A 39-year-old man with no significant medical history presented to the emergency department with back pain after a fall. Plain lumbosacral x-ray films were only significant for osteopenia. He was sent home with a prescription for nonsteroidal anti-inflammatory medication. Two weeks later, he developed a strong cough that caused subconjunctival hemorrhages. After 3 weeks of continuous low back pain, he underwent magnetic resonance imaging of the lumbar spine, which showed small midline disk protrusions at L4 through L5 and L5 through S1 with a decreased bone marrow signal suggestive of a marrow infiltrate.
The physical examination was only significant for tachycardia, a 2/6 systolic ejection murmur, and mild splenomegaly. A complete blood cell count showed the following laboratory values: white blood cells, 74 800/μL (reference range, 4500–11 00/μL); hemoglobin, 5.2 g/dL (reference range, 13.8–17.2 g/dL); hematocrit, 14.6% (reference range, 40.7%–50.3%); and platelets, 167 × 103/μL (reference range, 140–440 × 103/μL). Review of the peripheral blood smear revealed marked neutropenia and lymphocytopenia, with most leukocytes demonstrating a relatively high nuclear-cytoplasmic ratio, basophilic cytoplasm, eccentrically located nuclei with loose reticular chromatin, and prominent nucleoli. Rouleaux formation was prominent (Figure 1, Wright-Giemsa, original magnifications ×50 and ×100 [inset]). Other pertinent laboratory values included the following: blood urea nitrogen, 60 mg/dL (21.42 mmol/L); serum creatinine, 6.2 mg/dL (548 μmol/ L); total protein, 10.1 g/dL; albumin, 2.7 g/dL; calcium, 12.2 mg/dL; uric acid, 14.5 mg/dL (0.86 mmol/L); lactate dehydrogenase, 122 U/L; and a persistently elevated erythrocyte sedimentation rate. Serum and urine protein electrophoresis with immunofixation showed the presence of free λ light chains and an immunoglobulin (Ig) A monoclonal spike quantified at 4810 mg/dL; IgG and IgM levels were low at 201 and 6 mg/dL, respectively (Figure 2, serum protein electrophoresis). Serum viscosity was normal at 1.7 centipoises.
The subsequently performed skeletal survey revealed multiple lytic bone lesions in skull and spine and a large epidural mass that extended from C6 to T2, causing marked cord compression; in addition, a left-sided pleural effusion was noted. A trephine bone marrow biopsy and aspiration specimen demonstrated sheets of atypical, immature plasmacytoid cells with frequent mitoses that extensively replaced normal trilineage hematopoiesis (Figure 3, A [hematoxylin-eosin] and B [Leder], original magnification ×50; Figure 4, Wright-Giemsa, original magnification ×100). Immunophenotypic analysis by flow cytometry demonstrated a cytoplasmic λ light chain–restricted CD38+, CD138+ lymphoid population that lacked surface expression of CD20 and CD56. A Wright-Giemsa– stained cytospin of the pleural effusion showed similar cells to those noted in the peripheral blood and bone marrow. Emergent radiation therapy combined with high-dose steroids was initiated for the spinal cord compression. In addition, the patient began bortezomib chemotherapy, which was switched to cyclophosphamide 1 week later due to a steadily rising white blood cell count (150 000/μL). The left-sided malignant pleural effusion required a chemical pleurodesis with doxycycline.
What is your diagnosis?
Pathologic Diagnosis: Plasma Cell Leukemia
Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder (<5% of all malignant plasma cell disorders) characterized by the presence of greater than 2.0 × 109/L plasma cells in the peripheral blood or more than 20% plasma cells of the peripheral blood differential count.1,2 The disease can present as primary PCL in the absence of a previously diagnosed multiple myeloma (MM) or as secondary PCL, representing a leukemic transformation of an advanced, previously established MM. Primary PCL accounts for approximately 60% of all cases of PCL.1–3
Cases of primary PCL occur more frequently in younger patients and show a higher incidence of organomegaly and lymphadenopathy.4–6 Extramedullary involvement of spleen and liver are most common. Other visceral sites of involvement include kidneys, lungs, heart, pleura, testes, skeletal muscles, central nervous system, and, very rarely, skin.4 However, clinical manifestation of extraosseous PCL is not frequent at the time of initial diagnosis. Comparison of clinical and biologic data for PCL and MM reveals a higher incidence of advanced disease (stage III), extramedullary involvement, anemia, thrombocytopenia, and hypercalcemia in patients who present with primary PCL.5,6 Furthermore, PCL is associated with higher levels of lactate dehydrogenase and more extensive bone marrow replacement by plasma cells, exceeding 40% of all nucleated marrow elements.6
The PCL cases more frequently express isolated free light chains than MM; monoclonal IgG and IgA are seen in PCL but appear to be less frequent than in MM.5,6 Immunophenotypically, CD20 is expressed more frequently in PCL than MM, whereas HLA-DR and the adhesion molecule CD56 are more commonly found on MM than PCL cells. CD38 and the syndecan-1 (CD138) are strongly expressed on both PCL and MM cells and therefore not useful in distinguishing between the two.6
Complex karyotypes with multiple chromosomal gains and losses are the most frequent genetic abnormalities in plasma cell dyscrasias, and statistically significant differences between PCL and MM have been observed by Garcia-Sanz et al6 and Lloveras et al7 for monosomy 13, with a higher frequency in PCL and trisomies 6 and 9 detected more commonly in MM. In addition, Avet-Loiseau et al8 have reported that analysis of rearrangements of the 14q32 (immunoglobulin heavy-chain) region revealed a significant higher incidence of t(11;14) and t(14; 16) in PCL than MM, whereas no differences were observed for t(4;14) between these two. Generally, t(11; 14)(q13;q32) that involves rearrangement of the bcl-1 locus is the most common translocation encountered in all types of plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance, accounting for approximately 20% to 35% of all cases. This translocation transposes the cyclin D1 gene into an IgH γ switch region leading to overexpression of the proto-oncogene cyclin D1. Although t(14;16)(q32;q23), an IgH translocation that involves the proto-oncogene c-MAF, is mostly observed in PCL and cell lines, t(4;14)(p16;q32), a rearrangement between IgH and fibroblast growth factor receptor 3 or multiple myeloma SET domain, appears to be specifically associated with MM, PCL, and cell lines but not with monoclonal gammopathy of undetermined significance.8 Overexpression of these proto-oncogenes may provide MM cells with a growth advantage, such as prolonged survival abilities and escape from immunosurveillance. The development of MM and progression to more aggressive disease is believed to be linked to the accumulation of these nonrandom molecular alterations.9
Plasma cell leukemia is associated with a poor prognosis, with a reported median survival rate between 8 months and 2 years, depending on the intensity of chemotherapy.5,6 Overall survival is significantly worse for patients with PCL than for patients with MM, showing a median survival rate of 8 versus 36 months, respectively.6 However, survival for patients with PCL treated with multiagent chemotherapy appears to be significantly better than for those treated with melphalan and prednisone only.6
References
The authors have no relevant financial interest in the products or companies described in this article.