Case Discussion      A 28-year-old woman was admitted to the general ward because of fever and right neck masses for about 3 weeks. She had been in her usual state of health until three weeks earlier before this admission, when she developed a low-grade fever, for which she took antipyretics. However, a few days later recurrent fevers were noted. In addition, she started to note several painful masses at the right neck region. She felt discomfort from the neck masses in turning her head, but there was no limitation of range of motion of the upper limbs, neck, or shoulders. She sought medical attention at a local clinic 5 days earlier prior to this entry, and cervical lymphadenopathy was noted. The pain subsided after she took some medications, but the masses did not regress in size. The low-grade fever persisted and she felt worsening pain at the right neck region one day before admission. She denied skin rash or petechiae, headache, abdominal pain, diarrhea, passage of bloody stool, shortness of breath and weight loss. She did not take any medications other than antipyretics and analgesics. There was no recent travel and family history was unremarkable.      On physical examination, she was in no acute distress and her consciousness was clear and oriented. She was febrile, and the blood pressure was 116/72 mmHg, the pulse rate 100 beats per minute, and the respirations 24 breaths per minute. The neck examination showed three tender, soft, and fixed masses at the right neck. There were no bruises, ecchymoses, petechiae, purpuric rashes, or hepatosplenomegaly, and the remainder of the physical examination was normal. A routine blood test and chest X-ray (see figure 1) were performed. < Laboratory data > CBC/DC: (Time: December 2nd, 2009, at ER) WBC /μL 1940 Blast % 40 Mono % 3 RBC M/μL 3.0 Promyl % 0 Lym % 50 Hb g/dL 9.1 Myelo % 0 Aty. Lym % 0 Hct % 27.6 Meta % 0 Plasma cell % 0 MCV fl 92 Band % 0     MCH pg 30.3 Seg % 5     MCHC g/dL 33.0 Eos % 0     PLT. /μL 102000 Baso % 0     Biochemistry: (Time: December 2nd, 2009, at ER) BUN     mg/dL 10.0 UA mg/dL 3.7 Cre       mg/dL 0.8 ALT U/L 10 Na        mmol/L 142 LDH U/L 423 K          mmol/L 4.1 C-Reactive Protein mg/dL 0.59 Cl         mmol/L 111       T-Bil    mg/dL 0.38       Ca        mmol/L 2.24       Mg       mmol/L 0.78       Venous blood gas: (Time: December 2nd, 2009, at ER) pH 7.401 PCO2    mmHg 39.1 PO2       mmHg 42.9 HCO3   mEq/L 23.8 BE        mEq/L -0.3 Chest X-ray: (Time: December 2nd, 2009, at ER) (see figure 1) Widening of the right mediastinum, a normal heart size and no active lung lesion were noted. <Course and Treatment>        Potassium-free fluid hydration, allopurinol, and empirical antibiotics were given on the day the patient was admitted to the general ward. Flow cytometry of a peripheral blood specimen revealed DR (89.1%), CD34 (97.7%), anti-MPO (12.8%), CD33 (12.5%), CD7 (66.9%), CD3 (59.8%), and TdT (74.4%). Bone marrow aspiration was performed and a smear of the aspirate showed morphology diagnostic of acute lymphocytic leukemia (ALL; L2). Flow cytometry of a bone marrow specimen showed CD41a (0.1%), GPA (0.3%), CD33 (1.6%), anti-MPO (1.9%), CD7 (97.6%), and cytochemistry showed MPO (-).      Pre-chemotherapy evaluations, including dental evaluation, serologies of viral hepatitis, HIV, and PPD skin test, were done, and echocardiography showed normal cardiac function. Computed tomography of the chest and abdomen after administration of contrast material in multiple axial sections showed extensive lymphadenopathies near the right scalenous region and right carotid space, and a mass lesion at the right anterior mediastinum, about 4.3 cm in diameter (see figures 2, 3). There was no focal density changes at the liver, spleen, pancreas and kidneys. Port-A was inserted on 12/7, and Triple Intrathecal Therapy (TIT) was given on 12/7. The induction therapy started since 12/9. < Discussion >      這個病人主要的臨床表現為fever加上lymphadenopathy，針對fever及lymphadenopathy的鑑別診斷如下：      發燒超過一個星期可歸類為FUO (fever of unknown origin)，做differential diagnosis要往四個大方向想：infection, malignancy, autoimmune disease, drug; 由於這位病人的用藥史比較沒那麼複雜，這幾個星期只有服用退燒藥和止痛藥，並沒使用其他的藥品或中藥，所以可以暫時先排除drug fever。Neck mass的鑑別診斷很多，但是在28歲女孩子身上常看到的主要有以下五類： a)Inflammation/infection Abscess Lymphadenitis b)Malignancy Lymphoma leukemia c)Endocrine Thyroid mass d)Congenital Thyroglossal duct cyst Branchial cyst e)Others Vascular aneurysm      其中，endocrine、congenital、others這三類的疾病要合併感染或autoimmune disease才會導致fever，否則只是會造成單純的頸部腫塊及其它的症狀。所以目前可以暫時把這三類的疾病放在differential diagnosis list後面。剩下的就是malignancy、 inflammation和infection，但這三大項的疾病，無法單單由病患的病史來判斷，所以還是得靠hemogram辨別。       除此之外，雖然ALL（acute lymphocytic leukemia, or acute lymphoblastic leukemia）的主要臨床症狀是由neutropenia、anemia和thrombocytopenia造成的，如：fever、weakness、fatigue和bleeding，其它如weight loss、abdominal discomfort和bone pain也是可看到的。而這位病人自述只有fever，其它如shortness of breath、diarrhea、dysuria、frequent urinating, urgency都沒有，這些negative symptoms指出這不太像一般的上呼吸道感染或泌尿道感染的表現。理學檢查除了lymphadenopathy外也沒有其他特別的findings（如看到petechiae、gingival bleeding或hepatomegaly等等），因此需要進一步藉助lab.和image studies來幫助診斷。       12/2在急診抽血，其中可看到除了有neutropenia (ANC，97 /μL) 外，還有anemia (Hb 9.1 g/dL) 和thrombocytopenia (PLT，102k/μL) 的情形，但這不足以區分infection和malignancy，因為嚴重的infection同樣會導致類似的狀況，如hemophagocytosis。接下來要看的是白血球的differential count。這個病人的blast比例非常高（40%），通常患有infection或autoimmune disease不會有這麼高的blast cells比例；另外，此病人segment只有5%，如果是細菌感染，segment一般會高達70~80%，因此這點也不支持bacterial infection，所以這些數值顯示這位患者的fever和lymphadenopathy不太像是infection造成的。反觀周邊血液的blast比例高達40%，WHO對leukemia的定義為blast >20%，而FAB（French-American-British classification）的定義為blast >30%，因此應考慮leukemia。經過一連串的檢查，first impression應為fresh leukemia，至於是acute myeloid leukemia (AML)還是acute lymphocytic leukemia (ALL)還得依靠其他的檢查來幫助區分並規劃治療療程。      X-ray可看到一個mass lesion在right upper mediastinum，可懷疑是thymus腫大、lymphadenopathy、infection、或tumor。Chest CT的右前側可看到一個直徑約4.3公分的mass lesion，懷疑是lymphadenopathy、infection (如TB或fungus)、或tumor。       一般而言，lymphoma 可以lymphadenopathy表現，在contrast-enhanced CT的findings為necrosis，ill-defined margin，及homogeneous enhancement。TB早期在contrast-enhanced CT的findings為homogeneous non-necrotic淋巴結，當病情愈來愈嚴重時，則可看到necrosis以及central low density的現象。一半以上的ALL患者有會在contrast-enhanced CT看到lymphadenopathy。 血液檢查報告 (see figure 4 also) a) Flow cytometry of a peripheral blood specimen： T-lineage Myeloid lineage Other CD7 66.9% MPO 12.8% DR 89.1% CD3 59.8% CD33 12.5% CD34 97.7%         不論何種cell markers要大於20%才有意義。ALL一般又分為T-lineage和B-lineage，其中CD7和CD3代表T- lineage的markers，此病人CD7和CD3明顯大於20%。另外ALL是一種immature cells大量複製的疾病，DR和CD34為immature cells的markers，因此在這個病人也呈現異常的情形。所以可見此為病患比較像是T-lineage ALL。 b) Flow cytometry of a bone marrow specimen： Megakaryocytes Red blood cells Myeloid lineage T-lineage CD41a 0.1% GPA 0.3% MPO 1.9% CD7 97.6%         CD33 1.6%          同樣在這個檢查裡，只有CD7明顯大於20%，可看出此病患比較像是T-lineage ALL。      Cytochemistry的檢查結果顯示病人的MPO為 (-)，TdT為(+)，一般而言ALL blasts是myeloperoxidase (MPO) (-)和terminal deoxynucleotidyl transferase (TdT) (+)，AML則是MPO (+)。Bone marrow aspiration的smear也證實此病患是ALL。根據以上所有的檢查可診斷此病患是T-lineage ALL。 ALL介紹 ALL是骨髓裡不正常、不成熟的lymphocytes單株大量複製，它是種惡性疾病，除了血液和骨髓外，也很容易侵犯其它的器官組織，特別是中樞神經。ALL沒有AML (acute myeloid leukemia) 常見，在急性血癌裡，ALL只佔了30%，AML則佔了70%。ALL在全世界的盛行率為每十萬人中就有1~1.5案例，有將近四分之三的ALL發生在兒童、青少年身上，四分之一在成人。ALL的好發年齡為二到五歲，男性的發生率比女性高。 大部分造成ALL的原因並不清楚，少見的原因則包括了ionizing radiation或benzene的暴露、化療史（特別是topoisomerase II inhibitors）等等。有些基因疾病也跟此病有相關，例如Down syndrome、Fanconi anemia、neurofibromatous type 1、ataxia telangiectasia。 臨床表現並不specific，通常病人的症狀/徵兆包括了臉色蒼白和疲勞（anemia）、易出血和瘀青（thrombocytopenia）、發燒和感染（leukopenia）。肝脾腫大、淋巴結腫大也很常見。若大量的癌細胞充滿骨髓，病患也會感覺到骨頭疼痛。而T-cell ALL的病人常常會有mediastinal mass。 常見的檢查包括： Complete blood count：WBC count對病人的治療計畫及預後有很大的相關性，同時依照疾病的輕重也可觀察到anemia、thrombocytopenia。WHO對leukemia的定義為blast cells >20%，而FAB的定義為blast cells >30%，若是落在5~20%則定義為MPD/MDS (myeloproliferative disorder/myelodysplastic syndrome)。 Peripheral blood film：可用來觀察blast cell的型態 Bone marrow aspiration and biopsy：bone marrow biopsy較適用於aplastic anemia（看Bone marrow cellularity）和solid tumor（看bone marrow involvement），而大部分ALL患者做bone marrow aspiration以做接下來第4~7項的檢查即可 Morphologic analysis：The presence of Auer rods is pathognomonic of AML，所以看到Auer rods就可排除ALL的可能性 Cytochemistry：可用來分辨ALL和AML。ALL blasts是myeloperoxidase (MPO) (-)和terminal deoxynucleotidyl transferase (TdT) (+)，AML則是MPO (+) Flow cytometry with immunophenotypic studies：細胞表面的cell markers大於20%才有意義，可分辨myeloid或lymphoid origins以及T或B cells。(see figure 4) Cytogenetic studies：做karyotyping Lumbar puncture：除非同一時間合併intrathecal chemotherapy，否則acute leukemia的病人不應該做lumbar puncture，因為過程中容易讓循環中的leukemia cells跑到CNS裡。 如果病人有發燒，blood culture、urine culture、和chest X-ray也是standard work-up。 AML和ALL的比較：   AML ALL Chest X-ray   Mass in mediastinum Morphologic analysis of blood cell Auer rods (pathognomonic)   Cytochemistry MPO (+) TdT (+) Flow cytometry CD 31 & CD 33: myeloid lineage Glycophorin A (GPA): M6 CD 41: M7 Precursor B-cell: CD19 Precursor T-cell: CD2,3,5,7 ALL的分類： WHO Type FAB Classification Immunohistochemistry Precursor B-cell L1, L2 TdT (+) CD19 (+) Precursor T-cell L1, L2 TdT (+) T-cell Ag (CD2,3,5,7): (+) CD10 (-) Mature T-cell Ag (CD4,8): (-) B-cell L3 TdT (-), surface Ag (+) Note: FAB, French-American-British classification. 治療方式： Chemotherapy： 1)CNS prophylaxis (TIT): methotrexate, hydrocortisone, cytarabine (Ara-C)。因一般的化療藥物到達腦部的濃度不夠高，藉此法抗癌藥物可循著CSF來保護腦膜，並消滅躲藏在CNS的癌細胞；若不做此預防，80%的leukemia會由CNS復發，治療容易失敗。 2)Induction therapy: vincristine，corticosteroids (prednisone或 dexamethasone) 和anthracycline (e.g. daunorubicin)；若是high-risk的病人，常會再加上cyclophosphamide。Induction therapy的主要目的是為了引導骨髓恢復正常功能。 3)Consolidation therapy: High dose methotrexate，6-mercaptopurine cytarabine，vincristine，L-asparaginase，mitoxantrone，cyclophosphamide，和etoposide。為期四至六個月，把殘留的癌細胞消滅。 4)Maintenance therapy: 6-mercaptopurine，methotrexate，vincristine，dexamethasone。定期注射及口服抗癌藥物約二至三年。 Imatinib/Dasatinib：indication為Philadelphia chromosome-positive (Ph+)，若已有抗藥性則可選擇dasatinib。 Allogeneic stem cell transplantation     治療的目標為complete clinical remission，包括骨髓內少於5%的blasts（以morphology的觀點來看）、器官腫大消除和血球數目正常。在兒童裡ALL有高達80~90%的治癒率，但在成人裡預後比較差，治癒率只有30~40%且容易復發，若帶有Philadelphia chromosome t(9,22)則預後更不好，治癒率低於10%。有些因素也會影響病人的預後，如年齡、白血球數、CNS status及immunophenotype。以年齡來說，一歲到九歲的小孩有最好的預後，隨著年齡增加預後愈差；在成人裡，就醫時白血球數大於30,000/μL或有CNS invasion的病人通常預後都不是很好；在兒童裡，immunophenotype為precursor B-cell ALL有最好的預後；反觀在成人裡，precursor T-cell ALL有較好的預後。     總而言之，根據此病人的臨床表現（fever、lymphadenopathy）、chest X-ray and chest CT（mediastinal widening、lymphadnopathy）、CBC with D/C（blast cells >20%）、peripheral blood flow（CD7: 66.9%、CD3: 59.8%、TdT: 74.4%）、bone marrow smear（L2 morphology）、bone marrow flow cytometry（CD33: 1.6%、anti-MPO negative、CD7: 97.6%）、cytochemistry（MPO negative），得知此病人的診斷為precursor T-cell ALL。所以，經過pre-chemotherapy evaluation後開始做化療並追蹤其治療效果。 < References > Longo Dan L, "Chapter 105. Malignancies of Lymphoid Cells" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e: http://www.accessmedicine.com/content.aspx?aID=2890045 Linker Charles A, "Chapter 13. Blood Disorders" (Chapter). McPhee SJ, Papadakis MA, Tierney LM, Jr.: CURRENT Medical Diagnosis & Treatment 2010: http://www.accessmedicine.com/content.aspx?aID=5476 Bene MC; Review: Immunophenotyping of acute leukaemias. Immunology Letters. 2005; 98(1): 9-21

繼續教育考題
1. (A)	血液抹片看到Auer rods時，即可診斷
	A	AML
	B	ALL
	C	aplastic anemia
	D	Thalassemia
2. (C)	做cytochemistry時，ALL blast cells會染出：
	A	MPO(+)、TdT(+)
	B	MPO(+)、TdT(-)
	C	MPO(-)、TdT(+)
	D	MPO(-)、TdT(-)
3. (A)	ALL 在下列哪個年齡層常見？
	A	1~19歲
	B	30~45歲
	C	46~60歲
	D	60歲以上
4. (D)	ALL 常見的臨床表現為：
	A	weakness and fatigue
	B	bleeding
	C	fever
	D	all of above
5. (D)	CNS prophylaxis (Triple Intrathecal Therapy)不包括哪種藥物？
	A	Methotrexate
	B	Hydrocortisone
	C	Cytarabine (Ara-C)
	D	Vincristine
6. (E)	下列哪些因素會影響ALL病人的預後？
	A	年齡
	B	白血球數
	C	CNS involvement
	D	Immunophenotype
	E	以上皆是

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