HAEM5:Plasma cell neoplasms with associated paraneoplastic syndrome: Difference between revisions

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 {{DISPLAYTITLE:Plasma cell neoplasms with associated paraneoplastic syndrome}}
 [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
 {{Under Construction}}
-<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:POEMS Syndrome]].
+<blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:POEMS Syndrome]].
 Other relevent pages include: [[HAEM4:TEMPI Syndrome]]
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-==Definition / Description of Disease==
-POEMS syndrome is a rare blood disorder which is considered to be a subtype of plasma cell neoplasm. It is a multisystem disorder and stands for '''<u>P</u>'''olyneuropathy, '''<u>O</u>'''rganomegaly, '''<u>E</u>'''ndocrinopathy/edema, '''<u>M</u>'''onoclonal-protein (increased levels in blood), and '''<u>S</u>'''kin changes. In this condition, abnormal monoclonal proteins are secreted by plasma cells leading to its clinical presentations which include nerve damage, enlargement of spleen and/or lymph nodes, endocrine involvement leading to diabetes, thyroid abnormalities and certain skin/ hair changes such as hyperpigmentation, thickening of skin, red spots and increased facial hair growth.
-==Synonyms / Terminology==
-*<ref name=":0">https://rarediseases.org/rare-diseases/poems-syndrome/</ref>Crow-Fukase syndrome
-*<ref name=":0" />Osteosclerotic myeloma
-*<ref name=":0" />PEP syndrome (Polyneuropathy-endocrinopathy-plasma cell dyscrasia syndrome)
-*<ref name=":0" />Shimpo syndrome
-*<ref name=":0" />Takatsuki syndrome<ref name=":1">{{Cite journal|last=Suichi|first=Tomoki|last2=Misawa|first2=Sonoko|last3=Beppu|first3=Minako|last4=Takahashi|first4=Sho|last5=Sekiguchi|first5=Yukari|last6=Shibuya|first6=Kazumoto|last7=Amino|first7=Hiroshi|last8=Tsuneyama|first8=Atsuko|last9=Suzuki|first9=Yo-Ichi|date=2019-09-03|title=Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey|url=https://pubmed.ncbi.nlm.nih.gov/31371568|journal=Neurology|volume=93|issue=10|pages=e975–e983|doi=10.1212/WNL.0000000000008062|issn=1526-632X|pmid=31371568}}</ref>
-==Epidemiology / Prevalence==
-Not much information can be derived regarding the incidence and prevalence of POEMS syndrome.<ref group="Epidemiology">https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2905</ref>. Some information can be derived from the study conducted in Japan in the year 2015. The result showed that the prevalence is 0.3 per 1,00,000 with a male: female ratio of 1.5:1.<ref name=":1" /> The median age of  occurrence is 54.<ref>{{Cite journal|last=Suichi|first=Tomoki|last2=Misawa|first2=Sonoko|last3=Beppu|first3=Minako|last4=Takahashi|first4=Sho|last5=Sekiguchi|first5=Yukari|last6=Shibuya|first6=Kazumoto|last7=Amino|first7=Hiroshi|last8=Tsuneyama|first8=Atsuko|last9=Suzuki|first9=Yo-Ichi|date=2019-09-03|title=Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey|url=https://pubmed.ncbi.nlm.nih.gov/31371568|journal=Neurology|volume=93|issue=10|pages=e975–e983|doi=10.1212/WNL.0000000000008062|issn=1526-632X|pmid=31371568}}</ref> However, few cases have also been seen in patients in their twenties.<ref name=":0" /> Mean survival is 13.7 years.<ref>{{Cite journal|last=Marinho|first=Flauberto Sousa|last2=Pirmez|first2=Rodrigo|last3=Nogueira|first3=Renata|last4=Cuzzi|first4=Tullia|last5=Sodré|first5=Celso Tavares|last6=Silva|first6=Marcia|date=2015|title=Cutaneous Manifestations in POEMS Syndrome: Case Report and Review|url=https://www.karger.com/Article/FullText/381302|journal=Case Reports in Dermatology|language=english|volume=7|issue=1|pages=61–69|doi=10.1159/000381302|issn=1662-6567|pmc=PMC4448059|pmid=26034475}}</ref>
-==Clinical Features==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
-{| class="wikitable"
-|'''Signs and Symptoms'''
-|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
-<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
-<span class="blue-text">EXAMPLE:</span> Fatigue
-<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
-|-
-|'''Laboratory Findings'''
-|<span class="blue-text">EXAMPLE:</span> Cytopenias
-<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}</blockquote>
-As mentioned earlier, POEMS syndrome is a rare disorder which comprises of constellation of clinical presentations with neuropathy present in almost 100% of the cases. Following are the clinical features:
-*'''<u>Polyneuropathy</u>:''' One of the earliest presentations or may be the only presentation. The onset is usually sub-acute with mixed (sensory-motor) distal & symmetrical involvement. This is often associated with abnormal sensations like allodynia. Sensory involvement precedes motor loss. Most patients need assistance soon after developing polyneuropathy either because of  loss of function or pain.<ref name=":2">{{Cite journal|last=Brown|first=Rachel|last2=Ginsberg|first2=Lionel|date=2019|title=POEMS syndrome: clinical update|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342878/|journal=Journal of Neurology|volume=266|issue=1|pages=268–277|doi=10.1007/s00415-018-9110-6|issn=0340-5354|pmc=6342878|pmid=30498913}}</ref>
-*'''<u>Organomegaly and Organ dysfunction:</u>'''  There are multiple organ involvement and damage leading to organ dysfunction. Most common involved organs are lymph nodes, liver, kidney and spleen. Other organs which can be affected are CNS, renal, lung which can lead to asymptomatic parenchymal thickening, decreased GFR and pulmonary HTN; respectively. <ref name=":2" /> Furthermore, arterial vascular involvement  has been noted which can lead to cerebro-vascular accidents and ischemic strokes. <ref name=":2" />
-*'''<u>Endocrinopathy:</u>''' Multiple endocrinal organs can be involved. Most common presentation noted in males are erectile dysfunction because of hypogonadism which may be because of involvement of hypothalamus, pituitary or the primary organ itself(testes).<ref>{{Cite journal|last=Dispenzieri|first=Angela|last2=Kourelis|first2=Taxiarchis|last3=Buadi|first3=Francis|date=2018-02|title=POEMS Syndrome|url=http://dx.doi.org/10.1016/j.hoc.2017.09.010|journal=Hematology/Oncology Clinics of North America|volume=32|issue=1|pages=119–139|doi=10.1016/j.hoc.2017.09.010|issn=0889-8588}}</ref>  Other presentations can be diabetes, hypo/hyperthyroidism or adrenal gland abnormalities.
-*'''<u>Monoclonal antibodies</u>''': POEMS syndrome is typically considered to be a plasma cell abnormality where plasma cells produce excessively high paraproteins particularly light chains (lambda proteins mainly of IgA type). The unique feature of POEMS which distinguish this condition from rest of the gammopathies is that- it is found that in approximately 50% of the pre-treatment specimens have reactive lymphoid aggregates which  contain a mixture of both B and T cells with a thin rim of plasma cells. Other consistent finding are atypically appearing megakaryocytes with hyperplasia. Increased platelets counts are seen in 54% of the cases.<ref name=":4">{{Cite journal|last=Dispenzieri|first=Angela|date=2019|title=POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25495|journal=American Journal of Hematology|language=en|volume=94|issue=7|pages=812–827|doi=10.1002/ajh.25495|issn=1096-8652}}</ref>  PBS is usually normal. <ref name=":2" />
-*'''<u>Skin involvement:</u>''' About 68% patients diagnosed with POEMS syndrome present with skin involvement. Most common is diffuse hyperpigmentation(purplish hue), acrocyanosis, calciphylaxis, thickening of skin, papular lesions, excessive sweating; aka; hyperhidrosis. Areas most commonly involved are extensor surfaces, neck,  arm pit. Nail changes such as leukonychia. Hypertrichosis has also been reported. In few cases, hemangiomas such as cherry and capillary hemangiomas has been noted.
-*'''<u>Other findings</u>'''- fluid accumulation in body cavities leading to peritoneal effusion, pleural effusion and ascites.
-*'''<u>Papilledema</u>'''
-*'''<u>Polycythemia</u>'''
-*'''<u>Specific finding in males</u>'''- gynecomastia and  impotence noted in male patients.
-*'''<u>Specific findings in Females</u>'''- amenorrhea and galactorrhea have been reported in female patients with POEMS syndrome
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Sites of Involvement==
-POEMS syndrome involves multiple systems of the body.
-*'''<u>Peripheral nerves and spinal cord</u>''': Peripheral neuropathy is present in 100% of the cases. This is the most common manifestation of POEMS syndrome.
-*'''<u>Reticuloendothelial system</u>'''- Lymph node, spleen and Liver are also most frequently involved. Lymph node simulates Castleman disease. Hepatosplenomegaly is present in almost 50% of the cases.
-*'''<u>Bone</u>'''- Bone is involved in 95% of the POEMS patient. Bone lesions are mostly sclerotic, but occasionally can be lytic lesions surrounded by thin rim of sclerosis. "Soap bubble" appearances have also been reported.<ref>{{Cite journal|title=POEMS Syndrome - an overview {{!}} ScienceDirect Topics|url=https://www.sciencedirect.com/topics/medicine-and-dentistry/poems-syndrome}}</ref>
-*'''<u>Skin</u>'''- About 90% of the POEMS patients develop skin changes. Most commonly being skin pigmentations.
-*'''<u>Kidney-</u>''' Kidney damage has been reported which can alter GFR and can lead to CKD.
-*<u>'''Pancreas-'''</u>  Diabetes type2 has been noted.<ref name=":3">{{Cite journal|title=POEMS Syndrome - Hormonal and Metabolic Disorders|url=https://www.merckmanuals.com/home/hormonal-and-metabolic-disorders/polyglandular-deficiency-syndromes/poems-syndrome|language=en-US}}</ref>
-*'''<u>Adrenal gland-</u>''' Involvement of adrenal glands cause malfunctioning leading to Addison's disease.<ref name=":3" />
-*'''<u>Gonads</u>'''- decreased level of testosterone can lead to hypo functioning of male gonads eventually leading to hypogonadism.<ref name=":3" />
-*'''<u>Thyroids</u>'''
-*'''<u>Eye</u>'''
-==Morphologic Features==
-*'''<u>Bone marrow Findings</u>'''- Increased monoclonal plasma cells interspersed between polyclonal plasma cells with majority of monoclonal cells resembling λ chains. Plasma cell rimming around lymphoid aggregates. Also, Platelet precursors or megakaryocytes hyperplasia have been reported. <ref>{{Cite journal|last=Dao|first=Linda N.|last2=Hanson|first2=Curtis A.|last3=Dispenzieri|first3=Angela|last4=Morice|first4=William G.|last5=Kurtin|first5=Paul J.|last6=Hoyer|first6=James D.|date=2011-06-16|title=Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients|url=https://pubmed.ncbi.nlm.nih.gov/21385854|journal=Blood|volume=117|issue=24|pages=6438–6444|doi=10.1182/blood-2010-11-316935|issn=1528-0020|pmc=3123015|pmid=21385854}}</ref>
-*'''<u>Nerve fiber biopsies</u>'''- POEMS syndrome has predilection for peripheral nerves compared to autonomic nerve fibers. The manifestation is severe and progressive. Biopsy specimens have shown 2 specific findings including axonal degeneration and epineural blood vessels formation which can be helpful in differentiating from C IDP(Chronic Inflammatory Demyelinating Polyradiculoneuropathy). CIDP presents as endoneurial inflammation and characteristic "onion bulb appearance".<ref>{{Cite journal|last=Piccione|first=Ezequiel A.|last2=Engelstad|first2=Janean|last3=Dyck|first3=Peter J.|last4=Mauermann|first4=Michelle L.|last5=Dispenzieri|first5=Angela|last6=Dyck|first6=P. James B.|date=2016-10-31|title=Nerve pathologic features differentiate POEMS syndrome from CIDP|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088652/|journal=Acta Neuropathologica Communications|volume=4|doi=10.1186/s40478-016-0389-1|issn=2051-5960|pmc=5088652|pmid=27799073}}</ref>
-*'''<u>Skin Biopsies</u>'''-   Cases who developed hemangioma, biopsy showed "glomeruloid pattern"; accumulation of blood vessels containing RBCs in dilated vascular space resembling renal glomeruli. Patients who presented with skin thickening showed sclerosis with dilation of blood vessels on biopsy. Livedo reticularis biopsies showed thrombosis with necrosis in arterioles.<ref>{{Cite journal|last=Barete|first=Stéphane|last2=Mouawad|first2=Roger|last3=Choquet|first3=Sylvain|last4=Viala|first4=Karine|last5=Leblond|first5=Véronique|last6=Musset|first6=Lucile|last7=Amoura|first7=Zahir|last8=Khayat|first8=David|last9=Francès|first9=Camille|date=2010-06-01|title=Skin Manifestations and Vascular Endothelial Growth Factor Levels in POEMS Syndrome: Impact of Autologous Hematopoietic Stem Cell Transplantation|url=http://archderm.jamanetwork.com/article.aspx?doi=10.1001/archdermatol.2010.100|journal=Archives of Dermatology|language=en|volume=146|issue=6|doi=10.1001/archdermatol.2010.100|issn=0003-987X}}</ref>
-*'''<u>Bone lesions biopsy</u>''':    Osteosclerotic bone lesions biopsy shows proliferation of plasma cells which stain positive for CD138.<ref>{{Cite journal|last=Hara|first=Daisuke|last2=Akiyama|first2=Hisanao|last3=Nukui|first3=Saki|last4=Shimizu|first4=Takahiro|last5=Hoshikawa|first5=Masahiro|last6=Hasegawa|first6=Yasuhiro|date=2017-10|title=Utility of osteosclerotic lesion biopsy in diagnosis of POEMS syndrome: A case report|url=https://pubmed.ncbi.nlm.nih.gov/29019884|journal=Medicine|volume=96|issue=41|pages=e8188|doi=10.1097/MD.0000000000008188|issn=1536-5964|pmc=5662307|pmid=29019884}}</ref>
-==Immunophenotype==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
-{| class="wikitable sortable"
-|-
-!Finding!!Marker
-|-
-|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
-|-
-|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
-|-
-|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
-|-
-|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Immunophenotype|The content below was from the old template. Please incorporate above.}}</blockquote>
-Plasma cells in BM biopsy ranges from<5% to 60%. 95% of the cases have value <5%.<ref name=":6">{{Cite journal|last=Dispenzieri|first=Angela|date=2012-06-14|title=How I treat POEMS syndrome|url=https://doi.org/10.1182/blood-2012-03-378992|journal=Blood|volume=119|issue=24|pages=5650–5658|doi=10.1182/blood-2012-03-378992|issn=0006-4971|pmc=PMC3425020|pmid=22547581}}</ref>  Usually there are a combination of normal polyclonal plasma cells and monoclonal plasma cells. The monoclonal plasma cells stains positive for λ chains (IgA and IgG). <ref>{{Cite journal|last=Dao|first=Linda N.|last2=Hanson|first2=Curtis A.|last3=Dispenzieri|first3=Angela|last4=Morice|first4=William G.|last5=Kurtin|first5=Paul J.|last6=Hoyer|first6=James D.|date=2011-06-16|title=Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients|url=https://doi.org/10.1182/blood-2010-11-316935|journal=Blood|volume=117|issue=24|pages=6438–6444|doi=10.1182/blood-2010-11-316935|issn=0006-4971|pmc=PMC3123015|pmid=21385854}}</ref>
-'''<u>POSITIVE</u>'''
-*CD138+ forms plasma cell rim around lymphoid aggregates
-*CD38+ rim around lymphoid aggregates
-*monoclonal Plasma cells stains positive for cytoplasmic λ chain immunoglobulins.
-*Bright expression of CD45 and normal expression of CD19 in polytypic CD19 (Normal finding).
-*Lymphoid aggregates were staining positive for CD20+ B cells and CD3+ T cells.
-'''<u>NEGATIVE</u>'''
-*Diminished expression of CD45 and loss of CD19 in monotypic plasma cells. (findings in POEMS).
-*κ chain immunoglobulin stain absent.
-*''JAK2<sup>V617F</sup>''  mutation absent
-*HHV8 staining absent
-<br />
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
 ==WHO Essential and Desirable Genetic Diagnostic Criteria==
 <span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
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-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
+<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
 * Chromosomal Rearrangements (Gene Fusions)
 * Individual Region Genomic Gain/Loss/LOH
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 Diagnosis of POEMS syndrome requires meticulous search for clinical features and testing because of clinical simulation with other common conditions. Being one of the rare disease entities it can easily be missed by clinicians.
-'''<u>MANAGEMENT</u>'''<ref name=":4" />
+'''<u>MANAGEMENT</u>'''<ref name=":4">{{Cite journal|last=Dispenzieri|first=Angela|date=2019|title=POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25495|journal=American Journal of Hematology|language=en|volume=94|issue=7|pages=812–827|doi=10.1002/ajh.25495|issn=1096-8652}}</ref>
 Management of POEMS syndrome requires multiple steps.
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 A study conducted at Peking Union Medical college Hospital from November 2011 to June 2012 showed the following chromosomal abnormalities associated with POEMS syndrome.<ref>{{Cite journal|last=Kang|first=Wen-Ying|last2=Shen|first2=Kai-Ni|last3=Duan|first3=Ming-Hui|last4=Zhang|first4=Wei|last5=Cao|first5=Xin-Xin|last6=Zhou|first6=Dao-Bin|last7=Li|first7=Jian|date=2013-12|title=14q32 translocations and 13q14 deletions are common cytogenetic abnormalities in POEMS syndrome|url=https://onlinelibrary.wiley.com/doi/10.1111/ejh.12189|journal=European Journal of Haematology|language=en|volume=91|issue=6|pages=490–496|doi=10.1111/ejh.12189}}</ref>. In this study, BM plasma cells CD138+ were collected using MACS system and then FISH technique was applied.
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 |}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
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 A study was conducted in 20 patients of POEMS syndrome. The study showed 7  gene shaving recurrent somatic gene mutations involved in POEMS syndrome.  It is important to know that none of the important gene mutations involved in MM such as NRAS, KRAS, BRAF, and TP53 were found in POEMS syndrome patients.<ref>{{Cite journal|last=Nagao|first=Yuhei|last2=Mimura|first2=Naoya|last3=Takeda|first3=June|last4=Yoshida|first4=Kenichi|last5=Shiozawa|first5=Yusuke|last6=Oshima|first6=Motohiko|last7=Aoyama|first7=Kazumasa|last8=Saraya|first8=Atsunori|last9=Koide|first9=Shuhei|date=2019-07|title=Genetic and transcriptional landscape of plasma cells in POEMS syndrome|url=https://www.nature.com/articles/s41375-018-0348-x|journal=Leukemia|language=en|volume=33|issue=7|pages=1723–1735|doi=10.1038/s41375-018-0348-x|issn=1476-5551}}</ref> [[HAEM4:Plasma Cell Neoplasms]]
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 '''<u>PATHOGENESIS OF POEMS SYNDROME</u>'''
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 *'''<u>Pro-inflammatory markers</u>''' concentrations are increased leading to wide spread inflammation. Some of them are- TNF- α (Tumor Necrotic Factor), IFN-γ ( Interferon γ), IL-1β, IL-2, IL-6 (Interleukins). The cause of increased levels of cytokines are not known, but it has been hypothesized that cytokines are secreted because of stimulation by λ IGs secreted by plasma cells or by the tumor itself.
 *'''<u>Decreased</u>''' level of '''<u>anti-inflammatory cytokines</u>-'''  A decreased level of TGF-β (Transforming Growth Factor β) may lead to imbalance between the pro and anti inflammatory factors resulting in disastrous clinical representation.
-*Role of '''<u>VEGF</u>'''- Again, it is being hypothesized that VEGF (Vascular Endothelial Growth Factor) may lead to neovascularization leading to proliferation of small  blood vessels. It is important to note that disease activity correlates with VEGF levels even more than M proteins.<ref name=":6" />
+*Role of '''<u>VEGF</u>'''- Again, it is being hypothesized that VEGF (Vascular Endothelial Growth Factor) may lead to neovascularization leading to proliferation of small  blood vessels. It is important to note that disease activity correlates with VEGF levels even more than M proteins.<ref name=":6">{{Cite journal|last=Dispenzieri|first=Angela|date=2012-06-14|title=How I treat POEMS syndrome|url=https://doi.org/10.1182/blood-2012-03-378992|journal=Blood|volume=119|issue=24|pages=5650–5658|doi=10.1182/blood-2012-03-378992|issn=0006-4971|pmc=PMC3425020|pmid=22547581}}</ref>
 *'''<u>λ Immunoglobulins</u>'''
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 (use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
-'''
+<br />
 ==Notes==
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 <nowiki>*</nowiki>''Citation of this Page'': “Plasma cell neoplasms with associated paraneoplastic syndrome”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Plasma_cell_neoplasms_with_associated_paraneoplastic_syndrome</nowiki>.
-[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases P]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases P]]