Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Sohini Anand, MBBS TOC ==Cancer Category/Type== Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome ==Cancer S..."

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Created page with "{{Under Construction}} ==Primary Author(s)*== Sohini Anand, MBBS __TOC__ ==Cancer Category/Type== Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome ==Cancer S..."

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{{Under Construction}}
==Primary Author(s)*==

Sohini Anand, MBBS

__TOC__

==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 '''T'''elangiectasias, '''E'''rythropoiesis and elevated erythropoietin levels, '''M'''onoclonal gammopathy, '''P'''erinephric fluid collection and '''I'''ntrapulmonary shunting.<ref name=":1">{{Cite journal|last=RESERVED|first=INSERM US14-- ALL RIGHTS|title=Orphanet: Clinical Signs and Symptoms|url=https://www.orpha.net/consor/cgi-bin/Disease_HPOTerms.php?lng=EN&data_id=20584&Disease_Disease_HPOTerms_diseaseGroup=TEMPI&Disease_Disease_HPOTerms_disease|language=en}}</ref>

==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<ref name=":0">{{Cite journal|last=Sykes|first=David B.|last2=O’Connell|first2=Casey|last3=Schroyens|first3=Wilfried|date=2020-04-09|title=The TEMPI syndrome|url=https://doi.org/10.1182/blood.2019004216|journal=Blood|volume=135|issue=15|pages=1199–1203|doi=10.1182/blood.2019004216|issn=0006-4971}}</ref>. Only 22<ref name=":0" /> 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<ref>{{Cite journal|last=Mohammadi|first=F.|last2=Wolverson|first2=M. K.|last3=Bastani|first3=B.|date=2012-11-01|title=A new case of TEMPI syndrome|url=https://doi.org/10.1093/ckj/sfs139|journal=Clinical Kidney Journal|volume=5|issue=6|pages=556–558|doi=10.1093/ckj/sfs139|issn=2048-8505|pmc=PMC4400562|pmid=26069800}}</ref> and chronic renal insufficiency.<ref>{{Cite journal|last=Viglietti|first=D.|last2=Sverzut|first2=J.-M.|last3=Peraldi|first3=M.-N.|date=2011-08-02|title=Perirenal fluid collections and monoclonal gammopathy|url=https://doi.org/10.1093/ndt/gfr433|journal=Nephrology Dialysis Transplantation|volume=27|issue=1|pages=448–449|doi=10.1093/ndt/gfr433|issn=0931-0509}}</ref>

'''Skin manifestations'''- Telangiectasias can lead to "web like appearance" of skin. "Red facies" because of increased RBCs<ref name=":1" />. Clubbing of fingernails<ref>{{Cite journal|last=Khan|first=Javed|last2=Sykes|first2=David B.|date=2014-07-22|title=Case report: a 37-year-old male with telangiectasias, polycythemia vera, perinephric fluid collections, and intrapulmonary shunting|url=https://doi.org/10.1186/2052-1839-14-11|journal=BMC Hematology|volume=14|issue=1|pages=11|doi=10.1186/2052-1839-14-11|issn=2052-1839}}</ref>

'''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.<ref>{{Cite journal|last=Oljira|first=Robera|last2=Liang|first2=Brannen|date=2020-10|title=TEMPI SYNDROME: DISEASE PROGRESSION AND RESPONSE TO TREATMENT|url=https://doi.org/10.1016/j.chest.2020.08.1772|journal=Chest|volume=158|issue=4|pages=A2046|doi=10.1016/j.chest.2020.08.1772|issn=0012-3692}}</ref>

'''Thrombosis and intracranial bleeding-''' Spontaneous bleeding has been reported in some patients in absence of new blood vessel formations.<ref>{{Cite journal|last=Sykes|first=David B.|last2=Schroyens|first2=Wilfried|last3=O'Connell|first3=Casey|date=2011-08-04|title=The TEMPI syndrome--a novel multisystem disease|url=https://pubmed.ncbi.nlm.nih.gov/21812700/|journal=The New England Journal of Medicine|volume=365|issue=5|pages=475–477|doi=10.1056/NEJMc1106670|issn=1533-4406|pmid=21812700}}</ref>

==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.<ref name=":2">{{Cite journal|last=Rosado|first=Flavia G|last2=Oliveira|first2=Jennifer L|last3=Sohani|first3=Aliya R|last4=Schroyens|first4=Wilfried|last5=Sykes|first5=David B|last6=Kenderian|first6=Saad S|last7=Lacy|first7=Martha Q|last8=Kyle|first8=Robert A|last9=Hoyer|first9=James D|date=2014-09-12|title=Bone marrow findings of the newly described TEMPI syndrome: when erythrocytosis and plasma cell dyscrasia coexist|url=http://dx.doi.org/10.1038/modpathol.2014.117|journal=Modern Pathology|volume=28|issue=3|pages=367–372|doi=10.1038/modpathol.2014.117|issn=0893-3952}}</ref> 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.<ref name=":2" />

'''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.<ref name=":4">{{Cite journal|last=Sykes|first=David Brian|last2=Schroyens|first2=Wilfried|last3=O'Connell|first3=Casey|date=2011|title=The TEMPI Syndrome — A Novel Multisystem Disease|url=https://dash.harvard.edu/handle/1/37140304|journal=New England Journal of Medicine|language=en-US|doi=10.1056/NEJMc1106670|issn=0028-4793}}</ref>

'''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.<ref name=":0" />
{| class="wikitable"
|+PERINEPHRIC FLUID ANALYSIS
!clear, serous<ref name=":4" /> 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'''<ref name=":3" />

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

'''NEGATIVE'''<ref name=":3" />

*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:
{| class="wikitable sortable"
|-
!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)
|
|
|
|-
|
|
|
|
|-
|
|
|
|
|}

==<ref name=":3" />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<ref name=":3" /> 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

{| class="wikitable sortable"
|-
!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.<ref name=":3">{{Cite journal|last=Sun|first=Chunyan|last2=Xu|first2=Jian|last3=Zhang|first3=Bo|last4=Huang|first4=Haifan|last5=Chen|first5=Lei|last6=Yan|first6=Han|last7=Xu|first7=Aoshuang|last8=Zhao|first8=Fei|last9=Huang|first9=Daijuan|date=2021-06-22|title=Whole-genome sequencing suggests a role of MIF in the pathophysiology of TEMPI syndrome|url=https://pubmed.ncbi.nlm.nih.gov/34129019|journal=Blood Advances|volume=5|issue=12|pages=2563–2568|doi=10.1182/bloodadvances.2020003783|issn=2473-9537|pmc=8270661|pmid=34129019}}</ref>
{| class="wikitable sortable"
|-
!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
|}
{| class="wikitable"
|+
!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.
{| class="wikitable"
|+
!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.<ref name=":3" />

'''MIF Function-''' MIF is a proinflammatory cytokine which can act as an intracellular signaling molecule as well<ref>{{Cite journal|last=Oda|first=Seiko|last2=Oda|first2=Tomoyuki|last3=Nishi|first3=Kenichiro|last4=Takabuchi|first4=Satoshi|last5=Wakamatsu|first5=Takuhiko|last6=Tanaka|first6=Tomoharu|last7=Adachi|first7=Takehiko|last8=Fukuda|first8=Kazuhiko|last9=Semenza|first9=Gregg L.|date=2008-05-21|title=Macrophage Migration Inhibitory Factor Activates Hypoxia-Inducible Factor in a p53-Dependent Manner|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375051/|journal=PLoS ONE|volume=3|issue=5|doi=10.1371/journal.pone.0002215|issn=1932-6203|pmc=2375051|pmid=18493321}}</ref>. 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.
{| class="wikitable"
|+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==

 
{| class="wikitable"
|+Diagnostic criteria for TEMPI syndrome<ref name=":0" />
!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.<ref name=":4" /> 

==Familial Forms==

 

==Other Information==

'''Differential Diagnosis of TEMPI Syndrome'''<ref>{{Cite journal|title=VisualDx Cookie Check|url=https://www.visualdx.com/visualdx/diagnosis/tempi+syndrome?diagnosisId=56288&moduleId=101}}</ref>

*'''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- M'''onoclonal plasma cells concentration in BM are much higher in MM (>10%) compared to TEMPI syndrome along with absence of CRAB(hyper'''c'''alcemia, '''r'''enal insufficiency, '''a'''nemia, '''b'''ony 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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<references />
===EXAMPLE Book===

#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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HAEM4Backup:TEMPI Syndrome - Revision history

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Sohini Anand, MBBS __TOC__ ==Cancer Category/Type== Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome ==Cancer S..."

Bailey.Glen: Created page with "{{Under Construction}} ==Primary Author(s)*== Sohini Anand, MBBS TOC ==Cancer Category/Type== Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome ==Cancer S..."