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TEMPI Syndrome: Erythrocytosis in Plasma Cell Dyscrasia
Review
TEMPI Syndrome: Erythrocytosis in Plasma Cell Dyscrasia Xianrui Zhang,1 Meiyun Fang2 Abstract TEMPI (telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting) syndrome is a newly described clinical entity that is generally considered a plasma cell dyscrasia with multiple system involvement. The etiology and pathophysiology of this condition remains elusive. Nevertheless, clonal plasma cells and monoclonal protein appear to be major contributors. The early diagnosis of TEMPI syndrome is essential because therapies targeting the underlying plasma cells can lead to a dramatic response. Bortezomib-based chemotherapy, daratumumab monotherapy, and autologous hematopoietic stem cell transplantation can result in reversal of most manifestations. Nevertheless, the diagnosis of TEMPI syndrome remains a substantial challenge owing to its rarity and the complexity of clinical presentations. TEMPI syndrome is often misdiagnosed as other causes of erythrocytosis, resulting in a delayed diagnosis and further clinical deterioration. The aim of the present review was to present the clinical and biologic features of TEMPI syndrome, highlighting the differential diagnosis and outlining the present understanding of its pathophysiology and treatment. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Elsevier Inc. All rights reserved. Keywords: Bortezomib, Differential diagnosis, Erythrocytosis, Monoclonal gammopathy, Plasma cell dyscrasia
Introduction In 2011, Sykes et al1 coined the acronym “TEMPI” for a syndrome constituting telangiectasias (T), erythrocytosis with elevated erythropoietin levels (E), monoclonal gammopathy (M), perinephric fluid collections (P), and intrapulmonary shunting (I). TEMPI syndrome is included in the 2016 revised World Health Organization classification of tumors of hematopoietic and lymphoid tissues.2 TEMPI syndrome is best categorized as a plasma cell disorder with paraneoplastic manifestations. Little is known about the etiology, pathogenesis, or prevalence of this recently described entity. To the best of our knowledge, 15 cases have been reported to date. The complexity and rarity of the disorder and its common mimicking of other diseases suggest that more patients might have undiagnosed TEMPI syndrome. Although the diagnostic features are unique and clear, a misdiagnosis occurs 1
Department of Hematology, First Affiliated Hospital, Dalian Medical University, Dalian, People’s Republic of China 2 Department of Hematology, Affiliated ZhongShan Hospital of Dalian Medical University, Dalian, People’s Republic of China Submitted: Mar 31, 2018; Revised: Jun 22, 2018; Accepted: Jul 9, 2018 Address for correspondence: Meiyun Fang, PhD, Department of Hematology, Dalian Medical University, Affiliated ZhongShan Hospital, 6 Jiefang Road, Dalian 116011, China E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2018.07.284
frequently because the investigative findings could be misinterpreted. The constellation of erythrocytosis, M protein, and other clinical findings often lead patients with TEMPI syndrome to be considered to have a variety of renal, pulmonary, or hematologic disorders, such as polycythemia vera (PV)3 and/or monoclonal gammopathy of undetermined significance (MGUS).4 Despite its rarity, TEMPI syndrome is an important diagnosis because the appropriate therapy can dramatically improve a patient’s quality of life.5 In an attempt to improve recognition of this clinical entity and associated treatment options, the typical features of TEMPI syndrome and efficacy of therapies have been summarized in the present report. In addition, we have discussed its differential diagnosis with other plasma cell disorders.
Clinical Features and Pathophysiology The clinical findings and laboratory data of all reported patients with TEMPI syndrome are listed in Table 1. These 15 patients included 6 men and 9 women, aged 35 to 65 years (median age, 49 years). Given that these patients developed symptoms after middle age, Schroyens et al6 inferred that TEMPI syndrome was likely to be an acquired disease. The onset of TEMPI syndrome is occult, with slowly progressive symptoms.2 The clinical features have been reviewed in the next sections and the potential pathogenesis discussed.
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2
Demographic Investigator
TEMPI Syndrome M
P
I
Bone Marrow Plasma Cells
> 5000 mU/mL > 5000 mU/mL
IgGk (0.7 g/dL) IgGk (0.7 g/dL)
Yes Yes
Yes Yes
< 10% < 10%
Yes
> 5000 mU/mL
IgGk (0.7 g/dL)
Yes
Yes
< 10%
NR Yes NR Yes Yes
Yes Yes Yes Yes Yes
> 5000 mU/mL Increased NR > 8000 mU/mL 134 mU/mL
NR IgG NR IgGk IgAl (1.4 g/dL)
Yes NR Yes NR Yes
NR Yes NR Yes No
NR < 10% NR NR 10%
56 49 50 61
Yes Yes Yes Yes
Yes Yes Yes Yes
100 mU/mL 78 mU/mL 433 mU/mL 134 mU/mL
IgGl (3.6 g/dL) IgAl (0.2 g/dL) IgGk IgAl (1.4 g/dL)
Yes Yes Yes Yes
NR NR Yes NR
10%-15% NR < 10% 10%
49 54 65
NR Yes Yes
Yes Yes Yes
8144 mU/mL 5000 mU/mL > 5000 mU/mL
IgGk (1.8 g/dL) IgGk (0.8 g/dL) IgGk (2.3 g/dL)
Yes Yes No
Yes Yes Yes
5%-10% NR 10.5%
Pt. No.
Gender
Age, y
T
1 2
Male Female
42 36
Yes Yes
Yes Yes
3
Female
39
Yes
4 5 6 7 8
Male Male Male Female Female
35 56 36 49 58
Kwok et al,5 2012 Viglietti et al,7 2012 Ryden et al,8 2013 Jasim et al,9 2014
9 10 11 12
Female Male Male Female
Kenderian et al,10 2015 Belizaire et al,3 2015 Pascart et al,11 2015
13 14 15
Female Female Female
Sykes et al,1 2011
Schroyens et al,6 2012 Mohammadi et al,4 2012
Erythrocytosis and EPO
Others Venous thrombosis Venous thrombosis, spontaneous intracranial hemorrhage Venous thrombosis, spontaneous intracranial hemorrhage NR NR NR NR Diarrhea, hydronephrosis, hydroureter, liver hemangioma, hyperlipidemia, coronary artery disease, congestive heart failure, gallstone, left ventricular apical thrombus, dilation of common bile duct, indigestion, bloating Fatigue, diffuse pains Ascites, pleural effusion Focal segmental glomerulosclerosis Ischemic cardiomyopathy, hypothyroidism, hypertension, diarrhea, liver hemangioma Iatrogenic iron-deficient anemia Iatrogenic iron-deficient anemia Rheumatoid arthritis
Abbreviations: EPO ¼ erythropoietin; I ¼ intrapulmonary shunting; M ¼ monoclonal gammopathy; NR ¼ not reported; P ¼ perinephric fluid collections; Pt. No. ¼ patient number; T ¼ telangiectasias; TEMPI ¼ telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting.
A Review of TEMPI Syndrome
Clinical Lymphoma, Myeloma & Leukemia Month 2018
Table 1 Characteristics of Patients With TEMPI Syndrome
Xianrui Zhang, Meiyun Fang Monoclonal Plasma Cell Disorder A monoclonal component, the defining characteristic of TEMPI syndrome, was found in all patients assessed. IgGk predominated; however, IgAl and IgGl were also identified in individual cases. Recently, we found IgEl monoclonal gammopathy in 1 patient with TEMPI syndrome features (Hu, 2017, personal communication). All patients were reported to have < 3.0 g/dL of M protein, except for patient 9, in whom the monoclonal IgG level was 3.6 g/ dL.5 A slight preponderance of the k light chain subtype was found in patients with TEMPI syndrome (k-to-l ratio, 2:1), and the serum free light chain ratios were reportedly skewed in 3 cases (patients 8, 9, and 12). The results of Bence-Jones proteinuria testing was negative in all tested cases. Once a monoclonal plasma cell dyscrasia has been detected serologically or in urine, a bone marrow examination should be performed to ascertain the classification and extent of the disease. Most patients had marrow plasma cell percentages at MGUS levels (< 10%). Only 2 patients were reported to have > 10% bone marrow plasma cells (patients 9 and 15), and the levels in patient 9 reached the level of smoldering myeloma. However, the diagnostic criteria for symptomatic plasma cell myeloma were not fulfilled in any patient. No detailed reports are available on the immunophenotypic or genetic findings in TEMPI syndrome. Morphologically, a slight atypia in plasma cells was noted, with cytoplasmic vacuolization and frayed cytoplasm.12 Therapies targeted against plasma cell clones, including bortezomib-based regimens, daratumumab monotherapy,13 and autologous hematopoietic stem cell transplantation (ASCT),10 have yielded dramatic clinical responses, with reversal of most manifestations. Thus, TEMPI syndrome is best categorized as a plasma cell dyscrasia accompanied by paraneoplastic manifestations in which abnormal plasma cell clones and M protein play central pathogenic roles.
Hematologic Findings Erythrocytosis and extremely elevated serum erythropoietin (EPO) levels (range, 78-8144 mU/mL) are distinctive features of TEMPI syndrome. The initial manifestation of erythrocytosis led to the misdiagnosis of PV in patients with partial presentations, and some patients even developed iatrogenic iron-deficient anemia from therapeutic phlebotomy.3,10 The evaluation of serum EPO and Janus kinase 2 (JAK2) V617F genetic testing allow for differentiation of TEMPI syndrome and PV. Almost all patients with PV (> 95%) will have the acquired JAK2 V617F mutation,14 unlike those with TEMPI syndrome, in whom the JAK2 mutation will be absent. Moreover, the serum EPO levels in patients with PV and other primary erythrocytoses will be low (mean < 3.3 mU/mL).12 In the bone marrow of patients with TEMPI syndrome, erythroid hyperplasia was a recurrent finding. Megakaryocytic hyperplasia and mild atypia and moderate erythroid atypia and reactive lymphoid aggregates were also observed in bone marrow samples. No patient has been reported to exhibit the morphologic features of PV or other myeloproliferative neoplasms, such as megakaryocytic hyperchromia or clustering, osteosclerosis, intrasinusoidal hematopoiesis, or increased reticulin fibrosis.12 The etiology of erythrocytosis and elevated serum EPO levels remains unknown. Although a connection seems to exist between the EPO level and the degree of hypoxia,12 the hypoxemia
attributed to right-to-left intrapulmonary shunting cannot explain the erythrocytosis in patients with TEMPI syndrome. First, the erythrocytosis preceded the clinical appearance of hypoxemia in previous reports.9 Second, the elevated EPO level resulting from hypoxemia has typically been < 30 mU/mL.15 It has been hypothesized that perinephric fluid collections might be related to increased EPO secretion and consequent erythrocytosis.4,7 However, perinephric fluid was not observed at all in a few cases, and sometimes polycythemia has appeared before renal fluid collection has developed.8,10,11 Given the normalization of the red blood cell counts after bortezomib treatment in most patients, we can reasonably surmise that a direct association exists between erythrocytosis and the monoclonal immunoglobulin level. Considering the inhibitory effect of bortezomib on hypoxia-inducible factor-1a (HIF-1a), a crucial transcription factor for EPO production, Hutchison et al17 hypothesized that erythrocytosis might result from monoclonal immunoglobulins enhancing the function of HIF-1a and subsequently increasing EPO secretion. We suspect that the pathogenesis of polycythemia in TEMPI syndrome might have something in common with that of other plasma cell disorders, such as multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis. Lee et al18 suggested that the subclinical renal damage caused by Bence-Jones protein could explain the coexistence of MM and erythrocytosis. Nagasawa et al19 suggested that amyloid deposits in hemopoietic factor-producing tissues contributed to erythrocytosis in AL amyloidosis. We, therefore, postulated that the erythrocytosis in TEMPI syndrome might be caused by the deposition of monoclonal immunoglobulin or its fragments in kidney components and/or the bone marrow niche. Overt or subclinical renal damage from monoclonal gammopathy could result in local hypoxia and elevated EPO production. Plasma cell clones or paraproteins in bone marrow might trigger erythroid hyperplasia by stimulating erythroid progenitor cells and/or hemopoietic factor-producing cells. The etiology of the elevated EPO level and erythrocytosis in patients with TEMPI syndrome warrants further exploration.
Renal Findings A perinephric fluid collection is another diagnostic component of TEMPI syndrome. The typical clinical manifestations include bilateral flank fullness, nausea, renin-dependent hypertension, and a palpable abdominal mass. Renal dysfunction is less common. Proteinuria has not been reported, and the slightly elevated serum creatinine levels in a few patients with TEMPI syndrome (patients 8, 10, and 11) decreased after bilateral perirenal compressive fluid removal. A perinephric fluid collection can be diagnosed from the ultrasound or computed tomography (CT) findings. Abdominal ultrasonography and CT scans have revealed massive perinephric fluid collections compressing both kidneys. Aspiration showed clear, aseptic, and serous fluid containing few or no cells and small amounts of protein, cholesterol, triglycerides, and chylomicron.4,15 When kidney biopsy was performed, the reported histologic findings included hypertensive vascular changes without amyloidosis or light chain deposition.4,9 Viglietti et al7 attributed large perinephric fluid collections to malformation of renal lymphatic tissues, leading to blockage and accumulation of lymph in the subcapsular region. However, Jasim et al9 and Mohammadi et al4 failed to detect interstitial edema, dilated lymphatics, or any other evidence
Clinical Lymphoma, Myeloma & Leukemia Month 2018
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A Review of TEMPI Syndrome suggestive of renal lymphangiectasia in the renal biopsy specimens of patients with TEMPI syndrome. The regression of fluid collections after bortezomib treatment suggests that the perinephric fluid collections might be the consequence of M protein by an unknown mechanism.
Pulmonary Findings and Skin Changes The physical examination findings were notable for hypoxia in 9 of the 15 patients with TEMPI syndrome. Right-to-left intrapulmonary shunting was detected in all 15 TEMPI patients, with low oxygen saturation (mean < 90%). The normal portion of cardiac output in right-to-left shunting is 5%.20 However, all reported circulatory shunt indexes in those with TEMPI syndrome were > 10%.3,10 Quantitative evaluation of the shunt fraction can be performed using technetium-99m macroaggregated albumin scanning or the 100% oxygen method. The severity of hypoxemia will be proportional to the degree of shunting, and patients tend to present with severe symptoms, such as dyspnea on exertion and digital clubbing, when the shunt index is > 20%.21 Several patients with TEMPI syndrome have even required wheelchairs and continuous supplemental oxygen because of progressive hypoxia.6,10 Hypoxemia and intrapulmonary shunting resolved after treatment with bortezomib and ASCT. However, the mechanisms are as yet unknown. Telangiectasias, another cardinal presentation of TEMPI syndrome, affected 12 of the 15 patients. Telangiectasias are the persistence of dilated capillary vessels, forming small punctate red stains16 or having a spider-like appearance.9 Telangiectasias appeared most prominently on the face, neck, upper extremities, and trunk. Although the exact mechanism is unclear, hypoxia, causing increased blood flow beneath skin surface owing to dilation of capillaries, might explain the presence of telangiectasias in patients with TEMPI syndrome.
Other Clinical Features
4
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Of the 15 patients, 3 had venous thrombosis and 2 experienced complications with spontaneous intracranial hemorrhage.1 We believe that the presence of coagulation abnormalities in patients with TEMPI syndrome might not be a chance association. Recent studies have investigated the link between monoclonal gammopathy and a bleeding or thrombotic tendency. In a case series of patients with MGUS, the rate of venous thromboembolism was w7%, related to a variety of factors, including increased blood viscosity, delayed fibrinolysis, and procoagulant activity of the M component.21 Bleeding events due to the M protein have also been reported. The pathogenetic mechanisms could involve the inactivation of critical procoagulant proteins and impaired fibrin polymerization or platelet function.22 Reports have also connected hyperviscosity with an increased risk of bleeding.23 Further studies are needed to delineate a causal relationship between the presence of coagulation abnormalities and TEMPI syndrome. Other associated findings included heart disease in 2 patients,4,9 liver hemangiomas in 2 patients,4,9 hypothyroidism in 1 patient,9 diarrhea in 2 patients,4,9 focal segmental glomerulosclerosis in 1 patient,8 ascites and pleural effusion in 1 patient,7 and rheumatoid arthritis in 1 patient.11 These associated findings appeared to be coincidental rather than causal. However, a simultaneous outbreak
Clinical Lymphoma, Myeloma & Leukemia Month 2018
of rheumatoid arthritis and TEMPI syndrome was noteworthy, because microangiogenesis is a common pattern of both diseases, suggesting a link underlying their pathophysiologic pathways.11
Diagnostic Criteria and Differential Diagnosis No diagnostic reference standard has yet emerged for TEMPI syndrome. Rosado et al12 suggested that the coexistence of plasma cell dyscrasia and erythrocytosis should elicit an in-depth search for TEMPI syndrome. On confirmation of a plasma cell clone and erythrocytosis, in conjunction with the clinical, radiologic, and biologic findings and the exclusion of other causes, the diagnosis of TEMPI syndrome can be established. In particular, the following diseases should be excluded: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, MM, AL amyloidosis, and Schnitzler syndrome. The major features of these diseases are listed in Table 2.
POEMS Syndrome POEMS syndrome is a rare paraneoplastic disorder secondary to an underlying plasma cell dyscrasia.24 POEMS syndrome can mimic TEMPI syndrome because of its paraproteinemia, polycythemia, skin changes, and abnormal pulmonary function test results. However, some distinctive features of POEMS syndrome can differentiate between these 2 disorders. First, patients with TEMPI syndrome will have a slight predominance of k light chains. In contrast, the proliferating monoclonal plasma cells in those with POEMS syndrome will be l-restricted in the vast majority of cases. Moreover, monoclonal Igl light chains (IGL) in POEMS syndrome belong to the Vl1 subfamily and are limited to IGLV1-44*01 and IGLV1-40*01 germlines.25 Second, in contrast to TEMPI syndrome, in which no elevation of vascular endothelial growth factor (VEGF) levels was observed in the reported cases, the serum VEGF level will be markedly increased in those with POEMS syndrome, correlating with disease activity. Measurement of serum EPO is also useful in distinguishing between the 2 diseases. Similar to TEMPI syndrome, polycythemia will be seen in w15% of patients with POEMS syndrome, with negative results for JAK2 V617F genetic testing.24 Nevertheless, the concentration of serum EPO in those with POEMS syndrome has been low (< 3.13 mU/mL) and correlates inversely with the VEGF level.26 Third, patients with TEMPI syndrome will not have certain features of POEMS syndrome, such as polyneuropathy, endocrinopathy, and organomegaly, and vice versa. From a morphologic perspective, plasma cell rimming around lymphoid aggregates will be present in nearly one half of patients with POEMS syndrome, in contrast to the lymphoid aggregates observed in those with TEMPI syndrome. Megakaryocytic hyperplasia can be encountered in both disorders, but bone marrow specimens from those with POEMS syndrome will usually demonstrate megakaryocytic clustering and cytologic atypia.27
Multiple Myeloma MM is a common hematologic malignancy, characterized by clonal bone marrow plasma cells that secrete monoclonal paraprotein. Patients with MM will exhibit myriad symptoms, from fatigue to “CRAB” criteria (hypercalcemia, renal impairment, anemia, and bone lesions). In contrast to TEMPI syndrome, in which the hemoglobin
Xianrui Zhang, Meiyun Fang Table 2 Differential Diagnosis of TEMPI Syndrome Clinical Findings
TEMPI Syndrome
POEMS Syndrome
Multiple Myeloma
AL Amyloidosis
Schnitzler Syndrome
< 10 10 < 15 5 IgG, IgA (l-restricted) IgG, IgA, IgM, IgD, IgE IgG, IgA, IgM, IgD Mainly IgM, IgG [ (15%), normal, or Y (70%) or normal Y (32.4%) or normal Y Y (< 5%) EPO [[ Y Y NR NR Skin changes Telangiectasias Hyperpigmentation, plethora, Cutaneous plasmacytoma Periorbital hematoma, Urticarial recurrent hemangiomata, acrocyanosis, (appears as reddish, nontender, various papules, nodules, rash, neutrophilic white nails, hypertrichosis dermal or subcutaneous nodules; patches, blisters urticarial dermatosis occasionally as diffuse erythematous rash) Pulmonary manifestation Intrapulmonary Pulmonary hypertension, Pulmonary plasmacytoma Diffuse alveolar-septal NR shunting restrictive lung disease, (appears as solitary pulmonary amyloidosis, nodular impaired neuromuscular nodule), diffuse alveolar pulmonary amyloidosis, respiratory function hemorrhage, pleural effusion tracheobronchial amyloidosis Renal manifestation Perinephric fluid Renal lesion (elevated serum Renal impairment (proteinuria, Heavy proteinuria, nephrotic NR collections; elevated cystatin C level, elevated Bence-Jones proteinuria, syndrome, decreased serum creatinine serum creatinine and elevated serum creatinine) glomerular filtration rate and proteinuria are relatively rare) elevated serum creatinine Bone manifestation NR Osteosclerotic lesion, Bone pain, lytic lesions, diffuse Osteolytic lesion, Bone and joint pain, pathologic fractures sclerotic lesions, lytic osteolytic lesion, hyperostosis osteoporosis, pathologic lesions fractures, plasmacytomas Liver or spleen Other manifestations Venous thrombosis, Papilledema, peripheral Hyperviscosity (mucosal Peripheral neuropathy, spontaneous neuropathy, organomegaly, membrane bleeding, neurologic tongue enlargement, liver enlargement, intermittent enlargement, impaired fever, elevated markers intracranial endocrinopathy, extravascular deficit, increased intracranial intestinal transit, occult of inflammation, hemorrhage, volume overload, Castleman pressure), infection, cytopenia, bleeding, arrhythmias, palpable adenopathy, iatrogenic disease, thrombocytosis, secondary amyloidosis (tongue coronary heart disease, fatigue, systemic iron-deficient heart failure enlargement, organomegaly, myocardial infarction amyloid A amyloidosis anemia peripheral neuropathy), hypercalcemia (confusion, muscle weakness, polydipsia)
Plasma cells, % M protein Hemoglobin
< 15 IgG, IgA [
Abbreviations: AL ¼ immunoglobulin light chain; EPO ¼ erythropoietin; NR ¼ not reported; POEMS ¼ polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; TEMPI ¼ telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting.
concentration is elevated, anemia is a hallmark of MM and will be found at diagnosis in w70% of patients.28 However, iatrogenic irondeficient anemia in patients with a partial presentation of TEMPI syndrome could mask the polycythemia of TEMPI syndrome. In addition, the levels of bone marrow plasma cells in several patients with TEMPI syndrome were > 10%. A combination of M protein, anemia, and 10% plasma cells in bone marrow biopsy specimens should raise the index of suspicion for MM. A detailed medical history has an important role in the differential diagnosis. The anemia of TEMPI syndrome is caused by therapeutic phlebotomy and is characterized by iron deficiency and microcytic and hypochromic erythrocytes. In contrast, the anemia of MM is typically normochromic and normocytic.28 In addition, patients with MM tend to have bone lesions and renal impairment, unlike TEMPI syndrome, in which the skeletal radiographic findings appear normal and renal dysfunction is rarely encountered. Moreover, bone marrow biopsy is characteristic, with the number of plasma cells > 10% and changes in the morphology of myeloma cells (eg, nuclear-tocytoplasmic asynchrony, low amount of cytoplasm, and the presence of plasmablasts) in most patients with MM.29
AL Amyloidosis AL amyloidosis is a rare, life-threatening condition caused by deposition of fibril-forming monoclonal light chains in the
extracellular matrix of organs and tissues.30 Although it can be discriminated by the presence of amyloid in tissues, AL amyloidosis has many features overlapping with TEMPI syndrome. For instance, the plasma cell burden is relatively low in AL amyloidosis, typically IgG or IgA when serum monoclonal immunoglobulin is measured.31 AL amyloidosis differs from TEMPI syndrome in that most morphologic abnormalities of bone marrow plasma cells in AL amyloidosis are superimposable with those of MM,29 and the l light chain isotype is more prevalent in AL. Regarding the clinical features, renal impairment is the most frequent manifestation in AL amyloidosis, characterized by proteinuria and full nephrotic syndrome in 73% and 30% of cases, respectively.30 Involvement of the lung is also common in AL amyloidosis but is rarely symptomatic, unlike in TEMPI syndrome, in which hypoxemia due to intrapulmonary shunting is prevalent.32
Schnitzler Syndrome Schnitzler syndrome, a rare disorder characterized by a chronic urticarial rash, fever, joint and/or bone pain, lymphadenopathy, and leukocytosis, also presents with monoclonal gammopathy,33 generating the differential diagnosis with TEMPI syndrome. However, the M component in Schnitzler syndrome is mainly IgMk (in w88% of cases) and the IgG subtype is found in < 10% of cases.34 The findings from bone marrow examination in patients
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A Review of TEMPI Syndrome with Schnitzler syndrome will either be normal or exhibit polytypic lymphocytic or plasmacytic infiltrates.12 The other salient distinguishing feature is the elevated inflammatory markers in Schnitzler syndrome, such as C-reactive protein and leukocytosis. Schnitzler syndrome is considered a late-onset acquired autoinflammatory disease in which interleukin-1b plays a pivotal role. Almost all patients develop fever, their skin biopsy examinations usually reveal neutrophilic dermal infiltrates, and inflammatory anemia has also been observed.33 In contrast, the white blood cell counts remain normal in those with TEMPI syndrome, and no increased inflammation or proinflammatory cytokines have been reported. Moreover, increased markers of bone remodeling, such as osteocalcin and alkaline phosphatase, and high levels of VEGF in Schnitzler syndrome, can effectively differentiate between the 2 conditions.
Treatment and Prognosis
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It is well accepted that eradication of underlying aberrant plasma cell clones and M protein is essential in the treatment of TEMPI syndrome. The therapeutic strategies can be borrowed from those for other plasma cell diseases (eg, POEMS syndrome, MM, and AL amyloidosis) and generally include chemotherapy and ASCT. In the experimental treatment of Sykes et al,1 an immunomodulatory agent (thalidomide), anti-VEGF antibody (bevacizumab), and immunosuppressive agent (sirolimus) were all ineffective. Only bortezomib led to elimination of monoclonal gammopathy and significant improvement of the clinical symptoms.1 The spectacular response of bortezomib-based regimens has been highlighted in multiple case reports.4,5,9 Bortezomib, a first-generation proteasome inhibitor, directly induced plasma cell death by inhibiting proteasome-mediated regulation of antiapoptotic and proapoptotic proteins.35 In addition, bortezomib also affected the function of HIF-1a by reinforcing factor inhibiting HIF-1aemediated inhibition of p300 recruitment. The attenuated HIF-1emediated activation of VEGF and EPO gene expression contributed to the inhibitory effect on cell proliferation and hypoxic adaptation.36 Because of the risk of peripheral neuropathy, Jasim et al9 advised caution with bortezomib administration and suggested a subcutaneous route and the use of novel protease inhibitors. If patients with TEMPI syndrome have an inadequate response to bortezomib-based regimens, ASCT could be a viable option for transplant-eligible patients. Kenderian et al10 reported the case of 1 patient who achieved a complete response after ASCT after melphalan conditioning. This patient continued to show complete clinical and hematologic remission at the annual follow-up examination. However, it is necessary to emphasize that, despite the beneficial effect, ASCT remains controversial owing to potential complications, such as infection and autoimmune hemolytic anemia.37 Therefore, bortezomib-based regimens remain the first option for the management of TEMPI syndrome, with ASCT considered if treatment with bortezomib is ineffective. More recently, Sykes and Schroyens13 reported the efficiency of daratumumab monotherapy in 2 patients with disease that had relapsed or was refractory to both bortezomib and ASCT. Daratumumab, a human IgG1k monoclonal antibody that targets CD38, had encouraging efficacy in patients with highly difficult-totreat myeloma.38 Treatment with single-agent daratumumab (a dose
Clinical Lymphoma, Myeloma & Leukemia Month 2018
of 16 mg/kg was given intravenously once each week for 8 weeks, followed by every 2 weeks for 16 weeks and every 4 weeks thereafter) in these 2 patients with TEMPI syndrome resulted in rapid and striking responses, including the disappearance of the paraprotein and normalization of the hematocrit and EPO levels.13 Daratumumab had an acceptable safety profile, and no side effects were observed in either patient.13 The successful results of the experimental therapeutic agent daratumumab further supported the hypothesis that monoclonal gammopathy and abnormal plasma cell clone are involved in the pathogenesis of TEMPI syndrome. However, the direct pathophysiologic link remains elusive, and the effect of daratumumab on longer term survival requires study. Supportive care is an integral part of the therapy of TEMPI syndrome. The management of clinical symptoms is necessary because the organ response can lag months behind the administration of plasma cell clone-targeted therapy.24 Continuous supplementary oxygen might be required to improve the oxygen saturation in patients with severe hypoxemia.10,11 As stated previously, iron-deficient anemia caused by therapeutic phlebotomy can exacerbate hypoxia10; thus, usage of oral iron has been suggested. In cases of perinephric fluid collections compressing the kidneys, patients have often complained of abdominal fullness and worsening blood pressure control. CT-guided drainage of perinephric fluid has been effective in resolution of renal function and compression symptoms. Patients with TEMPI syndrome have a potential risk of venous thrombosis and spontaneous intracranial hemorrhage. Therefore, we recommend that clinicians monitor the relevant clinical signs and laboratory parameters.
Conclusion A paucity of information is available regarding TEMPI syndrome, because it was first described in 2011. Thus, the follow-up times have been too short to draw any conclusions regarding the long-term outcomes. To date, no clinical or biologic markers to predict the survival of patients with TEMPI syndrome have been established. TEMPI syndrome appears to be an indolent plasma cell neoplasm with a low tumor burden. Early recognition and treatment of this disease before the development of advanced symptoms has been suggested to be key to successful management.2
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Sykes DB, Schroyens W, O’Connell C. The TEMPI syndrome—a novel multisystem disease. N Engl J Med 2011; 365:475-7. 2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haemotopoietic and Lymphoid Tissues. Revised 4th ed. Lyon, France: IARC Press; 2017. 3. Belizaire R, Sykes DB, Chen YB, et al. Difficulties in hematopoietic progenitor cell collection from a patient with TEMPI syndrome and severe iatrogenic iron deficiency. Transfusion 2015; 55:2142-8. 4. Mohammadi F, Wolverson MK, Bastani B, et al. A new case of TEMPI syndrome. Clin Kidney J 2012; 5:556-8. 5. Kwok M, Korde N, Landgren O. Bortezomib to treat the TEMPI syndrome. N Engl J Med 2012; 366:1843-5. 6. Schroyens WA, O’Connell CL, Lacy MQ, et al. TEMPI: a reversible syndrome following treatment with bortezomib. Blood 2012; 367:778-80. 7. Viglietti D, Sverzut JM, Peraldi MN. Perirenal fluid collections and monoclonal gammopathy. Nephrol Dial Transplant 2012; 27:448-9. 8. Ryden A, Wei K, Rodriguez R, et al. Too much blood: a case of the newly described TEMPI syndrome. Chest 2013; 144:927A.
Xianrui Zhang, Meiyun Fang 9. Jasim S, Mahmud G, Bastani B, et al. Subcutaneous bortezomib for treatment of TEMPI syndrome. Clin Lymphoma Myeloma Leuk 2014; 14:e221-3. 10. Kenderian SS, Rosado FG, Sykes DB, et al. Long-term complete clinical and hematological responses of the TEMPI syndrome after autologous stem cell transplantation. Leukemia 2015; 29:2414-6. 11. Pascart T, Herbaux C, Lemaire A, et al. Coexistence of rheumatoid arthritis and TEMPI syndrome: new insight in microangiogenic-related diseases. Joint Bone Spine 2016; 83:587-8. 12. Rosado FG, Oliveira JL, Sohani AR, et al. Bone marrow findings of the newly described TEMPI syndrome when erythrocytosis and plasma cell dyscrasia coexist. Mod Pathol 2015; 28:367-72. 13. Sykes DB, Schroyens W. Complete responses in the TEMPI syndrome after treatment with daratumumab. N Engl J Med 2018; 378:2240-2. 14. Malhotra J, Kremyanskaya M, Schorr E, et al. Coexistence of myeloproliferative neoplasm and plasma-cell dyscrasia. Clin Lymphoma Myeloma Leuk 2014; 14:31-6. 15. Mossuz P, Girodon F, Donnard M, et al. Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica 2004; 89:1194-8. 16. Schroyens W, O’Connell C, Sykes DB. Complete and partial responses of the TEMPI syndrome to bortezomib. N Engl J Med 2012; 367:778-80. 17. Hutchison EJ, Taverna JA, Yu Q, et al. Polycythaemia: an unusual presentation of multiple myeloma. BMJ Case Rep 2016; 2016. https://doi.org/10.1136/bcr-2016216686. 18. Lee SG, Lim G, Cho SY, et al. JAK2 mutation-negative secondary erythrocytosis in smoldering plasma cell myeloma: a case study and review of the literature. Acta Haematol 2011; 126:169-71. 19. Nagasawa T, Yanagisawa H, Hasegawa Y, et al. Polycythemia associated with primary systemic amyloidosis: elevated levels of hemopoietic factors and cytokines. Am J Hematol 1993; 43:57-60. 20. Cartin-Ceba R, Swanson KL, Krowka MJ. Pulmonary arteriovenous malformations. Chest 2013; 144:1033-44. 21. Glavey SV, Leung N. Monoclonal gammopathy: the good, the bad and the ugly. Blood Rev 2016; 30:223-31. 22. Fotiou D, Gerotziafas G, Kastritis E, et al. A review of the venous thrombotic issues associated with multiple myeloma. Expert Rev Hematol 2016; 9:695-706.
23. De Stefano V, Za T, Rossi E. Venous thromboembolism in multiple myeloma. Semin Thromb Hemost 2014; 40:338-47. 24. Warsame R, Yanamandra U, Kapoor P. POEMS syndrome: an enigma. Curr Hematol Malig Rep 2017; 12:85-95. 25. Abe D, Nakaseko C, Takeuchi M, et al. Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome. Blood 2008; 112: 836-9. 26. Dispenzieri A, Kourelis T, Buadi F. POEMS syndrome: diagnosis and investigative work-up. Hematol Oncol Clin North Am 2018; 32:119-39. 27. Dao LN, Hanson CA, Dispenzieri A, et al. Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients. Blood 2011; 117:6438-44. 28. Chavda SJ, Yong K. Multiple myeloma. Br J Hosp Med (Lond) 2017; 78:C21-7. 29. Ribourtout B, Zandecki M. Plasma cell morphology in multiple myeloma and related disorders. Morphologie 2015; 99:38-62. 30. Mollee P, Renaut P, Gottlieb D, et al. How to diagnose amyloidosis. Intern Med J 2014; 44:7-17. 31. Gertz MA. Immunoglobulin light chain amyloidosis: 2016 update on diagnosis, prognosis, and treatment. Am J Hematol 2016; 91:947-56. 32. Khoor A, Colby TV. Amyloidosis of the lung. Arch Pathol Lab Med 2017; 141: 247-54. 33. Palladini G, Merlini G. The elusive pathogenesis of Schnitzler syndrome. Blood 2018; 131:944-6. 34. Gusdorf L, Lipsker D. Schnitzler syndrome: a review. Curr Rheumatol Rep 2017; 19:46. 35. Shin DH, Chun YS, Lee DS, et al. Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia inducible factor-1. Blood 2008; 111:3131-6. 36. Khan S. The role of hypoxia-inducible factor-1 alpha in TEMPI syndrome. NDT Plus 2011; 4:454-5. 37. Zeher M, Papp G, Szodoray P. Autologous haemopoietic stem cell transplantation for autoimmune diseases. Expert Opin Biol Ther 2011; 11:1193-201. 38. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015; 373:1207-19.
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TEMPI Syndrome: Erythrocytosis in Plasma Cell Dyscrasia Xianrui Zhang,1 Meiyun Fang2 Abstract TEMPI (telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting) syndrome is a newly described clinical entity that is generally considered a plasma cell dyscrasia with multiple system involvement. The etiology and pathophysiology of this condition remains elusive. Nevertheless, clonal plasma cells and monoclonal protein appear to be major contributors. The early diagnosis of TEMPI syndrome is essential because therapies targeting the underlying plasma cells can lead to a dramatic response. Bortezomib-based chemotherapy, daratumumab monotherapy, and autologous hematopoietic stem cell transplantation can result in reversal of most manifestations. Nevertheless, the diagnosis of TEMPI syndrome remains a substantial challenge owing to its rarity and the complexity of clinical presentations. TEMPI syndrome is often misdiagnosed as other causes of erythrocytosis, resulting in a delayed diagnosis and further clinical deterioration. The aim of the present review was to present the clinical and biologic features of TEMPI syndrome, highlighting the differential diagnosis and outlining the present understanding of its pathophysiology and treatment. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2018 Elsevier Inc. All rights reserved. Keywords: Bortezomib, Differential diagnosis, Erythrocytosis, Monoclonal gammopathy, Plasma cell dyscrasia
Introduction In 2011, Sykes et al1 coined the acronym “TEMPI” for a syndrome constituting telangiectasias (T), erythrocytosis with elevated erythropoietin levels (E), monoclonal gammopathy (M), perinephric fluid collections (P), and intrapulmonary shunting (I). TEMPI syndrome is included in the 2016 revised World Health Organization classification of tumors of hematopoietic and lymphoid tissues.2 TEMPI syndrome is best categorized as a plasma cell disorder with paraneoplastic manifestations. Little is known about the etiology, pathogenesis, or prevalence of this recently described entity. To the best of our knowledge, 15 cases have been reported to date. The complexity and rarity of the disorder and its common mimicking of other diseases suggest that more patients might have undiagnosed TEMPI syndrome. Although the diagnostic features are unique and clear, a misdiagnosis occurs 1
Department of Hematology, First Affiliated Hospital, Dalian Medical University, Dalian, People’s Republic of China 2 Department of Hematology, Affiliated ZhongShan Hospital of Dalian Medical University, Dalian, People’s Republic of China Submitted: Mar 31, 2018; Revised: Jun 22, 2018; Accepted: Jul 9, 2018 Address for correspondence: Meiyun Fang, PhD, Department of Hematology, Dalian Medical University, Affiliated ZhongShan Hospital, 6 Jiefang Road, Dalian 116011, China E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2018 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2018.07.284
frequently because the investigative findings could be misinterpreted. The constellation of erythrocytosis, M protein, and other clinical findings often lead patients with TEMPI syndrome to be considered to have a variety of renal, pulmonary, or hematologic disorders, such as polycythemia vera (PV)3 and/or monoclonal gammopathy of undetermined significance (MGUS).4 Despite its rarity, TEMPI syndrome is an important diagnosis because the appropriate therapy can dramatically improve a patient’s quality of life.5 In an attempt to improve recognition of this clinical entity and associated treatment options, the typical features of TEMPI syndrome and efficacy of therapies have been summarized in the present report. In addition, we have discussed its differential diagnosis with other plasma cell disorders.
Clinical Features and Pathophysiology The clinical findings and laboratory data of all reported patients with TEMPI syndrome are listed in Table 1. These 15 patients included 6 men and 9 women, aged 35 to 65 years (median age, 49 years). Given that these patients developed symptoms after middle age, Schroyens et al6 inferred that TEMPI syndrome was likely to be an acquired disease. The onset of TEMPI syndrome is occult, with slowly progressive symptoms.2 The clinical features have been reviewed in the next sections and the potential pathogenesis discussed.
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2
Demographic Investigator
TEMPI Syndrome M
P
I
Bone Marrow Plasma Cells
> 5000 mU/mL > 5000 mU/mL
IgGk (0.7 g/dL) IgGk (0.7 g/dL)
Yes Yes
Yes Yes
< 10% < 10%
Yes
> 5000 mU/mL
IgGk (0.7 g/dL)
Yes
Yes
< 10%
NR Yes NR Yes Yes
Yes Yes Yes Yes Yes
> 5000 mU/mL Increased NR > 8000 mU/mL 134 mU/mL
NR IgG NR IgGk IgAl (1.4 g/dL)
Yes NR Yes NR Yes
NR Yes NR Yes No
NR < 10% NR NR 10%
56 49 50 61
Yes Yes Yes Yes
Yes Yes Yes Yes
100 mU/mL 78 mU/mL 433 mU/mL 134 mU/mL
IgGl (3.6 g/dL) IgAl (0.2 g/dL) IgGk IgAl (1.4 g/dL)
Yes Yes Yes Yes
NR NR Yes NR
10%-15% NR < 10% 10%
49 54 65
NR Yes Yes
Yes Yes Yes
8144 mU/mL 5000 mU/mL > 5000 mU/mL
IgGk (1.8 g/dL) IgGk (0.8 g/dL) IgGk (2.3 g/dL)
Yes Yes No
Yes Yes Yes
5%-10% NR 10.5%
Pt. No.
Gender
Age, y
T
1 2
Male Female
42 36
Yes Yes
Yes Yes
3
Female
39
Yes
4 5 6 7 8
Male Male Male Female Female
35 56 36 49 58
Kwok et al,5 2012 Viglietti et al,7 2012 Ryden et al,8 2013 Jasim et al,9 2014
9 10 11 12
Female Male Male Female
Kenderian et al,10 2015 Belizaire et al,3 2015 Pascart et al,11 2015
13 14 15
Female Female Female
Sykes et al,1 2011
Schroyens et al,6 2012 Mohammadi et al,4 2012
Erythrocytosis and EPO
Others Venous thrombosis Venous thrombosis, spontaneous intracranial hemorrhage Venous thrombosis, spontaneous intracranial hemorrhage NR NR NR NR Diarrhea, hydronephrosis, hydroureter, liver hemangioma, hyperlipidemia, coronary artery disease, congestive heart failure, gallstone, left ventricular apical thrombus, dilation of common bile duct, indigestion, bloating Fatigue, diffuse pains Ascites, pleural effusion Focal segmental glomerulosclerosis Ischemic cardiomyopathy, hypothyroidism, hypertension, diarrhea, liver hemangioma Iatrogenic iron-deficient anemia Iatrogenic iron-deficient anemia Rheumatoid arthritis
Abbreviations: EPO ¼ erythropoietin; I ¼ intrapulmonary shunting; M ¼ monoclonal gammopathy; NR ¼ not reported; P ¼ perinephric fluid collections; Pt. No. ¼ patient number; T ¼ telangiectasias; TEMPI ¼ telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting.
A Review of TEMPI Syndrome
Clinical Lymphoma, Myeloma & Leukemia Month 2018
Table 1 Characteristics of Patients With TEMPI Syndrome
Xianrui Zhang, Meiyun Fang Monoclonal Plasma Cell Disorder A monoclonal component, the defining characteristic of TEMPI syndrome, was found in all patients assessed. IgGk predominated; however, IgAl and IgGl were also identified in individual cases. Recently, we found IgEl monoclonal gammopathy in 1 patient with TEMPI syndrome features (Hu, 2017, personal communication). All patients were reported to have < 3.0 g/dL of M protein, except for patient 9, in whom the monoclonal IgG level was 3.6 g/ dL.5 A slight preponderance of the k light chain subtype was found in patients with TEMPI syndrome (k-to-l ratio, 2:1), and the serum free light chain ratios were reportedly skewed in 3 cases (patients 8, 9, and 12). The results of Bence-Jones proteinuria testing was negative in all tested cases. Once a monoclonal plasma cell dyscrasia has been detected serologically or in urine, a bone marrow examination should be performed to ascertain the classification and extent of the disease. Most patients had marrow plasma cell percentages at MGUS levels (< 10%). Only 2 patients were reported to have > 10% bone marrow plasma cells (patients 9 and 15), and the levels in patient 9 reached the level of smoldering myeloma. However, the diagnostic criteria for symptomatic plasma cell myeloma were not fulfilled in any patient. No detailed reports are available on the immunophenotypic or genetic findings in TEMPI syndrome. Morphologically, a slight atypia in plasma cells was noted, with cytoplasmic vacuolization and frayed cytoplasm.12 Therapies targeted against plasma cell clones, including bortezomib-based regimens, daratumumab monotherapy,13 and autologous hematopoietic stem cell transplantation (ASCT),10 have yielded dramatic clinical responses, with reversal of most manifestations. Thus, TEMPI syndrome is best categorized as a plasma cell dyscrasia accompanied by paraneoplastic manifestations in which abnormal plasma cell clones and M protein play central pathogenic roles.
Hematologic Findings Erythrocytosis and extremely elevated serum erythropoietin (EPO) levels (range, 78-8144 mU/mL) are distinctive features of TEMPI syndrome. The initial manifestation of erythrocytosis led to the misdiagnosis of PV in patients with partial presentations, and some patients even developed iatrogenic iron-deficient anemia from therapeutic phlebotomy.3,10 The evaluation of serum EPO and Janus kinase 2 (JAK2) V617F genetic testing allow for differentiation of TEMPI syndrome and PV. Almost all patients with PV (> 95%) will have the acquired JAK2 V617F mutation,14 unlike those with TEMPI syndrome, in whom the JAK2 mutation will be absent. Moreover, the serum EPO levels in patients with PV and other primary erythrocytoses will be low (mean < 3.3 mU/mL).12 In the bone marrow of patients with TEMPI syndrome, erythroid hyperplasia was a recurrent finding. Megakaryocytic hyperplasia and mild atypia and moderate erythroid atypia and reactive lymphoid aggregates were also observed in bone marrow samples. No patient has been reported to exhibit the morphologic features of PV or other myeloproliferative neoplasms, such as megakaryocytic hyperchromia or clustering, osteosclerosis, intrasinusoidal hematopoiesis, or increased reticulin fibrosis.12 The etiology of erythrocytosis and elevated serum EPO levels remains unknown. Although a connection seems to exist between the EPO level and the degree of hypoxia,12 the hypoxemia
attributed to right-to-left intrapulmonary shunting cannot explain the erythrocytosis in patients with TEMPI syndrome. First, the erythrocytosis preceded the clinical appearance of hypoxemia in previous reports.9 Second, the elevated EPO level resulting from hypoxemia has typically been < 30 mU/mL.15 It has been hypothesized that perinephric fluid collections might be related to increased EPO secretion and consequent erythrocytosis.4,7 However, perinephric fluid was not observed at all in a few cases, and sometimes polycythemia has appeared before renal fluid collection has developed.8,10,11 Given the normalization of the red blood cell counts after bortezomib treatment in most patients, we can reasonably surmise that a direct association exists between erythrocytosis and the monoclonal immunoglobulin level. Considering the inhibitory effect of bortezomib on hypoxia-inducible factor-1a (HIF-1a), a crucial transcription factor for EPO production, Hutchison et al17 hypothesized that erythrocytosis might result from monoclonal immunoglobulins enhancing the function of HIF-1a and subsequently increasing EPO secretion. We suspect that the pathogenesis of polycythemia in TEMPI syndrome might have something in common with that of other plasma cell disorders, such as multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis. Lee et al18 suggested that the subclinical renal damage caused by Bence-Jones protein could explain the coexistence of MM and erythrocytosis. Nagasawa et al19 suggested that amyloid deposits in hemopoietic factor-producing tissues contributed to erythrocytosis in AL amyloidosis. We, therefore, postulated that the erythrocytosis in TEMPI syndrome might be caused by the deposition of monoclonal immunoglobulin or its fragments in kidney components and/or the bone marrow niche. Overt or subclinical renal damage from monoclonal gammopathy could result in local hypoxia and elevated EPO production. Plasma cell clones or paraproteins in bone marrow might trigger erythroid hyperplasia by stimulating erythroid progenitor cells and/or hemopoietic factor-producing cells. The etiology of the elevated EPO level and erythrocytosis in patients with TEMPI syndrome warrants further exploration.
Renal Findings A perinephric fluid collection is another diagnostic component of TEMPI syndrome. The typical clinical manifestations include bilateral flank fullness, nausea, renin-dependent hypertension, and a palpable abdominal mass. Renal dysfunction is less common. Proteinuria has not been reported, and the slightly elevated serum creatinine levels in a few patients with TEMPI syndrome (patients 8, 10, and 11) decreased after bilateral perirenal compressive fluid removal. A perinephric fluid collection can be diagnosed from the ultrasound or computed tomography (CT) findings. Abdominal ultrasonography and CT scans have revealed massive perinephric fluid collections compressing both kidneys. Aspiration showed clear, aseptic, and serous fluid containing few or no cells and small amounts of protein, cholesterol, triglycerides, and chylomicron.4,15 When kidney biopsy was performed, the reported histologic findings included hypertensive vascular changes without amyloidosis or light chain deposition.4,9 Viglietti et al7 attributed large perinephric fluid collections to malformation of renal lymphatic tissues, leading to blockage and accumulation of lymph in the subcapsular region. However, Jasim et al9 and Mohammadi et al4 failed to detect interstitial edema, dilated lymphatics, or any other evidence
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A Review of TEMPI Syndrome suggestive of renal lymphangiectasia in the renal biopsy specimens of patients with TEMPI syndrome. The regression of fluid collections after bortezomib treatment suggests that the perinephric fluid collections might be the consequence of M protein by an unknown mechanism.
Pulmonary Findings and Skin Changes The physical examination findings were notable for hypoxia in 9 of the 15 patients with TEMPI syndrome. Right-to-left intrapulmonary shunting was detected in all 15 TEMPI patients, with low oxygen saturation (mean < 90%). The normal portion of cardiac output in right-to-left shunting is 5%.20 However, all reported circulatory shunt indexes in those with TEMPI syndrome were > 10%.3,10 Quantitative evaluation of the shunt fraction can be performed using technetium-99m macroaggregated albumin scanning or the 100% oxygen method. The severity of hypoxemia will be proportional to the degree of shunting, and patients tend to present with severe symptoms, such as dyspnea on exertion and digital clubbing, when the shunt index is > 20%.21 Several patients with TEMPI syndrome have even required wheelchairs and continuous supplemental oxygen because of progressive hypoxia.6,10 Hypoxemia and intrapulmonary shunting resolved after treatment with bortezomib and ASCT. However, the mechanisms are as yet unknown. Telangiectasias, another cardinal presentation of TEMPI syndrome, affected 12 of the 15 patients. Telangiectasias are the persistence of dilated capillary vessels, forming small punctate red stains16 or having a spider-like appearance.9 Telangiectasias appeared most prominently on the face, neck, upper extremities, and trunk. Although the exact mechanism is unclear, hypoxia, causing increased blood flow beneath skin surface owing to dilation of capillaries, might explain the presence of telangiectasias in patients with TEMPI syndrome.
Other Clinical Features
4
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Of the 15 patients, 3 had venous thrombosis and 2 experienced complications with spontaneous intracranial hemorrhage.1 We believe that the presence of coagulation abnormalities in patients with TEMPI syndrome might not be a chance association. Recent studies have investigated the link between monoclonal gammopathy and a bleeding or thrombotic tendency. In a case series of patients with MGUS, the rate of venous thromboembolism was w7%, related to a variety of factors, including increased blood viscosity, delayed fibrinolysis, and procoagulant activity of the M component.21 Bleeding events due to the M protein have also been reported. The pathogenetic mechanisms could involve the inactivation of critical procoagulant proteins and impaired fibrin polymerization or platelet function.22 Reports have also connected hyperviscosity with an increased risk of bleeding.23 Further studies are needed to delineate a causal relationship between the presence of coagulation abnormalities and TEMPI syndrome. Other associated findings included heart disease in 2 patients,4,9 liver hemangiomas in 2 patients,4,9 hypothyroidism in 1 patient,9 diarrhea in 2 patients,4,9 focal segmental glomerulosclerosis in 1 patient,8 ascites and pleural effusion in 1 patient,7 and rheumatoid arthritis in 1 patient.11 These associated findings appeared to be coincidental rather than causal. However, a simultaneous outbreak
Clinical Lymphoma, Myeloma & Leukemia Month 2018
of rheumatoid arthritis and TEMPI syndrome was noteworthy, because microangiogenesis is a common pattern of both diseases, suggesting a link underlying their pathophysiologic pathways.11
Diagnostic Criteria and Differential Diagnosis No diagnostic reference standard has yet emerged for TEMPI syndrome. Rosado et al12 suggested that the coexistence of plasma cell dyscrasia and erythrocytosis should elicit an in-depth search for TEMPI syndrome. On confirmation of a plasma cell clone and erythrocytosis, in conjunction with the clinical, radiologic, and biologic findings and the exclusion of other causes, the diagnosis of TEMPI syndrome can be established. In particular, the following diseases should be excluded: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, MM, AL amyloidosis, and Schnitzler syndrome. The major features of these diseases are listed in Table 2.
POEMS Syndrome POEMS syndrome is a rare paraneoplastic disorder secondary to an underlying plasma cell dyscrasia.24 POEMS syndrome can mimic TEMPI syndrome because of its paraproteinemia, polycythemia, skin changes, and abnormal pulmonary function test results. However, some distinctive features of POEMS syndrome can differentiate between these 2 disorders. First, patients with TEMPI syndrome will have a slight predominance of k light chains. In contrast, the proliferating monoclonal plasma cells in those with POEMS syndrome will be l-restricted in the vast majority of cases. Moreover, monoclonal Igl light chains (IGL) in POEMS syndrome belong to the Vl1 subfamily and are limited to IGLV1-44*01 and IGLV1-40*01 germlines.25 Second, in contrast to TEMPI syndrome, in which no elevation of vascular endothelial growth factor (VEGF) levels was observed in the reported cases, the serum VEGF level will be markedly increased in those with POEMS syndrome, correlating with disease activity. Measurement of serum EPO is also useful in distinguishing between the 2 diseases. Similar to TEMPI syndrome, polycythemia will be seen in w15% of patients with POEMS syndrome, with negative results for JAK2 V617F genetic testing.24 Nevertheless, the concentration of serum EPO in those with POEMS syndrome has been low (< 3.13 mU/mL) and correlates inversely with the VEGF level.26 Third, patients with TEMPI syndrome will not have certain features of POEMS syndrome, such as polyneuropathy, endocrinopathy, and organomegaly, and vice versa. From a morphologic perspective, plasma cell rimming around lymphoid aggregates will be present in nearly one half of patients with POEMS syndrome, in contrast to the lymphoid aggregates observed in those with TEMPI syndrome. Megakaryocytic hyperplasia can be encountered in both disorders, but bone marrow specimens from those with POEMS syndrome will usually demonstrate megakaryocytic clustering and cytologic atypia.27
Multiple Myeloma MM is a common hematologic malignancy, characterized by clonal bone marrow plasma cells that secrete monoclonal paraprotein. Patients with MM will exhibit myriad symptoms, from fatigue to “CRAB” criteria (hypercalcemia, renal impairment, anemia, and bone lesions). In contrast to TEMPI syndrome, in which the hemoglobin
Xianrui Zhang, Meiyun Fang Table 2 Differential Diagnosis of TEMPI Syndrome Clinical Findings
TEMPI Syndrome
POEMS Syndrome
Multiple Myeloma
AL Amyloidosis
Schnitzler Syndrome
< 10 10 < 15 5 IgG, IgA (l-restricted) IgG, IgA, IgM, IgD, IgE IgG, IgA, IgM, IgD Mainly IgM, IgG [ (15%), normal, or Y (70%) or normal Y (32.4%) or normal Y Y (< 5%) EPO [[ Y Y NR NR Skin changes Telangiectasias Hyperpigmentation, plethora, Cutaneous plasmacytoma Periorbital hematoma, Urticarial recurrent hemangiomata, acrocyanosis, (appears as reddish, nontender, various papules, nodules, rash, neutrophilic white nails, hypertrichosis dermal or subcutaneous nodules; patches, blisters urticarial dermatosis occasionally as diffuse erythematous rash) Pulmonary manifestation Intrapulmonary Pulmonary hypertension, Pulmonary plasmacytoma Diffuse alveolar-septal NR shunting restrictive lung disease, (appears as solitary pulmonary amyloidosis, nodular impaired neuromuscular nodule), diffuse alveolar pulmonary amyloidosis, respiratory function hemorrhage, pleural effusion tracheobronchial amyloidosis Renal manifestation Perinephric fluid Renal lesion (elevated serum Renal impairment (proteinuria, Heavy proteinuria, nephrotic NR collections; elevated cystatin C level, elevated Bence-Jones proteinuria, syndrome, decreased serum creatinine serum creatinine and elevated serum creatinine) glomerular filtration rate and proteinuria are relatively rare) elevated serum creatinine Bone manifestation NR Osteosclerotic lesion, Bone pain, lytic lesions, diffuse Osteolytic lesion, Bone and joint pain, pathologic fractures sclerotic lesions, lytic osteolytic lesion, hyperostosis osteoporosis, pathologic lesions fractures, plasmacytomas Liver or spleen Other manifestations Venous thrombosis, Papilledema, peripheral Hyperviscosity (mucosal Peripheral neuropathy, spontaneous neuropathy, organomegaly, membrane bleeding, neurologic tongue enlargement, liver enlargement, intermittent enlargement, impaired fever, elevated markers intracranial endocrinopathy, extravascular deficit, increased intracranial intestinal transit, occult of inflammation, hemorrhage, volume overload, Castleman pressure), infection, cytopenia, bleeding, arrhythmias, palpable adenopathy, iatrogenic disease, thrombocytosis, secondary amyloidosis (tongue coronary heart disease, fatigue, systemic iron-deficient heart failure enlargement, organomegaly, myocardial infarction amyloid A amyloidosis anemia peripheral neuropathy), hypercalcemia (confusion, muscle weakness, polydipsia)
Plasma cells, % M protein Hemoglobin
< 15 IgG, IgA [
Abbreviations: AL ¼ immunoglobulin light chain; EPO ¼ erythropoietin; NR ¼ not reported; POEMS ¼ polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; TEMPI ¼ telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, intrapulmonary shunting.
concentration is elevated, anemia is a hallmark of MM and will be found at diagnosis in w70% of patients.28 However, iatrogenic irondeficient anemia in patients with a partial presentation of TEMPI syndrome could mask the polycythemia of TEMPI syndrome. In addition, the levels of bone marrow plasma cells in several patients with TEMPI syndrome were > 10%. A combination of M protein, anemia, and 10% plasma cells in bone marrow biopsy specimens should raise the index of suspicion for MM. A detailed medical history has an important role in the differential diagnosis. The anemia of TEMPI syndrome is caused by therapeutic phlebotomy and is characterized by iron deficiency and microcytic and hypochromic erythrocytes. In contrast, the anemia of MM is typically normochromic and normocytic.28 In addition, patients with MM tend to have bone lesions and renal impairment, unlike TEMPI syndrome, in which the skeletal radiographic findings appear normal and renal dysfunction is rarely encountered. Moreover, bone marrow biopsy is characteristic, with the number of plasma cells > 10% and changes in the morphology of myeloma cells (eg, nuclear-tocytoplasmic asynchrony, low amount of cytoplasm, and the presence of plasmablasts) in most patients with MM.29
AL Amyloidosis AL amyloidosis is a rare, life-threatening condition caused by deposition of fibril-forming monoclonal light chains in the
extracellular matrix of organs and tissues.30 Although it can be discriminated by the presence of amyloid in tissues, AL amyloidosis has many features overlapping with TEMPI syndrome. For instance, the plasma cell burden is relatively low in AL amyloidosis, typically IgG or IgA when serum monoclonal immunoglobulin is measured.31 AL amyloidosis differs from TEMPI syndrome in that most morphologic abnormalities of bone marrow plasma cells in AL amyloidosis are superimposable with those of MM,29 and the l light chain isotype is more prevalent in AL. Regarding the clinical features, renal impairment is the most frequent manifestation in AL amyloidosis, characterized by proteinuria and full nephrotic syndrome in 73% and 30% of cases, respectively.30 Involvement of the lung is also common in AL amyloidosis but is rarely symptomatic, unlike in TEMPI syndrome, in which hypoxemia due to intrapulmonary shunting is prevalent.32
Schnitzler Syndrome Schnitzler syndrome, a rare disorder characterized by a chronic urticarial rash, fever, joint and/or bone pain, lymphadenopathy, and leukocytosis, also presents with monoclonal gammopathy,33 generating the differential diagnosis with TEMPI syndrome. However, the M component in Schnitzler syndrome is mainly IgMk (in w88% of cases) and the IgG subtype is found in < 10% of cases.34 The findings from bone marrow examination in patients
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A Review of TEMPI Syndrome with Schnitzler syndrome will either be normal or exhibit polytypic lymphocytic or plasmacytic infiltrates.12 The other salient distinguishing feature is the elevated inflammatory markers in Schnitzler syndrome, such as C-reactive protein and leukocytosis. Schnitzler syndrome is considered a late-onset acquired autoinflammatory disease in which interleukin-1b plays a pivotal role. Almost all patients develop fever, their skin biopsy examinations usually reveal neutrophilic dermal infiltrates, and inflammatory anemia has also been observed.33 In contrast, the white blood cell counts remain normal in those with TEMPI syndrome, and no increased inflammation or proinflammatory cytokines have been reported. Moreover, increased markers of bone remodeling, such as osteocalcin and alkaline phosphatase, and high levels of VEGF in Schnitzler syndrome, can effectively differentiate between the 2 conditions.
Treatment and Prognosis
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It is well accepted that eradication of underlying aberrant plasma cell clones and M protein is essential in the treatment of TEMPI syndrome. The therapeutic strategies can be borrowed from those for other plasma cell diseases (eg, POEMS syndrome, MM, and AL amyloidosis) and generally include chemotherapy and ASCT. In the experimental treatment of Sykes et al,1 an immunomodulatory agent (thalidomide), anti-VEGF antibody (bevacizumab), and immunosuppressive agent (sirolimus) were all ineffective. Only bortezomib led to elimination of monoclonal gammopathy and significant improvement of the clinical symptoms.1 The spectacular response of bortezomib-based regimens has been highlighted in multiple case reports.4,5,9 Bortezomib, a first-generation proteasome inhibitor, directly induced plasma cell death by inhibiting proteasome-mediated regulation of antiapoptotic and proapoptotic proteins.35 In addition, bortezomib also affected the function of HIF-1a by reinforcing factor inhibiting HIF-1aemediated inhibition of p300 recruitment. The attenuated HIF-1emediated activation of VEGF and EPO gene expression contributed to the inhibitory effect on cell proliferation and hypoxic adaptation.36 Because of the risk of peripheral neuropathy, Jasim et al9 advised caution with bortezomib administration and suggested a subcutaneous route and the use of novel protease inhibitors. If patients with TEMPI syndrome have an inadequate response to bortezomib-based regimens, ASCT could be a viable option for transplant-eligible patients. Kenderian et al10 reported the case of 1 patient who achieved a complete response after ASCT after melphalan conditioning. This patient continued to show complete clinical and hematologic remission at the annual follow-up examination. However, it is necessary to emphasize that, despite the beneficial effect, ASCT remains controversial owing to potential complications, such as infection and autoimmune hemolytic anemia.37 Therefore, bortezomib-based regimens remain the first option for the management of TEMPI syndrome, with ASCT considered if treatment with bortezomib is ineffective. More recently, Sykes and Schroyens13 reported the efficiency of daratumumab monotherapy in 2 patients with disease that had relapsed or was refractory to both bortezomib and ASCT. Daratumumab, a human IgG1k monoclonal antibody that targets CD38, had encouraging efficacy in patients with highly difficult-totreat myeloma.38 Treatment with single-agent daratumumab (a dose
Clinical Lymphoma, Myeloma & Leukemia Month 2018
of 16 mg/kg was given intravenously once each week for 8 weeks, followed by every 2 weeks for 16 weeks and every 4 weeks thereafter) in these 2 patients with TEMPI syndrome resulted in rapid and striking responses, including the disappearance of the paraprotein and normalization of the hematocrit and EPO levels.13 Daratumumab had an acceptable safety profile, and no side effects were observed in either patient.13 The successful results of the experimental therapeutic agent daratumumab further supported the hypothesis that monoclonal gammopathy and abnormal plasma cell clone are involved in the pathogenesis of TEMPI syndrome. However, the direct pathophysiologic link remains elusive, and the effect of daratumumab on longer term survival requires study. Supportive care is an integral part of the therapy of TEMPI syndrome. The management of clinical symptoms is necessary because the organ response can lag months behind the administration of plasma cell clone-targeted therapy.24 Continuous supplementary oxygen might be required to improve the oxygen saturation in patients with severe hypoxemia.10,11 As stated previously, iron-deficient anemia caused by therapeutic phlebotomy can exacerbate hypoxia10; thus, usage of oral iron has been suggested. In cases of perinephric fluid collections compressing the kidneys, patients have often complained of abdominal fullness and worsening blood pressure control. CT-guided drainage of perinephric fluid has been effective in resolution of renal function and compression symptoms. Patients with TEMPI syndrome have a potential risk of venous thrombosis and spontaneous intracranial hemorrhage. Therefore, we recommend that clinicians monitor the relevant clinical signs and laboratory parameters.
Conclusion A paucity of information is available regarding TEMPI syndrome, because it was first described in 2011. Thus, the follow-up times have been too short to draw any conclusions regarding the long-term outcomes. To date, no clinical or biologic markers to predict the survival of patients with TEMPI syndrome have been established. TEMPI syndrome appears to be an indolent plasma cell neoplasm with a low tumor burden. Early recognition and treatment of this disease before the development of advanced symptoms has been suggested to be key to successful management.2
Disclosure The authors have stated that they have no conflicts of interest.
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