TEMPI Syndrome

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Primary Author(s)*

Sohini Anand, MBBS

Cancer Category/Type

Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome

Cancer Sub-Classification / Subtype

Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome

Definition / Description of Disease

TEMPI syndrome is an extremely rare blood disorder which involves multiple systems of the body. TEMPI syndrome stands for Telangiectasias, Erythropoiesis and elevated erythropoietin levels, Monoclonal gammopathy, Perinephric fluid collection and Intrapulmonary shunting.[1]

Synonyms / Terminology

TEMPI Syndrome

Epidemiology / Prevalence

TEMPI syndrome is a new disease entity. This term was coined in the year 2011. Prevalence is <1/106. The disease commonly occurs in 4th-5th decade of life. There is no sex, ethnic or geographical predilection[2]. Only 22[2] cases have been reported as of 2019 and only 10 cases have been included in the literature. TEMPI syndrome has been reported in 11 countries so far including USA, Sweden, Pakistan, Afghanistan, Germany.

Clinical Features

Renal manifestations- Nausea, flank pain, uncontrolled hypertension, fatigue, weight loss, hematuria, abdominal pain, hydronephrosis, hydroureter[3] and chronic renal insufficiency.[4]

Skin manifestations- Telangiectasias can lead to "web like appearance" of skin. "Red facies" because of increased RBCs[1]. Clubbing of fingernails[5]

Polycythemia- Fatigue, blurred vision, excessive sweating, headache.

Respiratory Failure- Presence of intrapulmonary shunting in TEMPI syndrome initially presents as dyspnea, hypoxia/hypoxemia leading to continuous oxygen requirement and ultimately respiratory failure.[6]

Thrombosis and intracranial bleeding- Spontaneous bleeding has been reported in some patients in absence of new blood vessel formations.[7]


Sites of Involvement

  • Kidney
  • Skin
  • Blood/lymph nodes- It has been reported that <10% of plasma cells are present in bone marrow, unlike MM. Erythropoietin levels are markedly increased in TEMPI syndrome patients.
  • Lung

Morphologic Features

Bone marrow biopsy- Plasma cell levels were approximately 10%. IgG κ is the most common monoclonal immunoglobulin reported in 6 out of 8 patients.[8] Erythroid hyperplasia with atypia and nuclear blebing. Vacuolization of plasma cells along with frayed of cytoplasm was noted. Lymphoid aggregates present without plasma cell rimming was reported.

Skin Biopsy for telangiectasia- dilated venules in histopathologic examination.

Erythropoietin levels- The titer can vary from 78mU/ml to 8144mU/ml. It is important to mention that hypoxemia driven erythropoiesis causes not more than 30mU/ml increase in erythropoietin levels.[8]

Kidney- Macroscopically, CT scan showed perinephric fluid collection between renal capsule and the kidney leading to compression of bilateral kidneys. No parenchymal cysts were reported.[9]

Pulmonary shunting- The extent of pulmonary shunting can be quantified using 99mTc macro-aggregated albumin scintigraphy. This is associated with decrease in resting oxygen saturation. This progresses to hypoxia and ultimately leading to use of supplemental oxygen.[2]

PERINEPHRIC FLUID ANALYSIS
clear, serous[9] and sterile fluid +
Proteins -
cells -
Lymphatic fluids/chyle -
Eletrolytes (Na+/K+/Cl-) same as serum

Immunophenotype

Loss of CD19 in plasma cells is one of the consistent findings while immunophenotyping the monoclonal PCs.


POSITIVE[10]

  • CD56+
  • CD38+,
  • CD138+,
  • IgG kappa+
  • IgG κ


NEGATIVE[10]

  • CD19
  • CD20
  • JAK2V617F
  • JAK2 exon 12
  • CALR
  • MFL
  • IGH (14q32)
  • RB1 (13q14) deletion
  • 1q gain
  • hyperdiploidy
  • 17p deletion

Chromosomal Rearrangements (Gene Fusions)

Somatic Structural variants of translocation:

Chromosomal Rearrangement Breaking Genes Pathogenic Derivative Prevalence
t(2;3) (2p22.3;q11.2)
t(2;4) (2p22.3;p1531)
t(2;5)(2p22.3/p15.3)
t(2;5)(2p22.3/q21.1)
t(2;6)(2p22.3/p12.1)
t(2;6)(2p22.3/q13)
t(2;8)(2p22.3/p21.2)
t(2;9)(2q13/p24.3)
t(2;9)(2p22.3/21.1)
t(2;10)(2p22.3/p11.21)
t(2;11)(2p22.3/p14.2)
t(2;11)(2p22.3/q22.3)
t(2;13)(2p22.3/q14.2)
t(2;13)(2p22.3/q21.31)
t(2;15)(2p22.3/q13.1)
t(2;19)(2q24.13/p13.2)
t(2;20)(2p22.3/12.1)
t(2;20)(p22.3/q11.21)
t(2,x)(p22.3/p22.12)
t(2;x)(p22.3/13.1)
t(2;x)(p22.3/q21.2)

[10]Characteristic Chromosomal Aberrations / Patterns


TEMPI syndrome is a newly discovered disorder; therefore, nothing much is known about pathophysiology of the same. Supplemental pdf file attached in this research paper[10] demonstrates the involvement of possible genomic aberrations leading to development of TEMPI syndrome.

Genomic Gain/Loss/LOH

Put your text here and/or fill in the table

Chromosome Number Gain/Loss/Amp/LOH Region Cytoband
2 deletion 33141401-62435304 2p22.3-p15
7 deletion 72788842-72789445 7q11.23
13 deletion 113518013-113519239 13q34
2 duplication 3925437-33141405 2p25.3-p22.3
10 duplication 53984356-54034064 10q21.1
15 duplication 23103187-231041416 15q11.2
22 duplication 23686256-25070295 22q11.23
2 inversion 14091693-33141660 2p24.3-p22.3
2 inversion 33141401-126175986 2q21.1
6 inversion 19429630-19430529 6p22.3
7 inversion 5943362-6861029 7p22.1
13 inversion 111736773-112875947 13q34
19 inversion 14508801-14876285 19p13.12

Gene Mutations (SNV/INDEL)

Molecular basis of TEMPI syndrome was studied using WES (Whole-Exome Sequencing). 25 somatic exonic SNVs( Single Nucleotide Variations) were reported. 18 out of 25 SNVs were non-synonymous. These 18 SNVs resides on the following 17 genes.[10]

Chromosome Gene Mutation
1 SZT2 Missense
1 IGSF3 Missense
1 NBPF10 Missense
2 POTEE Misense
2 NRP2 Missense
6 HIST1H2BM Missense
9 AQP7 Missense
9 AQP7 Missense
9 TMEM245 Missense
11 PGA3 Missense
12 TAS2R43 Missense
14 SLC7A8 Missense
15 MCTP2 Missense
17 PLCD3 Missense
17 LRRC37A3 Missense
18 CLUL1 Missense
18 LOXHD1 Missense
21 KRTAP10-4 Missense
X ATG4A Missense
Chromosome Gene Mutation
1 OR2T2 Synonymous
6 MDF1 Synonymous
7 MUC12 Synonymous
14 RBM23 Synonymous
22 IGLL5 Synonymous
7 IQCA1L Unknown


Other Mutations


Epigenomics (Methylation)

Molecular analysis in TEMPI syndrome showed involvement of chromosome2 and associated mutations. For example- deletion of 2p22.3-p15, duplication of 2p25.3-p22.3, inversion of 2p24.3-p22.3, 2q21.1. Chromosome 2 harbors important tumor genes as well. Therefore, it has be hypothesized that proximity of tumor associated genes and SVs can play a major role in the pathophysiology of TEMPI syndrome.

Tumor associated genes Location
MYCN 2p24.3
REL 2p16.1
BCL11A 2p16.1
BCL2L11 2q13
MAPK4 2p22.1
TP53I3 2p23.3

Genes and Main Pathways Involved

Macrophage MIF (Migratory Inhibitory Factor)- Gene synthesizing MIF is located at 22q11.23. Duplication of 22q11.23 which has been demonstrated by TEMPI syndrome which may lead to increased expression of MIF mRNA by CD138+ PCs and MIF proteins in the bone marrow of patients of TEMPI syndrome.[10]

MIF Function- MIF is a proinflammatory cytokine which can act as an intracellular signaling molecule as well[11]. It plays a major role in neovascularization by inducing erythropoietin, VEGFs and hypoxia-inducible factor1a. The pathogenesis of intrapulmonary shunting and telangiectasias are considered to be vascular dilations and neovascularization which can be explained by secretion of MIF from monoclonal plasma cells.

Diagnostic Testing Methods

Monoclonal plasma cells from TEMPI syndrome and healthy donors(control) collected for WGS (Whole Genome Sequence) and PCR (Polymerase Chain Reaction)

using Ficoll density gradient centrifugation. Following that, tumor cells can be isolated using CD138+ magnetic bead selection.

WES (Whole Genome Sequencing)
Sample Preservation- Preserved as dry pellets at -80o C
Extraction of DNA genome TIANamp Genomic DNA Kit (Tiangen)
Quality of DNA Nanophotometer
Quantity of DNA Qubit 3.0 flourometer


Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications) using


Diagnostic criteria for TEMPI syndrome[2]
MAJOR CRITERIA
  • Telangiectasias
  • EPO and erythrocytosis
  • Monoclonal gammopathy
MINOR CRITERIA
  • KIDNEY- PERINEPHRIC FLUID COLLECTION
  • LUNG- INTRAPULMONARY SHUNTING
OTHERS
  • VENOUS THROMBOSES


MANAGEMENT: It is important to mention here that because of rarity of TEMPI syndrome, most patients are treated empirically for Polycythemia Vera with phlebotomy, which ultimately leads to Iron deficiency anemia.


  • Proteasome Inhibitors- example- Bortezomib (8 cycles, 4 doses of 1.3 mg/m2BSA/cycle) was tried in one of the patients with TEMPI syndrome showed marked improvement in clinical presentations- with resolution of telangiectasias, improvement in intrapulmonary shunting and perinephric fat, normalization of erythropoietin levels as well. Drastic response with use of bortezomib indicates the pathophysiological role of IgG κ paraproteins in development of TEMPI syndrome.
  • No improvement was seen when other immunomodulators were used such as- Thalidomide, anti-VEGF (Bevacizumab) and immunosuppressants- Sirolimus.[9]

Familial Forms


Other Information

Differential Diagnosis of TEMPI Syndrome[12]

  • Polycythemia Vera- TEMPI syndrome's patients and PV patients both have increased RBC concentration. PV have + JAK2 V617F contrary to TEMPI syndrome which is negative for the JAK2 V617F.
  • POEMS syndrome- EPO levels are decreased in POEMS syndrome along with constellation of clinical features which are different from TEMPI syndrome. POEMS Syndrome
  • Multiple myeloma- Monoclonal plasma cells concentration in BM are much higher in MM (>10%) compared to TEMPI syndrome along with absence of CRAB(hypercalcemia, renal insufficiency, anemia, bony lesions) features in TEMPI syndrome.
  • Schnitzler syndrome- This disorder is characterized by urticarial eruptions and neutrophilic urticarial dermatoses. Also, Plasma cells concentration in Bm aspirate is restricted to <5%.
  • Generalized essential telangiectasia

Links

Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome

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References

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  1. 1.0 1.1 RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Clinical Signs and Symptoms".
  2. 2.0 2.1 2.2 2.3 Sykes, David B.; et al. (2020-04-09). "The TEMPI syndrome". Blood. 135 (15): 1199–1203. doi:10.1182/blood.2019004216. ISSN 0006-4971.
  3. Mohammadi, F.; et al. (2012-11-01). "A new case of TEMPI syndrome". Clinical Kidney Journal. 5 (6): 556–558. doi:10.1093/ckj/sfs139. ISSN 2048-8505. PMC 4400562. PMID 26069800.CS1 maint: PMC format (link)
  4. Viglietti, D.; et al. (2011-08-02). "Perirenal fluid collections and monoclonal gammopathy". Nephrology Dialysis Transplantation. 27 (1): 448–449. doi:10.1093/ndt/gfr433. ISSN 0931-0509.
  5. Khan, Javed; et al. (2014-07-22). "Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting". BMC Hematology. 14 (1): 11. doi:10.1186/2052-1839-14-11. ISSN 2052-1839.
  6. Oljira, Robera; et al. (2020-10). "TEMPI SYNDROME: DISEASE PROGRESSION AND RESPONSE TO TREATMENT". Chest. 158 (4): A2046. doi:10.1016/j.chest.2020.08.1772. ISSN 0012-3692. Check date values in: |date= (help)
  7. Sykes, David B.; et al. (2011-08-04). "The TEMPI syndrome--a novel multisystem disease". The New England Journal of Medicine. 365 (5): 475–477. doi:10.1056/NEJMc1106670. ISSN 1533-4406. PMID 21812700.
  8. 8.0 8.1 Rosado, Flavia G; et al. (2014-09-12). "Bone marrow findings of the newly described TEMPI syndrome: when erythrocytosis and plasma cell dyscrasia coexist". Modern Pathology. 28 (3): 367–372. doi:10.1038/modpathol.2014.117. ISSN 0893-3952.
  9. 9.0 9.1 9.2 Sykes, David Brian; et al. (2011). "The TEMPI Syndrome — A Novel Multisystem Disease". New England Journal of Medicine. doi:10.1056/NEJMc1106670. ISSN 0028-4793.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 Sun, Chunyan; et al. (2021-06-22). "Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome". Blood Advances. 5 (12): 2563–2568. doi:10.1182/bloodadvances.2020003783. ISSN 2473-9537. PMC 8270661 Check |pmc= value (help). PMID 34129019 Check |pmid= value (help).
  11. Oda, Seiko; et al. (2008-05-21). "Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner". PLoS ONE. 3 (5). doi:10.1371/journal.pone.0002215. ISSN 1932-6203. PMC 2375051. PMID 18493321.
  12. "VisualDx Cookie Check".

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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