FINAL DIAGNOSIS: Plasma cell neoplasm, favor solitary plasmacytoma of bone.
Immunosecretory disorders, or gammopathies, result from the proliferation of monoclonal B cells, which may be plasma cells or plasmacytoid lymphocytes. The secretion of a single homogenous immunoglobulin, known as an M protein or monoclonal protein, characterizes these proliferations. Monoclonal protein expansion is responsible for a range of clinical diseases, with the common finding of an M protein in serum by electrophoresis. True plasma cell entities include multiple myeloma, plasmacytoma, amyloidosis, and light chain deposition disease. In addition, monoclonal gammopathy of undetermined significance (MGUS) denotes the presence of an M protein in the serum of patients in the absence of other clinical, radiologic, or pathologic findings.
The most common plasma cell neoplasm is multiple myeloma, also known as plasma cell myeloma, accounting for 15 percent of all hematologic malignancies in the United States . Multiple myeloma is a multi-focal plasma cell proliferation in bone marrow, in which neoplastic cells replace normal marrow cells, produce excess immunoglobulin, and infiltrate bone. Free light chains are also produced along with the intact proteins, which are small enough to be excreted in urine. These light chains are detected by urine protein electrophoresis and are designated Bence-Jones proteins.
A spectrum of clinical, laboratory, and pathologic findings is encountered in multiple myeloma. Excess cytokines activate osteoclasts, leading to bone destruction and subsequent discrete lytic lesions or diffuse osteopenia. Increased bone resorption also leads to hypercalcemia with its attendant neurologic manifestations. Marrow replacement causes anemia, leukopenia, or thrombocytopenia. Patients are susceptible to recurrent bacterial infections due to the suppression of normal humoral immunity, which is frequently the cause of death. The excess monoclonal protein in blood may lead to hyperviscosity syndrome, or adhesion of red blood cells with rouleaux formation on a peripheral smear. Bence-Jones proteins are toxic to renal tubular cells, and thus may contribute to renal insufficiency or failure. Some light chains produced by the neoplastic cells may deposit in organs leading to secondary amyloidosis .
Diagnosis of multiple myeloma requires the presence of an M protein in serum and/or urine, the presence of bone marrow clonal plasma cells, and the presence of related organ or tissue impairment, such as lytic bone lesions, hypercalcemia, or anemia. Although no specific concentration is definitive, the serum M protein is typically greater than 3 g/dl. Bone marrow biopsy usually contains greater than 10 percent plasma cells in sheets or nodules, although involvement may be focal rather than diffuse, and may not be sampled by the biopsy . Multiple myeloma has a median survival of 3 years, with 10 percent survival at 10 years .
MGUS is important because approximately 25 percent of patients develop multiple myeloma, amyloidosis, or other lymphoproliferative disease within 20 years, with a median interval of 10 years . Thus, patients with MGUS must be followed indefinitely for evidence of progressive disease. Patients with MGUS are asymptomatic, and laboratory and clinical findings demonstrate serum M protein less than 3 mg/dl, fewer than 10 percent plasma cells in marrow biopsy, and the absence of lytic bone lesions, hypercalcemia, anemia, or renal insufficiency . The prevalence of MGUS is 1 percent in patients older than 50 years and 3 percent in patients older than 70 years .
Plasmacytomas are tumors composed of monoclonal plasma cells, which are cytologically, immunophenotypically, and genetically identical to those seen in multiple myeloma, but occur as solitary lesions. This tumor may arise in bone or soft tissue. In bone, it is designated solitary plasmacytoma and is characterized by the absence of multiple osteolytic lesions. In soft tissue, it is known as extramedullary plasmacytoma, most commonly occurring in the head and neck or lungs.
Epidemiology and Clinical Presentation:
Solitary plasmacytoma of bone is relatively rare, accounting for 3 to 5 percent of all plasma cell neoplasms . The median age at diagnosis is 55 years, occurring 10 years earlier than multiple myeloma . However, this tumor has been reported in patients as young as 15 years . Males are more frequently affected than females.
The tumor more commonly involves the axial skeleton than the appendicular skeleton, and distal appendicular disease is extremely rare. As in multiple myeloma, areas of marrow with the most active hematopoiesis are targeted, including the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula, in order of frequency . The thoracic vertebrae are more frequently involved than the lumbar, sacral, or cervical spine. The tumor begins in the medullary cavity and erodes through the cancellous bone and cortex. Thus, punched-out defects are seen on radiographs, usually 1 to 4 cm. Patients may present with pathologic fracture or skeletal pain. Cord compression may be the presenting feature of a solitary plasmacytoma involving the vertebrae. A soft tissue extension of the tumor may result in a palpable mass, particularly if a rib is involved.
The diagnosis of solitary plasmacytoma of bone depends on ruling out multiple myeloma. Specifically, the International Myeloma Working Group has established the following requirements :
An MRI can be useful to identify additional unsuspected plasma cell lesions which do not appear on skeletal surveys. The gross and microscopic features of solitary plasmacytoma are identical to those of multiple myeloma. The neoplastic tissue has a soft, gelatinous, fleshy gross appearance with hemorrhagic areas. Bone marrow biopsy demonstrates an excess of plasma cells, which occur as masses in sheets or nodules, displacing normal marrow. In contrast, normal or reactive plasma cells tend to occur in small clusters of five or six cells around arterioles. In general, plasmacytomas occupy at least 30 percent of the biopsy marrow volume. Occasionally, prominent osteoclastic resorptive activity can be seen on the biopsy corresponding to the lytic lesions seen on radiographs.
Neoplastic plasma cells are of variable maturity ranging from immature, pleomorphic, or anaplastic cells, to mature forms indistinguishable from normal plasma cells. Immature forms, or plasmablasts, show a high nuclear/cytoplasmic ratio, prominent nucleoli, and loose reticular chromatin. Multinucleated and polylobulated cells can also occur. Mature cells are oval with a round eccentric nucleus and coarsely clumped "clock-face" chromatin, with abundant basophilic cytoplasm and a prominent pale perinuclear Golgi zone. Plasmablastic morphology is associated with a poorer prognosis. Because immaturity and pleomorphism rarely occur in reactive plasma cells, these features are reliable indicators of neoplastic plasmacytosis.
The cytoplasm contains abundant endoplasmic reticulum with retained immunoglobulin producing morphologically distinctive findings. These include blue-white grape-like accumulations (Mott cells, Morula cells), cherry-red refractive round bodies (Russell bodies), vermillion-staining glycogen-rich IgA (flame cells), overstuffed fibrils, and crystalline rods. Although these cytoplasmic features are suggestive of neoplastic plasma cells, they can also be found in reactive cells as well.
Plasmacytomas contain cytoplasmic immunoglobulin and demonstrate monotypic expression. For example, cells may express kappa light chain immunopositivity in the absence of lambda light chain expression, or gamma heavy chain immunopositivity in the absence of mu and alpha heavy chain expression. In 85 percent of multiple myelomas, both heavy and light chains are produced, while only light chains are produced in the remaining 15 percent. The most common immunoglobulin produced by neoplastic plasma cells is IgG. IgA is occasionally encountered, while IgD, IgE, and IgM are rare. Neoplastic plasma cells lack immunopositivity for surface immunoglobulin.
Plasmacytomas typically lack expression of the pan-B-cell antigens CD19 and CD20, and express CD56, a neural cell adhesion molecule. This is in contrast to normal plasma cells which express the opposite profile. The majority of cases also express CD38 and the immunoglobulin-associated antigen CD79. Most cases express CD138, a collagen-binding proteoglycan, which may be important for anchoring in the marrow. Occasional cases may express CD10 .
Plasma cells have low proliferative activity, making cytogenetic studies inherently difficult to perform. However, numerical and structural chromosomal aberrations have been described in 20 to 60 percent of newly diagnosed multiple myeloma patients . Complex karyotypes with multiple chromosomal gains and losses are the most frequent changes, but translocations, deletions, and mutations have all been reported. Monosomy or partial deletion of 13 (13q14) is the most common finding, occurring in 15 to 40 percent cases. Deletion of 17p13, associated with allelic loss of p53, is reported in 25 percent of cases, and may predict a poor outcome . The most common structural abnormality is a t(11;14)(q13q32) translocation, resulting in over-expression of cyclin D1, occurring in 10 to 31 percent of cases .
Treatment and Prognosis:
Radiation is the current treatment for solitary plasmacytoma. Localized radiotherapy should be administered even if the tumor is completely removed for diagnostic purposes. The local response rate has been shown to be 80 to 90 percent, and appears to be highest in tumors less than 5 cm in diameter. There is no clear evidence that adjuvant or prophylactic chemotherapy will prevent the ultimate development of multiple myeloma. However, there is considerable disagreement on this point, with some studies suggesting that adjuvant chemotherapy may at least delay the median time of progression of solitary plasmacytoma to multiple myeloma . After completion of radiotherapy, patient monitoring should include serum and urine immunofixation, complete blood count, serum calcium, and creatinine every 4 to 6 months for one year, and annually thereafter. Patients should also receive a bone survey or MRI annually, or sooner if the patient develops a serum M protein after treatment, or an increase in a persistent M protein.
Even with treatment, approximately 55 percent of patients with an apparent solitary plasmacytoma of bone develop multiple myeloma within 10 years. Ten percent develop local recurrence or a solitary plasmacytoma at a different location. . Predictors of conversion to multiple myeloma include size of the solitary lesion, the presence of osteopenia, reduction in uninvolved immunoglobulin levels (e.g., low IgA in a patient with an IgG plasmacytoma), and the presence of high-grade angiogenesis in a tumor section .
In the case of this 68-year-old patient, the appearance of even borderline anemia raised suspicion for lymphoproliferative disease, based on his history of MGUS. As discussed, MGUS progresses to malignant disease in 25 percent of cases, and patients must be carefully monitored. Diagnosis could not be made on bone marrow biopsy. Although a slightly atypical lymphoid aggregate was noted, as in many cases, the significance of these few cells could not be ascertained. Immunohistochemistry, flow cytometry, and cytogenetics did not show evidence of a plasma cell neoplasm. However, the small number of atypical cells identified in the biopsy made the utility of these studies questionable as well. When a bony lesion manifested clinically, a plasma cell neoplasm was readily apparent in the surgical specimen. A sheet of atypical plasma cells was seen on H&E staining, with immunohistochemical staining yielding strongly positive kappa light chains and CD138.
Although solitary plasmacytoma of bone is less common than multiple myeloma, this diagnosis is favored based on the absence of clearly lytic lesions on a skeletal survey, and clinical evidence of end organ damage. However, the relevance of the atypical cells found earlier on bone marrow biopsy remains undetermined. Over half of patients with an apparent solitary plasmacytoma progress to multiple myeloma in their lifetime. The International Myeloma Working Group guidelines for ruling out multiple myeloma specify that no evidence of multiple myeloma should be evident in a marrow biopsy or aspirate. It is possible that this patient's marrow is focally involved by multiple myeloma, rather than diffusely, and the biopsy only marginally sampled an affected area. It will also be important to see if this patient's serum M protein disappears after radiation therapy, which would further support the diagnosis of solitary plasmacytoma.