translocation of FGFR3/NSD2 , deletion 13, and hypodiploidy are associated with intermediate risk; while deletion of 17p ( TP53 ), and translocations involving MAF or MAFB are associated with high risk.

SPB by itself may be associated with significant morbidity, although it is typically unassociated with death. Progression to myeloma results in poorer survival. The 5- and 10-year overall survival (OS) of patients presenting with SPB (most of whom progress to myeloma) are mostly in the ranges of 70–80% and 40–60%, respectively. Among patients with myeloma, those with standard risk cytogenetic changes have an OS of 8 to 10 years; intermediate-risk changes are associated with an OS of 4 to 5 years; and high-risk changes are associated with an OS of 3 years.

Clinical Features

Myeloid sarcoma is a rare neoplasm, with an annual incidence of approximately two cases per million adults. Some reports describe an increase in the extramedullary relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplant or after targeted therapy. It can occur in one of several clinical settings: myeloid sarcoma with concurrent AML; extramedullary relapse of AML; blast phase or transformation of a myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), or MDS/MPN, such as chronic myelomonocytic leukemia; or as an isolated finding in a patient with no history of a myeloid neoplasm and no concurrent evidence of other myeloid neoplasm. Isolated myeloid sarcoma accounts for a minority of cases and may be more common among patients status post-allogeneic hematopoietic stem cell transplant (allo-SCT) who relapse. The most common sites are the skin, soft tissue, and lymph nodes; less common are the bone, central nervous system, GI tract, testis, and other sites. In some cases, more than one site is involved. The bones most often involved are the skull, sternum, ribs, vertebrae, and pelvis.

Myeloid sarcoma affects children and adults; it has a male preponderance. Myeloid sarcoma appears more common among children who have AML than among adults with AML. The patients present with swelling, pain, or dysfunction of the affected organ or tissue.

Radiologic Features

Myeloid sarcoma commonly begins in a subperiosteal location; as it expands and invades the cortical bone, it results in the formation of one or more lytic lesions which may be accompanied by a periosteal reaction on plain films. By CT scan, myeloid sarcoma is isodense compared to muscle, with moderate enhancement with intravenous contrast medium. With MRI, on T2-weighted images, most myeloid sarcomas are hyperintense, or occasionally isointense, compared to muscle. On T1-weighted images, myeloid sarcoma is isointense or hypointense. Myeloid sarcoma shows elevated FDG uptake on PET/CT. The radiographic features are not specific for myeloid sarcoma and can be observed in other neoplastic and inflammatory conditions.

Pathologic Features

Microscopic Findings

Myeloid sarcomas are composed of primitive myeloid and/or monocytic cells. In a subset of cases there is some maturation of the neoplastic clone to more mature myeloid forms. In rare cases, there is erythroid or megakaryocytic differentiation; this exceptional finding is most common when there is an underlying myeloproliferative neoplasm. On microscopic examination the tumors typically have a diffuse pattern, sometimes with sparing of the normal structures. In some instances, the neoplastic cells infiltrate the stroma in a linear pattern ( Fig. 19.6 ). Mitoses are readily identified; apoptotic debris is commonly seen. Some cases display scattered tingible body macrophages, imparting a “starry sky” pattern ( Fig. 19.7 ). The neoplastic cells are discohesive, with round, oval, irregular, or bean-shaped, small to medium-sized, rarely large, nuclei with finely dispersed chromatin and variably prominent nucleoli. The cytoplasm ranges from scant in primitive cells to moderately abundant, sometimes with a distinct eosinophilic color due to the presence of granules if there is maturation of the blasts. Eosinophils and their precursors may be admixed ( Fig. 19.6 ). A few cases have plasmacytoid or signet ring-like features.