Plasmacytoma presenting as jugular foramen tumor in a young woman with multiple myeloma
Authors: Joan How, Patrick Connor Johnson, Carleton Eduardo Corrales, Kyle Wright, Natalie Justicz, Jenny X. Chen, Adam S. Sperling, Nathan T. Connell
Journal: American Journal of Hematology (2019)

A 29-year-old African American woman with a history of iron-deficiency anemia presented with 1 year of ear fullness and hearing loss. She also endorsed right unilateral pulsatile tinnitus and loss of sense of taste on the right side. She initially failed to improve on oral antibiotics and was referred to otolaryngology when symptoms worsened over the next several months. She otherwise denied vertigo, otorrhea, or history of trauma. Exam was pertinent for a pulsatile mass impinging on the right tympanic membrane arising from the hypotympanum (Figure 1 A). Neurologic exam was otherwise normal including cranial nerve function although audiometric testing showed right conductive hearing loss. She received a temporal bone CT and MRI that showed a large tumor centered in the right jugular foramen with extensive osseous erosion and a moth-eaten appearance (Figure 1 B). This is a 29-year-old woman who originally presented with symptoms and physical exam findings concerning for a right middle ear neoplasm. Subsequent imaging showed a tumor centered in the right jugular foramen with extension into the middle ear as well as significant osseous erosion and involvement of multiple vascular structures (Figure 1B). The overall presentation and radiographic features were most concerning for a paraganglioma jugulare, which is the most common jugular fossa tumor (Table 1). The differential also included schwannoma, meningioma, or an endolymphatic sac tumor. Although this patient had no significant family history, given her young age at presentation a genetics referral was also recommended, as hereditary paragangliomas tend to develop about a decade earlier compared to sporadic disease.1 Due to the extensive vascular involvement preoperative embolization with angiography was planned before surgical resection. A complete blood count performed as part of routine preoperative labs demonstrated a hemoglobin of 8 g/dL (baseline unknown) with a mean corpuscular volume of 93.6 fL. A complete metabolic panel showed unremarkable chemistries including normal creatinine of 0.6 mg/dL and calcium of 9.9 mg/dL; however, her total protein was elevated at 11.1 g/dL with an albumin that was 3.1 g/dL. Urinalysis was consistent with nephrotic range proteinuria. The peripheral blood smear showed Rouleaux formation (Figure 2 ). Given these abnormalities, further hematologic workup was performed. Iron studies showed a normal iron level of 81 μg/dL with a total iron binding capacity of 205 μg/dL for an iron saturation of 40% and the ferritin was 9 μg/L. The reticulocyte count was at 2.4% and hemolysis labs including haptoglobin and lactate dehydrogenase were normal and a direct Combs test was negative. Vitamin B12 and folate levels were within normal limits and erythrocyte sedimentation rate (ESR) was markedly elevated at >140 mm/h. Partial thromboplastin time (PTT) and prothrombin time (PT) were mildly elevated at 39.4 and 15.4 s, respectively, with otherwise normal Factor II, V, VIII, and X activity. Preoperative labs demonstrated a significant normocytic anemia with an inappropriately low reticulocyte count. Iron deficiency remains the most common cause of anemia in young premenopausal women.2 Microcytosis would be expected in iron deficiency with this degree of anemia, although concomitant nutritional deficiencies such as in folate or B12 can obscure the microcytosis. Ultimately this patient did have some laboratory evidence of iron deficiency given her low ferritin, although we would also expect a high total iron binding capacity and low iron saturation, and she had no evidence of other nutritional deficiencies. Of greater concern in the preoperative laboratory work was the elevated protein gap of 8 g/dL. The protein gap is the difference between the total protein concentration and albumin concentration and is increased in any process that leads to an increase in non-albumin serum proteins. A value above 4 g/dL is considered abnormal. While generalized inflammation may lead to an elevated protein gap, the degree of elevation combined with Rouleaux formation on peripheral blood smear and nephrotic range proteinuria warranted further investigation. The elevated ESR was likely a reflection of significant paraproteinemia, which causes neutralization of the negative electric charge (zeta potential) on the surface of red blood cells leading to interference of erythrocyte sedimentation. It was unclear initially if this paraproteinemia was an incidental finding concomitant with the recently diagnosed paraganglioma, or if the two disease processes were related. This patient also had demonstrated mild abnormalities in her coagulation profile including prolonged PT and PTT which might have implications for surgical outcomes. Paragangliomas have been associated with secondary reactive amyloidosis in the literature, with amyloid leading to adsorption of coagulation factors X and II.3 To determine if coagulation factor replacement would be necessary before the surgery, factor activity levels were sent; activity of coagulation factors II, V, VIII, and X was within laboratory reference ranges. Disease states with increased paraprotein levels such as multiple myeloma and Waldenstrom's macroglobulinemia have also been associated with abnormalities in hemostasis, most commonly manifesting as a prolonged PT.4 The mechanism is attributed to disrupted fibrin polymerization and clot formation from paraprotein interference.5 Due to concern for an underlying paraproteinemia, a serum protein electrophoresis (SPEP) with immunofixation, serum free light chains (FLC), and immunoglobulin studies were ordered. She was then found to have an initial IgA level of 685 mg/dL, subsequently corrected to 8282 mg/dL with kappa FLC of 35.9 mg/dL and lambda FLC of 5.2 mg/dL with an abnormal kappa/lambda ratio of 6.9. SPEP confirmed a monoclonal spike of 4.88 g/dL consistent with an IgA kappa monoclonal gammopathy. Results of the SPEP, serum FLC, and immunoglobulins confirmed the diagnosis of an IgA kappa monoclonal gammopathy as the etiology of her paraproteinemia. Interestingly, the initial IgA level returned falsely low at 685 mg/dL, which was inconsistent with the degree of the protein gap (8 g/dL) seen on initial chemistries and the IgA kappa M-spike seen on SPEP. Given this discrepancy, immunoglobulins were retested on a diluted specimen, resulting in the corrected value of 8282 mg/dL. This artificially low value was due to a phenomenon known as the “hook effect,” in which an unusually high concentration of analytes saturated the capture antibodies of the immunoassay, resulting in a falsely low response signal.6 The diagnosis of an IgA kappa monoclonal gammopathy also raised the question of whether the jugular foramen tumor was in fact a plasmacytoma rather than a paraganglioma. The distinction becomes critical given the difference in management between a paraganglioma and plasmacytoma, with the latter being exquisitely radiosensitive while the former is typically treated with primary resection. To avoid a potentially morbid and unnecessary procedure, these findings were discussed with the surgical team and it was decided to perform a transmastoid biopsy with flash frozen pathology at the start of the case. The patient underwent a transmastoid biopsy before definitive resection. Frozen sections returned as a plasmacytoma, and so only minimal decompression was performed (Figure 3 ). A positron emission tomography-computed tomography (PET-CT) scan showed diffuse marrow involvement throughout the appendicular skeleton and abnormal signal in multiple lymph nodes in addition to the base of skull mass (Figure 4 ). A bone marrow biopsy showed 70% involvement with kappa restricted plasma cells, confirming the diagnosis of multiple myeloma. Beta-2 microglobulin was 1.1 mg/L, making her Stage II by International Staging System criteria. Given the significant proteinuria on initial urinalysis, a 24-h urine collection with urine protein electrophoresis was also performed and demonstrated 806 mg of excreted protein, of which 51% of urinary protein excretion was albumin and 31% was beta globulin (M-spike protein 228 mg in beta fraction). The findings of 70% plasma cell involvement of the bone marrow established the diagnosis of multiple myeloma as the ultimate disease etiology. Besides bone marrow involvement, this patient also had evidence of significant kidney involvement, with an initial spot urine protein:creatinine ratio of 2.7 and 806 mg of excreted protein on 24-h urine collection. Renal injury is common in multiple myeloma, and the most frequent etiologies of proteinuria or nephrotic syndrome specifically include monoclonal immunoglobulin deposition disease (MIDD) and AL amyloidosis. In MIDD, monoclonal immunoglobulins deposit along either glomerular or tubular basement membranes of the kidney, while in AL amyloidosis these depositions are due to misfolded fibrils from monoclonal light chains and other proteins. Ultimately, MIDD was favored as the etiology of this patient's proteinuria rather than AL amyloidosis. The percentage of urinary albumin excretion (UAE) of 51% is in range with typically seen UAE percentages in MIDD,7 and the significant urine M-protein with kappa rather than lambda involvement is also more consistent with MIDD. However, a renal biopsy would be the only definitive way to determine the etiology of this patient's proteinuria, but this was ultimately deferred after consultation with nephrology. The patient was then started on dexamethasone in conjunction with palliative radiation to the skull base. Cytogenetics showed a normal karyotype, although FISH demonstrated monosomy 13 with IGH gene rearrangement and loss of MAF bZIP transcription factor. She ultimately was initiated on carfilzomib, lenalidomide, and dexamethasone (KRd) as an outpatient for treatment of her multiple myeloma and has completed three cycles. She has had a partial response to therapy with resolution of her presenting symptoms and significant improvement of her proteinuria. This case illustrates an unusual presentation of plasmacytoma manifesting as a jugular foramen tumor. Plasmacytomas may occur in the presence of other features of multiple myeloma or as a single lesion (solitary plasmacytoma), and more commonly involves bony rather than soft tissue (or extramedullary) sites. Extramedullary disease is estimated to occur in approximately 7% to 18% of patients with multiple myeloma at diagnosis and develops in up to 20% of patients on follow-up, and is associated with worse prognosis.8, 9 Of note, extramedullary multiple myeloma has higher incidence in patients less than 55 years of age.9 The most commonly implicated anatomic locations of plasmacytomas include bony sites such as the vertebrae, ribs, sternum, and skull. Soft tissue involvement from hematogenous spread can occur in any organ, including skin, lymph nodes, liver, kidney, or the central nervous system. Of note, given the presence of significant bony erosion seen on imaging, it is difficult to discern whether the tumor originated as an extramedullary tumor in the jugular foramen with subsequent bony involvement, or if the tumor originated in the skull base and then extended into the jugular foramen. Regardless, plasmacytomas in this anatomic location are uncommon, with incidence of jugular foramen involvement restricted to case reports in the literature.10-13 In comparison, paragangliomas make up approximately 60% of jugular foramen tumors in one retrospective review.14 Ultimately the diagnostic consideration of a plasmacytoma was critical given the significant differences in management between a typical skull base tumor such as paraganglioma and a plasmacytoma. Radiotherapy is the recommended first-line local therapy to plasmacytoma given its excellent local and regional control.15 Complete surgical resection typically occurs only as part of initial diagnosis. Our patient received palliative radiotherapy to a total dose of 2000 cGy followed by chemotherapy for her underlying multiple myeloma. Given her young age and overall disease burden, an aggressive regimen with carfilzomib, lenalidomide, and dexamethasone followed by high dose melphalan and autologous stem cell rescue was selected for induction.16 Interestingly, while monosomy 13 is not typically associated with poor prognosis, her FISH panel showed an IGH rearrangement with loss of MAF on chromosome 16, suggesting a possible cryptic t(14;16) translocation and thus a higher cytogenetic risk category.17 This case also illustrates the importance of dynamic clinical decision-making and the avoidance of anchoring biases throughout patient management. Ultimately, plasmacytomas uncommonly present as skull base tumors, and multiple myeloma is also a rare disease in younger adults, with only 0.3% of all patients diagnosed before the age of 30.18 However, this diagnosis was ultimately considered due to the disproportionate anemia and protein gap found on routine labs, and further supported by additional hematologic work-up. Interdisciplinary collaboration and close communication between teams become essential in these complex cases with unusual presentations.