Primary myelofibrosis Definition Primary myelofibrosis is a distinct clonal myeloproliferative neoplasm (MPN) characterized by a proliferation of abnormal megakaryocytes and granulocytes in the bone marrow, which in fibrotic stages is associated with a polyclonal increase in fibroblasts that drive a secondary marrow fibrosis (reticulin fibrosis and/or collagen fibrosis), osteosclerosis, and extramedullary haematopoiesis. ICD-O coding 9961/3 Primary myelofibrosis 9961/3 Primary myelofibrosis, prefibrotic* 9961/3 Primary myelofibrosis, fibrotic* ICD-11 coding 2A20.2 Primary myelofibrosis Related terminology Not recommended: Primary myelofibrosis, overt fibrotic stage; chronic idiopathic myelofibrosis; myelofibrosis/?sclerosis with myeloid metaplasia; agnogenic myeloid metaplasia; megakaryocytic myelosclerosis; idiopathic myelofibrosis; myelofibrosis with myeloid metaplasia; osteomyelofibrosis; osteomyelosclerosis Subtype(s) Primary myelofibrosis, prefibrotic Primary myelofibrosis, fibrotic Localization The blood and bone marrow are always involved. In the later stages of the disease, extramedullary haematopoiesis (also known as myeloid metaplasia) becomes prominent, particularly in the spleen { 14871248 }, which harbours neoplastic stem cells { 23023702 }. In the initial stages, the number of randomly distributed CD34+ progenitors is slightly increased in the bone marrow, but not in the peripheral blood. The frequency of bone marrow CD34+ cells is inversely related to the number of circulating CD34+ cells { 15899773 ; 16019508 }; only in the later stages do they appear in large numbers in the peripheral blood. This increase in the number of circulating CD34+ cells is a phenomenon largely restricted to PMF, fibrotic stage; it is not seen in non-fibrotic polycythaemia vera or essential thrombocythaemia { 12071933 ; 11719361 ; 14555308 }. It has been postulated that extramedullary haematopoiesis is a consequence of the unique ability of the spleen to sequester the numerous circulating CD34+ cells { 11907788 ; 23023702 }. Other possible sites of extramedullary haematopoiesis are the liver, lymph nodes, kidneys, adrenal glands, duramater, gastrointestinal tract, lungs and pleura, breasts, skin, and soft tissue { 25124313 }. 血液と骨髄は常に関与している。疾患の後期には、髄外造血（骨髄異形成としても知られる）が顕著になり、特に脾臓{ 14871248 }では腫瘍性幹細胞{ 23023702 }が存在する。初期段階では、ランダムに分布するCD34+前駆細胞の数は骨髄でわずかに増加するが、末梢血では増加しない。骨髄CD34+細胞の頻度は、循環CD34+細胞数{ 15899773 ; 16019508 }と反比例の関係にあり、末梢血にCD34+細胞が大量に出現するのは後期段階になってからである。この循環CD34+細胞数の増加は、主に線維化期のPMFに限定される現象であり、非線維化期の真性多血症や本態性血小板血症では見られない{ 12071933 ; 11719361 ; 14555308 }。髄外造血は、循環している多数のCD34+細胞を隔離する脾臓のユニークな能力の結果であると仮定されている{ 11907788 ; 23023702 }。その他の髄外造血部位としては、肝臓、リンパ節、腎臓、副腎、十二指腸、消化管、肺と胸膜、乳房、皮膚、軟部組織などが考えられる{ 25124313 }。 Clinical features PMF is a more aggressive condition than ET, PV, or pre-MF. It is progressive and profoundly affects the quality of life for affected patients. Those patients with ET, PV, or pre-MF are at risk of transformation to myelofibrosis where it may be known as post-ET-MF, post-PV-MF etc. Analogous to the concept of clonal evolution in CML, it seems likely that PMF represents the presentation in the advanced phase of a previously undiagnosed MPN. Consistent with this concept, patients with PMF harbour more mutations, have more cytogenetic abnormalities, and display an increased risk of leukaemic transformation { 30304655 ; 28778261 ; 28351937 }. Up to a third of patients are asymptomatic at diagnosis and many of these are discovered after unrelated blood tests show modest abnormalities, such as anaemia and thrombocytopenia. Splenomegaly is common, progressive, and often massive { 28351937 }. The spleen is the commonest site of extramedullary haemopoiesis in PMF. The liver is also usually involved and this can lead to significant hepatomegaly. Unusual sites can sometimes be affected, leading to haemopoietic tumours surrounded by a capsule of connective tissue. Such sites include lymph nodes, central nervous system, skin, pericardium, peritoneum, pleura, ovaries, kidneys, adrenals, gastrointestinal tract, and lungs. PMFは、ET、PV、pre-MFよりも進行性の疾患である。PMF は進行性で、罹患患者の QOL に重大な影響を及ぼす。ET、PV、pre-MFの患者は、骨髄線維症に移行する危険性があり、post-ET-MF、post-PV-MFなどと呼ばれます。CMLにおけるクローン進化の概念と同様に、PMFは未診断のMPNが進行した段階で発症する可能性が高い。この概念と一致して、PMF患者はより多くの変異を保有し、より多くの細胞遺伝学的異常を有し、白血病転化のリスクが高い{ 30304655 ; 28778261 ; 28351937 }。 患者の3分の1までは診断時に無症状であり、その多くは、無関係な血液検査で貧血や血小板減少などのわずかな異常が認められた後に発見される。脾腫はよくみられ、進行性で、しばしば巨大である{ 28351937 }。 脾臓はPMFで最もよくみられる髄外造血の部位である。肝臓も通常侵され、肝腫大を起こすことがある。通常とは異なる部位が侵されることもあり、結合組織の被膜に囲まれた造血器腫瘍が生じる。そのような部位には、リンパ節、中枢神経系、皮膚、心膜、腹膜、胸膜、卵巣、腎臓、副腎、消化管および肺が含まれる。 A hypermetabolic state presenting with fevers, anorexia, weight loss, and night sweats develops in many cases of PMF, sometimes early on in the disease. Other symptoms are often present in particular fatigue, bone pain and spleen-related symptoms such as pain and early satiety. The presence of specific symptoms, such as weight loss, night sweats and fever are prognostically significant. It is generally recommended that symptoms should be assessed using a specific score such as the MPN-symptom assessment form (MPN-SAF) or MPN-10 { 23071245 ; 33483290 }. Thrombosis and haemorrhage are prevalent in patients with PMF and pre-PMF in common with MPN in general { 33641861 }. Anaemia is frequent especially in more advanced stages and often coincides with thrombocytopenia { 28419426 }. Leukaemic transformation occurs in 20-25% of patients and is characterized by the persistent presence of 20% blasts in blood or bone marrow { 23071245 }. Pre-fibrotic PMF is viewed by some as inevitably a precursor of PMF. However, this may not be the case. Clinically, the condition requires careful review to distinguish it from ET and PV (Table #30702) and management has not been well-defined as yet. Guglielmeli and colleagues reported that patients with prePMF, compared with PMF, were younger, less anaemic, leukopenic and thrombocytopenic, had a smaller spleen, and were mainly in lower IPSS risk categories (74.8% in pre-PMF vs 51.9% in PMF) { 28351937 }. Pre-fibrotic myelofibrosis is a subtype of primary myelofibrosis characterized by a hypercellular bone marrow and minimal to absent reticulin fibrosis (grades 0 or 1) and a more latent disease course. Overt PMF is characterized by a hypercellular marrow with myelofibrosis (grade 2 or 3) with significant leukoerythroblastosis, anaemia, significant splenomegaly and/or hepatomegaly. 発熱、食欲不振、体重減少、寝汗を伴う代謝亢進状態がPMFの多くの症例で発症し、時には発症初期に見られることもある。その他の症状として、特に疲労、骨痛、痛みや早期満腹感などの脾臓に関連した症状がしばしばみられる。体重減少、寝汗、発熱などの特異的な症状の存在は予後的に重要である。一般的に、MPN-症状評価フォーム（MPN-SAF）やMPN-10{ 23071245 ; 33483290 }のような特定のスコアを用いて症状を評価することが推奨されている。 血栓症や出血は、一般的なMPNと同様に、PMF患者やその予備軍に多くみられます{ 33641861 }。貧血は、特に進行期で頻度が高く、しばしば血小板減少を伴う。白血病化は患者の20-25%にみられ、血液中または骨髄中に20%の芽球が持続的に存在することが特徴である{ 23071245 }。 前線維化型PMFは、必然的にPMFの前駆症状であると考える人もいる。しかし、そうではないかもしれない。臨床的には、この病態はETやPVと区別するために慎重な検討が必要であり（表#30702）、管理はまだ十分に定義されていない。Guglielmeliらの報告によると、PMFと比較してpre-PMFの患者は、若く、貧血、白血球減少、血小板減少が少なく、脾臓が小さく、主にIPSSリスクカテゴリーが低かった（pre-PMFでは74.8％、PMFでは51.9％）{ 28351937 }。 前線維化型骨髄線維症は、原発性骨髄線維症の亜型であり、骨髄が高細胞化し、レチクリン線維症がほとんどないか、ない（グレード0または1）ことが特徴であり、より潜伏性の疾患経過をとる。顕性PMFは、著しい白血球増加、貧血、著しい脾腫および/または肝腫大を伴う骨髄線維症（グレード2または3）を伴う高細胞性骨髄を特徴とする。 The diagnostic criteria for PMF-prefibrotic (pre-PMF) and PMF-fibrotic are summarized in -Tables #36104, #36106 and <<30702>> { 26832847 ; 27069254 ; 29426921 }.PMF-prefibrotic（pre-PMF）とPMF-fibroticの診断基準は表番号36104、36106、<<30702>> { 26832847 ; 27069254 ; 29426921 }に要約されている。 Epidemiology The estimated annual incidence of PMF, fibrotic stage is 0.44 ? 1.5 cases per 100,000 person-years { 23768070 ; 24372927 ; 25124313 ; 24971434 ; 34689695 }. Valid data on the incidence of pre-PMF are not available, but data from reference centers suggest that the pre-PMF accounts for 30?50% of all PMF cases. There are few reliable estimates of prevalence { 24372927 ; 24971434 }. The prevalence of PMF is probably increasing, due to earlier diagnosis (i.e. of pre-PMF) and prolonged survival { 22826273 }. PMF affects men and women nearly equally { 25124313 }. It occurs most commonly in the sixth to seventh decades of life, and only about 10% of overt PMF cases are diagnosed in patients aged 20% blasts qualifying the case as ‘blast’ phase, which also requires correlation with bone marrow findings. 巨視的外観 髄外造血はPMFでは腫瘍性である{ 16118625 ; 17707884 }。髄外造血の最も多い部位は脾臓で、次いで肝臓である。PMF患者が脾臓摘出術を受けることは稀であり、報告も少ない{ 16118626 ; 22388763 }。脾臓の形態学的パターンは、びまん性、結節性、混合結節性である。びまん性パターンのものは、異常浸潤が主に赤色パルプにみられる。結節性パターンのものは、結節性の膨張性 "腫瘍性 "増殖を示す。これらの増殖では、3つの造血系すべてが代表的である。びまん性パターンでは、赤血球前駆体は主に脾洞内に、顆粒球前駆体は主に脾索内に、巨核球は両方の部位に認められる。巨核球はしばしば多形であり、骨髄でみられるようなあらゆる形態学的特徴を示す。一部の症例では巨核球に富む脾結節を示すことがあり、この結節は多数の異常巨核球を有する造血細胞で構成され、周辺にレチクリン線維{ 33934231 }が網目状に存在する。20％以上の芽球を認める症例もあり、骨髄所見との相関が必要である。 Histopathology The morphologic features of PMF can vary depending on the stage of disease presentation, pre-fibrotic or fibrotic stages, which are dependent on the fibrosis grades. Since disease progression is associated with progressive accumulation of reticulin and collagen fibrosis and development of osteosclerosis, serial grading of bone marrow fibrosis using reproducible and standard criteria is necessary { 16421727 }. A semiquantitative grading system is shown in Table #30704 { 26402166 ; 16079113 }. To refine stratification in cases with higher myelofibrosis grades, grading of collagen fibrosis using trichrome stain and osteosclerosis are recommended (Tables #30705 and #30706) { 26402166 }. In addition to quantification of the degree of myelofibrosis at baseline, sequential grading of myelofibrosis is important for follow-up evaluation. Unlike cytoreductive therapies { 14636273 ; 12854892 ; 12520711 }, interferon alpha { 26271725 } and JAK1/2 inhibitors have been shown to delay progression and potentially reverse BM fibrosis as well as improve splenomegaly { 24056820 ; 29544547 ; 27211272 ; 24633869 ; 26357842 ; 27983880 }, similar to allogeneic stem cell transplantation { 17976523 ; 15899773 ; 15944939 }. Prompt reduction in BM fibrosis post-allogeneic stem cell transplant is a favourable marker of overall survival { 24589549 }. 病理組織学 PMFの形態学的特徴は、線維化前段階、線維化段階、線維化グレードによって異なる。疾患の進行は、レチクリンとコラーゲンの線維化の進行性蓄積と骨硬化症の発症に関連するので、再現性のある標準的な基準を用いた骨髄線維化の連続的な等級付けが必要である{ 16421727 }。 半定量的な分類法を表30704に示す{ 26402166 ; 16079113 }。骨髄線維症の悪性度が高い症例では、トリクローム染色による膠原線維化と骨硬化の分類が推奨される（表#30705と#30706）{ 26402166 }。ベースライン時の骨髄線維症の程度を定量化することに加え、骨髄線維症の逐次的な等級付けは、追跡評価にとって重要である。細胞還元療法{ 14636273 ; 12854892 ; 12520711 } とは異なり、インターフェロンα{ 26271725 } と JAK1/2 阻害剤は、脾腫{ 24056820 ; 29544547 ; 27211272 ; 24633869 ; 26357842 ; 27983880 } を改善するだけでなく、同種幹細胞移植{ 17976523 ; 15899773 ; 15944939 } と同様に、骨髄線維症の進行を遅らせ、逆転させる可能性があることが示されている。同種幹細胞移植後のBM線維症の速やかな減少は、全生存の好ましいマーカーである{ 24589549 }。 PMF, pre-fibrotic (pre-PMF) It is estimated that 30-50% of PMF cases are first detected in the prefibrotic/ early stage { 28351937 ; 25189724 ; 8321741 ; 15034237 ; 16202684 }, with no significant increase in reticulin and/or collagen fibers (i.e. fibrosis grades 0 and 1). The peripheral blood smear may show thrombocytosis, leukocytosis or leukoerythroblastosis { 8819080 }. A bone marrow aspirate shows a hypercellular marrow with myeloid predominance, with relatively normal myeloid and erythroid maturation. Megakaryocytes are increased in numbers and they show variation in size and in nuclear lobulation. Abnormalities in megakaryocytes are best appreciated by histological evaluation. The bone marrow core biopsy is hypercellular and the sinuses are more prominent. Sinuses are highlighted on the CD34 immunostain. Bone marrow usually shows significant myeloid predominance { 19704052 }. Myeloid maturation is not altered with sufficient numbers of mature myeloid cells present, but some cases may show a mild left-shift. There is no significant excess of blasts. On the CD34 immunostain, there may a be minimal but no significant increase in CD34-positive cells { 16019508 }. Erythroid islands may not be well-formed, but erythroid precursors do not show any dysplastic features { 16202684 ; 15034237 }. The most significant changes are seen among megakaryocytes. The megakaryocytes are increased in numbers and seen in clusters. They are frequently seen in perisinusoidal and paratrabecular locations. Megakaryocytes show marked variation in size and nuclear lobulation; larger forms are more characteristic although smaller forms are also seen. Megakaryocyte nuclei are frequently hyperchromatic and bulbous, and they show marked variability in the chromatin pattern ? variably described as “cloud-like chromatin”, or “balloon-shaped nuclei”, or “bare/naked nuclei”. Both hyperlobulated and hypolobulated forms are noted { 19844986 ; 16210032 ; 20425436 }. Megakaryocyte atypia or “dysplasia” is a component of PMF. Megakaryocyte numbers and their morphological features are best highlighted using an immunostain for either CD42b or CD61 antigens. A recent study suggested that the presence of megakaryocytic activation (M-ACT), a morphologic triad comprising megakaryocytic emperipolesis, clustering (3 or more), and peri-megakaryocytic fibrosis, was specific to as a predictor of fibrotic evolution { 33543865 }. PMF、プレフィブロティック(pre-PMF) PMFの30?50％は、レチクリンや膠原線維の有意な増加を認めない（すなわち線維化グレード0および1）、前線維化／初期段階で初めて発見されると推定される{ 28351937 ; 25189724 ; 8321741 ; 15034237 ; 16202684 }。 末梢血塗抹標本では、血小板増多、白血球増多、白血球赤芽球癆がみられる{ 8819080 }。 骨髄吸引では、骨髄優位の高細胞性骨髄を示し、骨髄および赤血球の成熟は比較的正常である。巨核球は増加し、大きさおよび核小葉の変異を示す。巨核球の異常は組織学的評価によって最もよく理解される。骨髄コア生検では細胞数が多く、洞が目立つ。洞はCD34免疫染色で強調される。骨髄は通常、骨髄性優位を示す{ 19704052 }。十分な数の成熟した骨髄系細胞が存在するため、骨髄系の成熟に変化はないが、症例によっては軽度の左シフトを示すことがある。芽球の著しい過剰は認められない。CD34免疫染色では、CD34陽性細胞の増加はわずかであるが、有意な増加はない{ 16019508 }。赤血球島は形成されていないかもしれないが、赤血球前駆体は異形成の特徴を示さない{ 16202684 ; 15034237 }。最も顕著な変化は巨核球にみられる。巨核球は増加し、集団で見られる。巨核球は類洞周囲や傍小胞に多くみられる。巨核球の大きさおよび核小葉の形成には顕著な変異があり、より大きい形態がより特徴的であるが、より小さい形態もみられる。巨核球の核はしばしば高色素性で球根状であり、クロマチンパターンに顕著な変異を示す。"雲様クロマチン"、"風船状核"、または "裸/裸核 "と表現される。高lobulated型と低lobulated型の両方が認められる{ 19844986 ; 16210032 ; 20425436 }。巨核球の異型または「異形成」はPMFの構成要素である。CD42bまたはCD61抗原に対する免疫染色を用いると、巨核球の数とその形態学的特徴が最も強調される。最近の研究では、巨核球の過分極、クラスター化（3個以上）、および巨核球周囲の線維化からなる形態学的三徴である巨核球活性化（M-ACT）の存在が、線維化進展の予測因子として特異的であることが示唆された{ 33543865 }。 PMF, fibrotic The peripheral blood smear shows anisopoikilocytosis of red blood cells, dacrocytes (tear drop forms), and leukoerythroblastosis. Majority of cases present in the fibrotic stage, where fibrosis is grades 2 or 3, and/or osteosclerosis noted in the core biopsy { 16210038 ; 26402166 ; 16079113 ; 16202685 ; 25124313 ; 28028026 }. Due to the fibrosis, the BM cellularity, which was hypercellular-for-age in the initial stages, is either normal or decreased for age. Marrow eventually gets replaced by reticulin and/or collagen fibers, connective and adipose tissue interspersed with scattered foci of residual haematopoiesis. The key morphologic feature is atypical megakaryocytic proliferation. The megakaryocytes are increased in number, often seen in tight clusters, and show abnormal paratrabecular, perisinusoidal and intrasinusoidal localization. The megakaryocytes show defects in maturation leading to abnormal nuclear: cytoplasmic ratios, dense chromatin clumping, nuclear hyperchromatism, bulbous nuclear lobes (cloud-like), and naked nuclei { 12520711 ; 16202684 }. CD61 or CD42b can help in detailing the number and topography of megakaryocytes. Staining of megakaryocytes using CAL2 immunohistochemistry can establish clonality, as it correlates with the presence of mutations of CALR, which could be particularly helpful for rapid assessment, especially in low resource settings { 27686170 }. There is a dense intersecting network of reticulin fibers with focal or diffuse bundles of collagen. Additional characteristic features include prominent vasculature with increased numbers of vessels with dilated sinuses showing intrasinusoidal haematopoiesis { 18028479 ; 15375769 ; 11071630 ; 16891200 }. Osteosclerosis can show varying degrees, ranging from focal bud-like appositional new bone formation to broad interconnecting bridges extensively replacing the marrow { 16202684 }. Erythropoiesis is relatively decreased compared to granulopoiesis. There is no significant dysplasia in erythroid or granulocytic precursors at the time of initial diagnosis. The immature cells represent <10% of the cellularity { 16202684 }. CD34 and/or CD117 for accurate enumeration of blasts is often helpful due to underlying fibrosis { 16019508 }. PMF、線維性 末梢血塗抹標本では、赤血球のanisopoikilocytosis、涙滴型（dacrocyte）、白血球赤芽球癆を認める。大部分の症例は線維化期を呈し、線維化はグレード2または3であり、コア生検では骨硬化が認められる{ 16210038 ; 26402166 ; 16079113 ; 16202685 ; 25124313 ; 28028026 }。 線維化のために、初期には年齢相応に高細胞性であったBM細胞性は、正常か年齢相応に低下している。骨髄は最終的にレチクリンおよび/またはコラーゲン線維、結合組織、脂肪組織に置換され、残存造血巣が散在する。主要な形態学的特徴は、非典型的な巨核球の増殖である。巨核球は増加し、しばしば密な集塊を形成し、傍海綿体、類洞周囲および類洞内に異常な局在を示す。巨核球は成熟不全を示し、核：細胞質比の異常、高密度のクロマチン塊、核高彩度化、球状核小葉（雲様）、裸核を示す{ 12520711 ; 16202684 }。CD61またはCD42bは、巨核球の数とトポグラフィーの詳細に役立つ。CAL2免疫組織化学を用いた巨核球の染色は、CALRの変異の有無と相関するため、クローン性を確定することができ、特に資源の少ない環境での迅速な評価に有用である{ 27686170 }。コラーゲンの局所的またはびまん性束を伴うレチクリン線維の密な交差網がある。さらに特徴的な特徴として、拡張した洞内造血を示す血管数の増加した顕著な血管系がある{ 18028479 ; 15375769 ; 11071630 ; 16891200 }。骨硬化の程度は様々で、限局した芽のような付着性の新生骨形成から、骨髄を広範囲に置換する広範な連結橋まである{ 16202684 }。赤血球造血は、顆粒球造血に比べて相対的に低下している。初診時には、赤血球系前駆体および顆粒球系前駆体に顕著な形成異常はみられない。未熟細胞は細胞数の10％未満である{ 16202684 }。線維症があるため、芽球の正確な計数のためにCD34および/またはCD117がしばしば有用である{ 16019508 }。 Differential diagnosis The distinction of pre-fibrotic PMF from other MPNs and reactive proliferations is important as most patients of pre-PMF eventually evolve into fibrotic PMF. No single morphological feature will be able to assist in this distinction; a constellation of morphological features and clinical presentation is essential to evaluate cases that are diagnostically challenging. Bone marrow in cases of pre-fibrotic marrow is hypercellular (unlike most cases of ET) and most often shows a significant increase in myeloid:erythroid ratio (unlike both ET and PV) { 19704052 }. Prominent clustering of megakaryocytes and prominence of megakaryocytes with hyperchromatic nuclei and marked atypical features such as the presence of smaller cells favour a diagnosis of pre-PMF. Cases of fibrotic-PMF should be distinguished from fibrotic phases of PV and ET which may have been previously unrecognized, chronic myelomonocytic leukaemia with fibrosis { 29192651 }, desmoplasia associated with metastatic tumours such as malignancies such as splenic angiosarcomas { 23800601 } and autoimmune fibrosis { 25282037 }. The bone marrow in autoimmune conditions shows an erythroid predominant hypercellular marrow with lymphoid aggregates and polytypic plasmacytosis without megakaryocytic clustering or atypia. Autoimmune fibrosis also lacks peripheral blood changes of leukoerythroblastosis and teardrop poikilocytosis { 25282037 }. 鑑別診断 前線維化 PMF の患者のほとんどが最終的に線維化 PMF に移行するため、前線維化 PMF と他の MPN や反応性増殖との鑑別は重要である。 診断が困難な症例を評価するためには、形態学的特徴と臨床像の組み合わせが必須である。 前線維化骨髄の症例の骨髄は(ETのほとんどの症例とは異なり）高細胞性であり、（ETやPVとは異なり）骨髄：赤血球比の有意な増加を示すことが多い{ 19704052 }。 巨核球の顕著な集簇(dens cluster)、高色素性核を有する巨核球の顕著な集簇、小細胞の存在などの顕著な非典型的特徴は、前PMFの診断を支持する。 線維化-PMFの症例は、これまで認識されていなかった可能性のあるPVやETの線維化期、線維化を伴う慢性骨髄単球性白血病｛ 29192651 ｝、脾臓血管肉腫｛ 23800601 ｝などの悪性腫瘍の転移に伴う脱スモプラシア｛ 25282037 ｝、および自己免疫性線維化｛ 25282037 ｝と区別すべきである。 自己免疫疾患における骨髄は、巨核球の集積や異型性を伴わないリンパ球の凝集や多型性形質細胞症を伴う赤血球優位の高細胞性骨髄を示す。自己免疫性線維症はまた、白血球赤芽球癆と涙小球癆の末梢血変化を欠く{ 25282037 }。 Cytology See above Diagnostic molecular pathology The JAK2 p.V617F mutation is homozygous in a large proportion of patients with PMF. Mutations in the calreticulin (CALR) gene were identified in 2013 and are found in 25-35% of patients with PMF, type 1 CALR mutations are much commoner than type 2 mutations in PMF and in this context carry a more favourable prognosis than other mutations. Activating point mutations in the thrombopoietin receptor gene, MPL, are found in 5-10% of patients with ET and PMF. In addition, mutations in other cancer driver genes are found in over half of patients with MPN. The most frequent include mutations in TET2 (10-15% of MPN patients), ASXL1 (5-10%), and DNMT3A (5-10%), with a lower prevalence in splicing regulators (SRSF2, SF3B1, U2AF1, ZRSR2) and other regulators of chromatin structure, epigenetic functions and cellular signaling (e.g. EZH2, IDH1, IDH2, CBL, KRAS, NRAS, STAG2, TP53). These additional mutations are more common in myelofibrosis and blast phases compared to pre-PMF, PV and ET. Some of these mutations are known to carry a worse prognostic risk (e.g., EZH2, IDH1, IDH2, SRSF2, and ASXL1 mutations in PMF). Mutation of TP53 is associated with leukaemic transformation and identifies a disease category with a particularly unfavourable outlook. In terms of comparison between PMF (fibrotic) and pre-PMF, the Italian study demonstrated that whilst driver mutation profiles were similar across the entities significantly more patients with PMF had mutations in ASXL1 (33.7%) and EZH2 (12.0%) compared with pre-PMF (18.0% and 3.6%, respectively; P<0.0001 for both). Also, the number of patients with 2 or greater so-called high molecular risk mutated genes, was more than double in PMF (13.6%) than pre-PMF (5.4%; P< .0001). Cytogenetic abnormalities occur in as many as 30% of cases {25037629 }. There is no Philadelphia (Ph) chromosome or BCR::ABL1 gene. Rare cases with concurrent BCR::ABL1 and mutations in JAK2 are often a result of the two distinct myeloproliferative neoplasms { 29327708 }. The presence of either del(13)(q12-22) or der(6)t(1;6)(q21-23;p21.3) is strongly suggestive (but not diagnostic) of PMF { 16029451 }. The most common recurrent abnormalities are del(20q) and partial trisomy 1q; gains of chromosomes 9 and/or 8 have also been reported { 12373082 ; 11380468 }. 分子病理診断 JAK2 p.V617F変異は、PMF患者の大部分でホモ接合体である。カルレティキュリン（CALR）遺伝子の変異は2013年に同定され、PMF患者の25〜35％に認められ、1型CALR変異はPMFでは2型変異よりもはるかに多く、この文脈では他の変異よりも予後が良好である。トロンボポエチン受容体遺伝子MPLの活性化点突然変異は、ETおよびPMF患者の5-10％に認められる。 さらに、MPN患者の半数以上に他のがんドライバー遺伝子の変異が認められる。最も頻度が高いのは、TET2（MPN患者の10〜15％）、ASXL1（5〜10％）、DNMT3A（5〜10％）の変異で、スプライシング制御因子（SRSF2、SF3B1、U2AF1、ZRSR2）や、クロマチン構造、エピジェネティック機能、細胞シグナル伝達の他の制御因子（EZH2、IDH1、IDH2、CBL、KRAS、NRAS、STAG2、TP53など）の有病率は低い。これらの追加変異は、PMF前、PV、ETと比較して、骨髄線維症や芽球期でより一般的である。これらの変異のいくつかは予後リスクを悪化させることが知られている（例えば、PMF における EZH2、IDH1、IDH2、SRSF2、ASXL1 変異）。TP53の変異は白血病化に関連し、特に予後が悪い疾患カテゴリーを特定する。 PMF（線維性）とプレPMFの比較という点では、イタリアの研究は、ドライバー変異のプロフィールは、PMF患者ではプレPMF患者（それぞれ18.0％と3.6％；両者ともP<0.0001）と比較して、ASXL1（33.7％）とEZH2（12.0％）の変異が有意に多いことを示した。また、いわゆる高分子リスク変異遺伝子を2つ以上有する患者数は、PMF前（5.4％；P<0.0001）と比較して、PMF（13.6％）では2倍以上であった。 細胞遺伝学的異常は症例の30％にみられる{25037629}。フィラデルフィア（Ph）染色体やBCR::ABL1遺伝子は認められない。BCR::ABL1 と JAK2 の変異を同時に認める稀な症例は、多くの場合、2つの異なる骨髄増殖性新生物{ 29327708 }の結果である。del(13)(q12-22)または der(6)t(1;6)(q21-23;p21.3)の存在は、PMFを強く示唆する(診断には至らない)。最も一般的な再発異常は、20q欠失と1q部分トリソミーであり、9番染色体および8番染色体の染色体異常も報告されている{ 12373082 ; 11380468 }。 Essential and desirable diagnostic criteria See Tables #36104 and #36106. Staging Not relevant Prognosis and prediction PMF, pre-fibrotic Please see pre-PMF, above. PMF, fibrotic Detection of 10-19% blasts in peripheral blood and/or bone marrow, especially with CD34 immunohistochemistry showing clusters of blasts, indicates progression to accelerated phase. Detection of ?20% blasts indicates transformation to blast phase. Other evidence of progression includes new onset monocytosis and/or the development of dysplastic changes. The prognosis for patients with fibrotic PMF has been studied extensively, whereas data on prognosis for pre-PMF is quite limited but suggests that PMF prognostic scoring tools are likely not applicable. Additionally, the prognosis for patients with post-ET or post-PV MF is distinct (based on multiple features, especially the fact that cytopenias are not as common or as severe in these disease states (Table 7 #30708 and the MYSEC PM prognostic score) { 27354022 ; 18988864 ; 21149668 ; 20008785 ; 27885272 ; 28561069 }. Survival in pre-PMF (median 14.7y, P<0.0001) appears shorter in general when compared with ET patients (median 31y). Furthermore, being diagnosed with fibrotic PMF corresponded to a hazard ratio for reduced survival of 2.3; P<0001) when compared with pre-PMF. Leukaemia-free survival was shorter in fibrotic PMF than pre-PMF; the cumulative incidence of leukaemia was 7% and 11% at 5 years, and 12% and 23% at 10 years, respectively, for pre-PMF and fibrotic PMF; much higher than that for ET cohort which was 0% and 1% at 5 years and at 10 years, respectively { 28351937 }. 必須および望ましい診断基準 表#36104および#36106を参照のこと。 病期分類 関連なし 予後と予測 PMF、前線維化 上記のPMF前を参照のこと。 線維化PMF 末梢血中および/または骨髄中に10〜19％の芽球が検出され、特にCD34免疫組織化学検査で芽球のクラスターが検出された場合は、加速期への進行を示す。芽球が20％以上検出された場合は、芽球期への移行を示す。その他の進行の証拠としては、新たな単球増加および/または異形成変化の発現がある。 線維化PMF患者の予後は広範に研究されているが、前PMFの予後に関するデータは極めて限られているが、PMFの予後スコアリングツールは適用できない可能性が高いことを示唆している。加えて、ET 後の MF と PV 後の MF の予後は異なる（複数の特徴、特にこれらの病態では細胞 減少症がそれほど多くなく、また重症でもないという事実に基づく）（表 7 #30708 と MYSEC PM 予後スコア）{ 27354022 ; 18988864 ; 21149668 ; 20008785 ; 27885272 ; 28561069 }。PMF前の生存期間（中央値14.7y、P<0.0001）は、ET患者（中央値31y）と比較すると、全般的に短いようである。さらに、線維化PMFと診断された場合、PMF前と比較して生存期間短縮のハザード比は2.3であった（P<0001）。無白血病生存期間は、線維化PMFではPMF前より短かった；白血病の累積発生率は、PMF前と線維化PMFでは、5年でそれぞれ7％と11％、10年でそれぞれ12％と23％であり、ETコホートの5年と10年でそれぞれ0％と1％よりはるかに高かった{ 28351937 }。 A few key observations have been made regarding the prognosis of PMF. The first is that survival can vary dramatically from <3 years on the higher-risk side to decades on the lower-risk side. The second is that the disease features that reproducibly impact prognosis include multiple disease features from patient features, peripheral blood counts, bone marrow features, and genetic studies. The third is that the clinical state, availability of data for the required variables, and usage need to be considered when applying. The fourth is that prognosis does not necessarily equate to clinical disease burden, as certain high-risk patients may be less symptomatic and certain lower-risk patients might be more symptomatic { 32198525 }. The main clinical utility of PMF prognostic scores is to separate lower-risk patients from everyone else and is more impactful on guiding decision-making on stem cell transplant than the selection of medical therapy. The prognostic scores themselves and required data elements are included in Table 7 #30708. The IPSS is unique in being able to be used solely at the time of diagnosis, whereas the others can be used throughout the disease course { 18988864 }. The DIPSS is likely the most universally used tool, while the DIPSS Plus provides greater clarity with karyotype is available { 20008785 ; 21149668 }. The MIPSS 70 (both versions) is applicable below age 70 (with an eye toward guiding stem cell transplant) but does require molecular phenotype. Although there are additional scores that have been published this portfolio serves most clinical needs, with additional scores perhaps refining the prognosis for the stem cell transplant decision { 29226763 ; 29708808 ; 29472717 }. PMFの予後に関しては、いくつかの重要な見解がある。 第一は、生存期間は高リスク側では3年、低リスク側では数十年と劇的に変化することである。 第二に、予後に再現性のある影響を与える疾患の特徴には、患者の特徴、末梢血数、骨髄の特徴、遺伝学的研究による複数の疾患の特徴が含まれるということである。 3つ目は、臨床状態、必要な変数のデータの入手可能性、使用法を考慮して適用する必要があることである。ある種の高リスク患者は症状が軽く、ある種の低リスク患者は症状が強いかもしれない{ 32198525 }。 PMFの予後スコアの主な臨床的有用性は、低リスク患者とそれ以外の患者を区別することであり、内科的治療の選択よりも幹細胞移植の意思決定の指針としてインパクトがある。 予後スコアそのものと必要なデータ要素は表7#30708に含まれている。IPSSは診断時のみに使用できるユニークなものであるが、他のスコアは病気の経過を通じて使用できる{ 18988864}。 DIPSSはおそらく最も普遍的に使用されるツールであり、DIPSS Plusは核型が利用可能であるため、より明確である{ 20008785 ; 21149668 }。 MIPSS 70（両バージョンとも）は70歳以下に適用可能（幹細胞移植の指針として）だが、分子表現型が必要である。追加スコアが発表されているが、このポートフォリオはほとんどの臨床ニーズに対応しており、おそらく追加スコアによって幹細胞移植決定の予後がより精緻化されるであろう{ 29226763 ; 29708808 ; 29472717 }。 WHO Classification of Tumours online. Haematolymphoid Tumours (5th ed.) //Myeloid proliferations and neoplasms //Myeloproliferative neoplasms //Myeloproliferative neoplasms //Primary myelofibrosis Authors Responsible editor(s) Andreas Hochhaus Co-editor(s) Joseph D. Khoury Responsible Author Rashmi Kanagal-Shamanna Co-author(s) Kikkeri N. Naresh Sandeep S. Dave Ruben Mesa Stephane Giraudier Claire Nicola Harrison Dragana Milojkovic Morphological features helpful in distinguishing essential thrombocythaemia (ET) from prefibrotic/early primary myelofibrosis (pre-PMF)a Morphological features that are helpful in distinguishing essential thrombocythaemia (ET) from prefibrotic/early primary myelofibrosis (pre-PMF)a Morphological feature ET Pre-PMF Cellularity (age-adjusted) Normal Increased Myeloid-to-erythroid ratio Normal Increased Dense megakaryocyte clusters Rare Frequent Megakaryocyte size Large/giant Variable Megakaryocyte nuclear lobulation Hyperlobulated Bulbous?/?hypolobulated Reticulin fibrosis, grade 1b Very rare More frequent a; On the basis of a representative, artifact-free bone marrow biopsy (> 1.5 cm) taken at a right angle (90°) 皮質骨から垂直に採取できた, アーティファクトのない, 15mm以上の長さの骨髄を評価すること。 from the cortical bone. bAccording to WHO grading { 16079113 }: see Table <<30704>>. #30704 Semiquantitative bone marrow myelofibrosis (MF) grading system {16079113} with minor modifications concerning collagen and osteosclerosis {26402166}a Semiquantitative bone marrow myelofibrosis (MF) grading system { 16079113 } with minor modifications concerning collagen and osteosclerosis { 26402166 }a Grade Definition MF-0 Scattered linear reticulin with no intersections (cross-overs), corresponding to normal bone marrow MF-1 Loose network of reticulin with many intersections, especially in perivascular areas MF-2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick fibres mostly consistent with collagen and/or focal osteosclerosisb MF-3 Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibres consistent with collagen, usually associated with osteosclerosisb aFibre density should be assessed only in haematopoietic areas; if the pattern is heterogeneous, the final grade is determined by the highest grade present in ?30% of the marrow area. bIn grades MF-2 and MF-3, an additional trichrome stain is recommended (Table <<36106>>). #30705 Semiquantitative grading of collagena {26402166} Table 5. Semiquantitative grading of collagena { 26402166 } Grade Definition 0 Perivascular collagen only (normal) 1 Focal paratrabecular or central collagen deposition with no connecting meshwork 2 Paratrabecular or central deposition of collagen with focally connecting meshwork or generalized paratrabecular apposition of collagen 3 Diffuse (complete) connecting meshwork of collagen in >30% of marrow spaces aIf the pattern is heterogeneous, the final grade is determined by the highest grade present in ?30% of the marrow area. #30706 Semiquantitative grading of osteosclerosisa,b {26402166} Table 6. Semiquantitative grading of osteosclerosisa,b { 26402166 } Grade Definition 0 Regular bone trabeculae (distinct paratrabecular borders) 1 Focal budding, hooks, spikes, or paratrabecular apposition of new bone 2 Diffuse paratrabecular formation of new bone with thickening of trabeculae, occasionally with focal interconnections 3 Extensive interconnecting meshwork of new bone with overall effacement of marrow spaces aIf the pattern is heterogeneous, the final grade is determined by the highest grade present in ?30% of the marrow area. bBone marrow core biopsy of sufficient length, taken at a right angle (90°) from the cortical bone, without fragmentation, is mandatory for the grading of osteosclerosis. #30708 Selected List of Myelofibrosis Prognostic Scoring Systems, prognostic elements and usage IPSS DIPSS DIPSS Plus MIPSS 70 MIPSS 70 2.0 MYSEC PM Patient features (Adverse Listed) Age X (>65Y) X (>65) X (>65) ALL UNDER 70Y ALL UNDER 70Y >65 Y Constitutional Symptoms Present Present Present Present Present Present Peripheral Blood (Adverse Listed) Anemia <100g/L <100g/L <100g/L (+ if TX DEP) <100g/L MOD/Severe <100g/L Leukocytes >25 x 10(9)/L >25 x 10(9)/L >25 x 10(9)/L >25 x 10(9)/L Platelets <100 x 10(9)/L Peripheral Blasts >1% >1% >1% >/=2% >/=2% >1% Bone Marrow Features Reticulin Fibrosis >/= Grade 2 Genetics (Adverse Listed) Karyotype Unfavourable 2 Tiers Unfavourable Driver Mutation Status NON CALR Type 1 NON CALR TYPE 1 NON CALR TYPE 1 Other Somatic Mutations 0, 1 or >/2 HMR 0, 1, or >/= 2 HMR Comments Scoring Tiers 4 4 4 3 5 4 Usage PMF at Diagnosis PMF Anytime PMF Anytime PMF Anytime under age 70 PMF Anytime Under age 70 POST ET/PV MF Footnotes Unfavourable Karyotype HMR=ASXL1, SRSF2, EXH2, IDH1, IDH2 HMR=ASXL1, SRSF2, EXH2, IDH1, IDH2, U2AF1q157 Copyright #36104 Diagnostic criteria for primary myelofibrosis, prefibrotic The diagnosis of pre-fibrotic primary myelofibrosis requires that all 3 major criteria and at least 1 minor criterion are met. Major criteria 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis grade >?1a, accompanied by increased age-adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased erythropoiesis 2. WHO criteria for BCR-ABL1?positive chronic myeloid leukaemia, polycythaemia vera, essential thrombocythaemia, myelodysplastic syndromes, or other myeloid neoplasms are not met 3. JAK2, CALR, or MPL mutation OR Presence of another clonal markerb OR Absence of minor reactive bone marrow reticulin fibrosisc Minor criteria Presence of at least one of the following, confirmed in 2 consecutive determinations: - Anaemia not attributed to a comorbid condition - Leukocytosis ??11 × 109/?L - Splenomegaly detected clinically and/or by imaging - Lactate dehydrogenase level above the upper limit of the institutional reference range - Leukoerythroblastosis a See Table <<30704>> b In the absence of any of the 3 major clonal mutations, a search for other mutations associated with myeloid neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help in determining the clonal nature of the disease. c Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies. #36106 Diagnostic criteria for primary myelofibrosis, fibrotic stage. The diagnosis of overt primary myelofibrosis requires that all 3 major criteria and at least 1 minor criterion are met. Major criteria 1. Megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3a 2. WHO criteria for essential thrombocythaemia, polycythaemia vera, BCR-ABL1?positive chronic myeloid leukaemia, myelodysplastic syndrome, or other myeloid neoplasmsb are not met 3. JAK2, CALR, or MPL mutation OR Presence of another clonal markerC OR Absence of reactive myelofibrosisd Minor criteria Presence of at least one of the following, confirmed in 2 consecutive determinations: - Anaemia not attributed to a comorbid condition - Leukocytosis ??11 × 109/?L - Splenomegaly detected clinically and/or by imaging - Lactate dehydrogenase level above the upper limit of the institutional reference range - Leukoerythroblastosis a See Table <<30704>> b Myeloproliferative neoplasms can be associated with monocytosis or they can develop it during the course of the disease; these cases may mimic chronic myelomonocytic leukaemia (CMML); in these rare instances, a history of MPN excludes CMML, whereas the presence of MPN features in the bone marrow and/or MPN-associated mutations (in JAK2, CALR, or MPL) tend to support the diagnosis of MPN with monocytosis rather than CMML. c In the absence of any of the 3 major clonal mutations, a search for other mutations associated with myeloid neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations) may be of help in determining the clonal nature of the disease. d Bone marrow fibrosis secondary to infection, autoimmune disorder or another chronic inflammatory condition, hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathy.