PRESS STATEMENT

Use of Over-the-counter COVID-19 Test Kits

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The College has noticed that a variety of over-the-counter Coronavirus Disease 2019 (COVID-19) self-test kits are being promoted in the market. We are concerned that the public could be misled by the results of these kits.

These over-the-counter test kits usually utilize pinprick blood samples to detect IgG or IgM antibodies against the SARS-CoV-2 virus. Antibodies are produced over days to weeks after infection; the level and timing of response vary among individuals. The performance of these kits, including sensitivity and specificity (i.e. respectively whether the test can accurately exclude COVID-19 infection and whether a positive result is reliable to indicate actual infection), also varies among assays. Thus, the public must be aware of the risk of false negative and false positive results.

A false negative result may cause a false sense of security, which could potentially increase transmission of the virus to others and result in delay in seeking medical consultation and management. On the other hand, a false positive result will lead to undue anxiety and unnecessary investigations, and even public health measures such as isolation of the person and his or her close contacts.

The College reiterates that the current test of choice for the diagnosis of active COVID-19 infection remains polymerase chain reaction (PCR)-based tests detecting viral nucleic acids. The detection of antibodies is neither a suitable nor a reliable alternative. The College urges the public to seek advice from medical professionals if COVID-19 infection is suspected.

End / Wednesday / 29 April 2020

Issued at HKT 14:00

hkcpath@hkcpath.org

Tel: +852 2871 8756

新聞稿

就市面上出售的新型冠狀病毒快速測試之聲明

下載原稿

近日坊間出現各式各樣的新型冠狀病毒快速測試,並透過不同媒體銷售。惟快速測試結果存疑，有誤導公眾之嫌,本學院非常關注。

市面上售賣之試劑盒，一般採用針刺血液樣本來檢測 SARS-CoV-2 病毒的 IgM 或 IgG 抗體。抗體於感染後數天至數週方能達至可偵測的水平，抗體之濃度及產生之時間亦因人而異。市場上不同牌子之測試劑,其敏感性 (sensitivity) 和特異性 (specificity) 不盡相同，因此市民應注意有假陰性和假陽性 結果之風險。

假陰性結果會令市民錯誤以為自己未有受感染，從而潛在增加將病毒傳播給他人的風險,及導致延誤最佳診治的時間。另一方面，假陽性結果則會引致不必要的焦慮,多重覆檢,甚至需要採取公共衞生措施，如本人及密切接觸者的隔離檢疫。

本學院重申，目前診斷新型冠狀病毒以聚合酶鏈反應(PCR)測試病毒核酸為首選。現時市場上出售之快速抗體測試並不適合及不可靠。本學院呼籲公眾如懷疑自己受感染,須及早向醫生求醫。

2020 年 4 月 29 日 (星期三) 2 時正

hkcpath@hkcpath.org

Tel: +852 2871 8756

Liver injury associated with immune checkpoint inhibitors - update on clinicopathological features

Volume 15, Issue 1, January 2020  (download full article in pdf)

Editorial note:

Immune checkpoint inhibitors revolutionize the field of immuno-oncology. They have demonstrated great potential in a wide range of adult cancers by reaching long-lasting objective responses and prolonging survival. Through completed and on-ongoing clinical trials, their indications continue to expand among different cancer types. However, one of their limitations is immune-related adverse events, which are most frequently reported in skin, gastrointestinal tract, and endocrine organs. Immune-related adverse events in liver are less common hepatotoxicity but still reported up to 4 to 10% of patients receiving immune checkpoint inhibitors. This Topical Update provides a concise review on the clinicopathological features of liver injury associated with immune checkpoint inhibitors. We welcome any feedback or suggestions. Please direct them to Dr. Anthony Chan (e-mail: awh_chan@alumni.cuhk.net) of Education Committee, the Hong Kong College of Pathologists. Opinions expressed are those of the authors or named individuals, and are not necessarily those of the Hong Kong College of Pathologists.

Dr. Regina Lo

Department of Pathology & State Key Laboratory of Liver Research

The University of Hong Kong

Current applications of immune checkpoint inhibitors

Immune checkpoint inhibitors [ICPI] have been introduced as a form of targeted therapy for human cancers. They exert anti-tumor effects by potentiating T cell functions via removing the inhibitory signals. Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are receptors located on T cells. Ligand-receptor interactions lead to inhibition of T cell activation, therefore suppressing T cell activity against tumor cells ⁽¹⁾. Currently, anti-PD1/PD-1 ligand (PD-L1) and anti-CTLA-4 are the two major forms of ICPI by exploiting an antagonistic approach using specific antibodies that target PD-1 and CTLA-4, respectively. Thus far, several ICPIs were approved by the US Food and Drug Administration for treating cancer ⁽²⁾. Nivolumab and pembrolizumab are FDA approved frontline anti-PD1 agents, while ipilimumab is an anti-CTLA-4 agent. These drugs are given either alone or in combination. Currently there are a number of on-going phase III/IV clinical trials with ICPI for various types of cancers ⁽³⁾.

Clinical features of hepatotoxicity associated with ICPI

Despite the encouraging clinical efficacy, adverse reactions related to ICPI administration have been observed, among which dermatological, gastrointestinal, endocrine manifestations were most frequently reported. These reactions are believed to result from the immune response elicited toward various organs. A meta-analysis of 17 studies revealed an increased risk of all-grade hepatotoxicity with ICPI compared with controls (pooled OR 4.10; PD-1 subgroup 1.94; CTLA-4 5.01) ⁽⁴⁾. Among all immune-related adverse reactions, hepatotoxicity was observed in a relatively small proportion of cases (up to 4-10%) in most reports ^{(2, 5-9)}. Susceptibility of adverse reactions in the liver appears to be dependent on the primary cancer, regimen/dose of ICPI, and host factors. It was reported that patients receiving ICPI for HCC were at a higher risk of hepatotoxicity in terms of transaminases levels compared with lung cancer and melanoma ⁽¹⁰⁾. Moreover, combination therapy or a higher dose of ICPI was associated with increased risk of hepatic injury ^{(6, 9, 11, 12)}. Patients may present with fever and jaundice but can also be asymptomatic ^(13,14). The median time from the first dose to immune-related hepatoxicity was 14.1 weeks (9.4–19.7) for anti-PD-1, 9.9 weeks (6.1–14.7) for anti-CTLA4, and 2.9 weeks for combined therapy ⁽¹⁵⁾. The biochemical derangement is usually of a hepatitic or mixed hepatitic/cholestatic pattern. Radiological findings most of the time do not offer additional diagnostic information. In general, hepatotoxicity associated with ICPI is classified according to Common Terminology Criteria for Adverse Events by the National Cancer Institute (CTCAE). This system comprises grades 1-5 (with grade 5 being fatal) based on the serum levels of AST, ALT, ALP, GGT and total bilirubin. Having said that, elevated bilirubin is a less frequent phenomenon than most forms of drug-induced liver injury.

Histological features of liver injury associated with ICPI

The commonest histological features of ICPI-associated hepatotoxicity are lobular hepatitis, portal lymphoid infiltrates and variable degrees of hepatocytic necrosis ^(16-19). A predominant biliary pattern has been reported but is much less frequently encountered ^{(20, 21)}. Cholestasis is not commonly seen, with bland cholestasis reported in 1 of 10 cases treated with pembrolizumab ⁽²²⁾. Two cases of ICPI-induced hepatitis histologically presenting with fibrin-ring granulomas have also been reported ⁽²³⁾. Steatosis is rare. Some histological features may be more readily observed with the use of a specific type of inhibitor. For instance, microgranulomas and central vein endotheliitis were seen in patients who received anti-CTLA4 therapy. With anti-PD1 therapy, more prominent portal tract inflammation was encountered. In contrast to autoimmune hepatitis, plasma cells are usually low in number ⁽²⁴⁾, which is line with the observation that serum IgG level is mostly normal and autoimmune serological markers are negative. Likewise, in a report comparing 7 cases of ICPI-associated hepatitis versus 10 cases of AIH and 10 cases of drug-induced liver injury (DILI) ⁽²⁴⁾, hepatocytic rosettes and emperipolesis were less commonly observed than AIH. When compared with DILI, bile plugs and eosinophils were less readily seen in ICPI-associated hepatitis. On immunohistochemical delineation of the lymphoid cell population in ICPI-associated hepatitis, several reports have consistently demonstrated a predominance of CD8+ lymphocytes ^{(17, 18, 22)}. This could be distinguishing feature with AIH, in which CD20+ or CD4+ lymphoid cells are frequently encountered.

Diagnostic considerations and implications

The diagnosis of ICPI-liver injury can seldom be made by histology alone as there are no pathognomonic features. Before attributing the cause to ICPI, potential etiologies for liver function derangement should be considered. In particular, exclusion of hepatic involvement by tumor and viral hepatitis is needed. According to a recent report, among 491 patients treated with pembrolizumab for melanoma, lung cancer or urothelial cancer, 70 developed liver injury. Among which, a probably drug-related cause was only made in 20 cases after adjudication ⁽²⁵⁾. Liver histology can help to exclude some differential diagnoses and assess the severity of liver tissue injury, which could be useful to guide management plan. The treatment options for adverse reactions would depend on the severity, and include withdrawal/discontinuation of ICPI, corticosteroids (oral or IV) +/- additional immunosuppressant e.g. mycophenolate mofetil ⁽²⁶⁾. The drugs are usually permanently discontinued in cases presenting with Grade 3 or Grade 4 adverse reactions. There are no standard guidelines with reference to reintroducing ICPI after recovery from Grade 1-2 adverse reactions. As far as histology is concerned, it remains an open question whether histological parameters could offer added values in the grading of ICPI-associated hepatotoxicity. Besides, further studies are awaited to better understand the histological features associated different types of ICPI, and to depict the development and progression of fibrosis in this subset of drug-induced liver injury.

References

1. Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7(2):95-106.
2. Nadeau A, Fecher LA, Owens SR, Razumilava N. Liver Toxicity with Cancer Checkpoint Inhibitor Therapy. Semin Liver Dis. 2018;38(4):366-78.
3. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):165.
4. Wang W, Lie P, Guo M, He J. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis of published data. Int J Cancer. 2017;141(5):1018-28.
5. Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int. 2018;38(6):976-87.
6. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(13):1270-1.
7. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol. 2015;33(13):1430-7.
8. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-7.
9. Cheung V, Gupta T, Payne M, Middleton MR, Collier JD, Simmons A, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterol. 2019;10(4):364-71.
10. Brown ZJ, Heinrich B, Steinberg SM, Yu SJ, Greten TF. Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. J Immunother Cancer. 2017;5(1):93.
11. Weber JS, Postow M, Lao CD, Schadendorf D. Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents. Oncologist. 2016;21(10):1230-40.
12. Sanjeevaiah A, Kerr T, Beg MS. Approach and management of checkpoint inhibitor-related immune hepatitis. J Gastrointest Oncol. 2018;9(1):220-4
13. Johnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA. 2018;320(16):1702-3.
14. De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68(6):1181-90.
15. Gauci ML, Baroudjian B, Zeboulon C, Pages C, Pote N, Roux O, et al. Immune-related hepatitis with immunotherapy: Are corticosteroids always needed? J Hepatol. 2018;69(2):548-50.
16. Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol 2018;71(8):665-71.
17. Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57(8):2233-40.
18. Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, et al. Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases. Am J Surg Pathol. 2015;39(8):1075-84.
19. Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019.
20. Kim KW, Ramaiya NH, Krajewski KM, Jagannathan JP, Tirumani SH, Srivastava A, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs. 2013;31(4):1071-7.
21. Aivazian K, Long GV, Sinclair EC, Kench JG, McKenzie CA. Histopathology of pembrolizumab-induced hepatitis: a case report. Pathology. 2017;49(7):789-92.
22. Zen Y, Chen YY, Jeng YM, Tsai HW, Yeh MM. Immune-related adverse reactions in the hepatobiliary system: Second generation checkpoint inhibitors highlight diverse histological changes. Histopathology. 2019.
23. Everett J, Srivastava A, Misdraji J. Fibrin Ring Granulomas in Checkpoint Inhibitor-induced Hepatitis. Am J Surg Pathol. 2017;41(1):134-7.
24. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31(6):965-73.
25. Tsung I, Dolan R, Lao CD, Fecher L, Riggenbach K, Yeboah-Korang A, et al. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Pharmacol Ther. 2019.
26. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-68.

College Fee PDF

All Fees are in HKD

Membership Entrance and Annual Subscription Fees

Membership Catgory	Subscription#
	Entrance	Annual
Honorary Fellows	Nil	Nil
Founder Fellows*1,*3	N/A	$3,000
Fellows*2,*3	$3,000	$3,000
Overseas Fellows*3, *4	$3,000	$1,500
Members	$1,500	$1,500
Associates	Nil	$800

Remarks:

^# The date of payment of annual subscription would be every 1st of January.

^# If the date of admission to membership is within 6 months from the coming 1st of January, only half of the annual subscription would be required for this period.

^# On change in the category of membership, payment of the balance of the annual subscription would be required.

*¹ For Founder Fellows residing overseas, the annual subscription would be HK$1,000. On residing in Hong Kong for more than 3 months, the annual subscription would be reverted back to the annual subscription of Founder Fellows.

*² For Fellows residing overseas, there would be no reduction of annual subscription. Fellows residing overseas can apply for changing their category of membership to Overseas Fellows (this category has no voting right).

*³ For Founder Fellows, Fellows and Overseas Fellows with Retired Fellow Status as recorded in the College Register, the annual subscription would be HK$1,000 before 1^st of November 2006. Afterwards, only a nominal annual subscription of HK$100 would be applied. Fellows concerned must inform the College immediately should there be any change of their retired status and the reduced rate will cease to apply thereafter.  Please refer to the form for “Application for Change of Fellowship Status” for the rights and privileges of Fellows with retired status.

*⁴ For Overseas Fellows residing in Hong Kong for more than 3 months, the annual subscription would be reverted back to the annual subscription of Fellows.

Training & Examinations Committee

Type of Examination	Examination / Exemption Fee
Fellowship Assessment	$22,000
Membership Examination	$18,000
Membership Examination Exemption	$18,000
Supplementary Examination	$18,000

Description	Administrative Fee
Annual Trainee Registration#	$800
Retrospective recognition of the whole or part of laboratory training period after 6 months from the commencement of training	$2,000
Late Submission of Annual Report	$500

Remark:

# The annual trainee registration fee is waived if the registered trainee is an Associate or Member of the College.

Education Committee

Description	Administrative Fee
Late submission of CME/CPD Record Annual Update	$500
Retrospective report of CME/CPD activities after submission of CME/CPD Annual Return	$500
Administration of CME/CPD activities for Retired Fellows	Balance of the Annual Subscriptions between Full and Retired Fellows

Credentials & Appeals Committee

Description	Administrative Fee
Appeal against examination result	$2,000

Remark:

^# A written request must be submitted to Registrar within 3 months from the date of the letter notifying the examination result.

Replacement of Certificate

Type of Certificate	Replacement Fee
Membership Certificate	$1,000/certificate
Fellowship Certificate	$2,000/certificate

Remark:

^# A written request must be submitted to Registrar.

Regalia Loan Service

Regalia Loan Period	Service Fee
1 to 3 days	$150/set
4 to 6 days	$250/set
7 to 10 days	$350/set
Each additional day after 10 days	$30/set/day

Remarks:

^# The College Regalia is available for loan to all Members and Fellows.

^# Users are required to submit the Regalia Loan Form to the College Secretary either by fax, post or email at least 2 weeks before the loan period, and inform the College Secretary of any additional day of Regalia loan service beforehand.

^# Payment for Regalia loan service should be made by cheque payable to “The Hong Kong College of Pathologists”. Cheque should be sent with the Regalia Loan Form by post or in person to the College Secretary.

^# Collection of Regalia will be arranged at the Chamber of the Hong Kong College of Pathologists when both the loan form and the cheque are received. Collection time: from 9:00 am to 5:00 pm, Monday to Friday.

^# Users are responsible for keeping the Regalia in good condition and are bound by the rules and regulations stipulated in the Regalia Loan Form.

2019 College Annual Report and Year Book 2018-19

The 2019 College Annual Report and Year Book are available for download

Annual Report 2019

Year Book 2018-19 2019

 

Results of College Exam 2019 (Council Meeting 24 September 2019)

 

Fellowship Assessment:

 

EXAM NO.	RESULT
E19201	PASS
E19202	FAIL
E19203	PASS
E19204	FAIL
E19205	FAIL
E19206	FAIL
E19207	FAIL
E19208	FAIL
E19209	FAIL
E19210	PASS
E19211	PASS
E19212	PASS
E19213	PASS
E19214	PASS
E19215	FAIL
E19216	PASS
E19217	FAIL
E19218	PASS
E19219	PASS
E19220	PASS

 

Membership Examination:

 

EXAM NO.	RESULT
E19101	PASS
E19102	FAIL
E19103	PASS
E19104	FAIL
E19105	FAIL
E19106	PASS
E19107	PASS
E19108	FAIL
E19109	PASS
E19110	FAIL
E19111	FAIL
E19112	PASS

 

 

 

Recent Advance in Acute Lymphoblastic Leukaemia

 

Volume 14, Issue 2, August 2019  (download full article in pdf)

 

Editorial note

Dr. Albert Sin
Clinical Assistant Professor

 

Introduction

Acute lymphoblastic leukaemia (ALL) is an aggressive and highly fatal malignancy resulting from clonal mutations of lymphoid progenitor cells. The incidence of ALL is the most common in childhood and age after 50.¹⁸The prognosis of childhood ALL is good with long-term survival rate approaching 90% treated by intensive chemotherapy.¹²Although the incidence of ALL is less in adolescent, young adult as well as adult, the prognosis of ALL in those people is very poor, with only 30-40% of adult patients able to remit.¹⁸ According to the data from US database which registered all patients with diagnosed ALL from 2000 to 2007, the survival rate was 75% at 17 years old, 45% at 20 years old and 15% at 70 years old.¹⁴An increasing knowledge of disease biology of ALL transformed into insights for development of novel therapies to improve the treatment outcome of ALL.

One of the reasons of adverse prognosis in adolescent and young adult (AYA) as well as adult patients is that they commonly harbored poor-risk genetic aberrations while less patients carried favorable genetic lesion.¹⁴This could explain the sudden drop in survival from 17 years old to 20 years old. 

 

Ph-like ALL

Ph-like ALL is a newly identified genetic subgroup. The genetic profile of this subgroup of ALL is similar to that of Philadelphia chromosome positive (Ph-positive) ALL but without BCR-ABL1 fusion.¹⁷They have a higher frequency of IKZF1 deletion and mutation in genes of lymphoid transcription factors with poor survival.¹⁹The incidence of Ph-like ALL increases with ages and approaching 27% of cases of adult B-ALL.¹⁴

The nature of genetic aberration is heterogeneous. Despite its complexity, it can be simply classified into five subgroups: 1. CRLF2 rearrangement 2. Rearrangement of ABL-class gene 3. Rearrangement of JAK2 and EPOR 4. Aberrations leading to activation of JAK-STAT or MAPK pathway 5. Other rare kinase alterations.¹⁹The distribution of different types of genetic alterations are different among childhood high risk ALL, young adult and adult (Figure 1). CRLF2 rearrangement is the most common type of genetic alteration in Ph-like ALL. CRLF2 gene is responsible for producing lymphopoietin receptor and regulate the process of lymphopoiesis. Common mechanisms of CRLF2 rearrangement include 1. Translocation of CRLF2 gene into IGH gene 2. Fusion between CRLF2 gene and P2RY8 gene. 3. Point mutation F232C at CRLF2 gene. Nearly 50% of CRLF2 rearranged Ph-like ALL have concomitant JAK mutations.¹⁹

Figure 1

 

Diagnosis of Ph-like ALL

Genetic profiling is the gold standard for the diagnosis of Ph-like ALL. However, it is difficult to implement in routine diagnostic laboratory. 

Cytogenetics analysis is a standard test for all cases of ALL which allows a global assessment of chromosomal abnormalities. Some of the recurrent genetic abnormalities, for example t(9;22), hyperdiploidy/hyperdiploidy,   rearrangement involving 11q23, etc, can be detected. However, most of the Ph-like ALL genetic alterations are cryptic, e.g. interstitial deletion of CRLF2, ETV6-RUNX1 fusion, etc and thus they cannot be detected by conventional cytogenetics.²

Fluorescent in-situ hybridization (FISH) can be utilized to detect Ph-like ALL genetic abnormalities. Breakapart probes targeting genes most frequently genes including ABL1, ABL2, PDGFRB, JAK2, CRLF2, and P2RY8 are currently available. Although the positive result upon FISH study needs additional fusion probe for confirmation, it provides a readily available and useful diagnostic tool for establishing the diagnosis of Ph-like ALL. However, some of the important Ph-like ALL genetic rearrangement including intrachromosomal inversions (e.g., inv(9) resulting in PAX5-JAK2 fusion), intra-chromosomal deletions (e.g., del(X)(p22p22)/del(Y)(p11p11) resulting in P2RY8-CRLF2 fusion) are undetectable by FISH technique.²Targeted sequencing by NGS platform is an evolving technique for diagnosis.¹⁶

Recently, antibody against CRLF2 is available for flow cytometry study. The expression of CRLF2 as detected by multiparametric flow cytometry is correlated with genetic testing for CRLF2 rearrangement.¹⁵This provides a rapid tool for identifying potential cases of Ph-like ALL before the result of genetic tests is available. 

Most of the genetic alterations of Ph-like ALL are targetable kinase lesions, which could be treated by tailored kinase inhibitor therapy (Table 1).¹⁹This approach of therapy is current undergoing extensive preclinical studies.⁹

 

Early T-cell precursor ALL (ETP-ALL)

ETP-ALL is recently characterized subtype of T-ALL. It constitutes around 12% of childhood ALL and 7.4% of adult ALL.¹¹Genetic profiling showed ETP cells are similar to that of haemopoietic stem cells and myeloid progenitor cells.⁴This subgroup of ALL is characterized by the unique immunophenotype: cytoplasmic CD3+, surface CD3-, CD1a-, CD2-, CD5 dim (<75% positive), CD7 and positive for one or more stem cell and/or myeloid markers including HLA-DR, CD13, CD33, CD34, or CD117.⁵

While activating mutation of NOTCH1 is a common mutation found in ALL and it account for 50% of cases of childhood ALL, this mutation is less common in ETP-ALL.³ETP-ALL commonly have mutations in FLT3, DNMT3A, IDH1, IDH2, etc.¹¹

ETP-ALL carries a poor prognosis with inferior overall survival when treated with standard chemotherapy regimen comparing with other subtypes of T-ALL.¹¹This subgroup of T-ALL represented a distinct subtype with unique genetic profile and poor prognosis. 

 

MRD in adult ALL

Minimal residual disease (MRD) describe the very low level of disease burden which cannot be detected by morphology. Measurement of MRD not only pick up a submicroscopic level of disease but also can monitor the disease kinetic during the treatment process of haematological malignancies.¹⁰

The following techniques can be used to detect MRD: 

1. Multiparametric flow cytometry to detect leukaemia-associated immunophenotype (LAIP)
   By using a 4-color or 6-color panel of antibodies, we can identify LAIP in 90% of ALL caes.¹⁰Flow cytometry is a quick method and the result of MRD can be generated in a short period of time for clinical decision. The sensitivity of MRD detection by this method is 0.01%. However, in order to define the positive MRD, we need 10-40 cluster of cells and thus higher number of cells are required for assessment which may be difficult for reassessment samples after intensive chemotherapy.⁷In addition, antigenic shift is commonly occurred in leukaemic cells and normal cells during the therapy. The use of monoclonal antibodies, e.g anti-CD19, anti-CD22 for treatment of ALL will affect the gating strategy used to identify the leukaemic cells.¹⁰


2. Detecting leukaemia-specific fusion transcript by PCR technique
   Quantitative reverse-transcriptase PCR can be employed to detect the amount of leukaemia-specific fusion transcript. The sensitivity is higher compared with flow cytometry (10^-4to 10^-6).⁷The test is relatively easy to be performed in standardized diagnostic laboratory. However, only 30-40% of cases of ALL carry leukaemia-specific fusion transcript and thus limited the eligibility of MRD detection by this method. Moreover, the interpretation is challenging for RNA-based test in those cases will poor RNA quality.


3. Quantitative PCR for immunoglobulin (IG)-T cell receptor (TCR) gene targets
   Quantitative PCR is employed to detect the specific sequence of rearranged IG gene or TCR gene in the sample. The sensitivity of this method is 10^-4to 10^-5and this method can be applied to all cases of ALL. However, this method of MRD detection requires prior characterization of IG or TCR gene rearrangement by sequencing and designs patient-specific primers for each case for subsequent MRD detection. Extensive standardization and experience are needed for the laboratory to set up this test, which limit the use of this method of MRD detection in diagnostic laboratory. Moreover, the clonal evolution in leukaemic blasts during treatment can make the original rearranged sequence to be lost and thus generate a false negative result. Also, the non-specific primer annealing occurs during the process of marrow regenerative may yield false positive result for the test.⁷

 

Application of MRD in treatment of adult ALL

MRD-guided therapy had been gained extensive experience in childhood ALL.⁸The study group of German Multicenter Study Group for Adult ALL (GMALL) had conducted largest study for the role of MRD in adult Ph-negative ALL. They showed that molecular remission is the only parameters significantly affect the remission duration and survival.⁶Patients with positive MRD after induction therapy achieved better overall survival after receiving haemopoietic stem cell transplant. Early achievement of MRD negativity after induction chemotherapy is associated with good outcome for adult ALL.¹⁰Study showed that MRD level correlates with post-transplant outcome.¹³Another group found that haemopoietic stem cell transplant benefits the patients with positive MRD at week 6.¹These findings may prompt reconsideration of the indications of haemopoietic stem cell transplant for adult patients with ALL, especially those patients achieve MRD negativity after treatment. 

 

Concluding landmark

The prognosis of acute lymphoblastic leukaemia in young adolescent and adult is poor. The recent discovery of new subtype of acute lymphoblastic leukaemia with characterization of genetic lesions make a breakthrough of understanding of disease biology. Precise disease prognostication can be made. Targeted therapies are being developed for treating those patients. Clinical trials are conducting for evaluating the targeted therapies in those new subtypes of acute lymphoblastic leukaemia. Moreover, the application of MRD monitoring and MRD-adapted therapy in adult ALL can further stratified the patients and select the appropriate candidates of haemopoietic stem cell transplant in order to reduce transplant-related mortality and morbidity. The advances in understanding of molecular mechanism and disease biology of ALL help to improve the risk stratification, rapid development of targeted therapies and hopefully improve the prognosis in young adolescent and adult patients. 

 

 

Reference

 

1. Beldjord K., Chevret S., Asnafi V., Huguet F., Boulland ML., Leguay T., Thomas X., Cayuela JM., Grardel N., Chalandon Y., Boissel N., Schaefer B., Delabesse E., Cavé H., Chevallier P., Buzyn A., Fest T., Reman O., Vernant JP., Lhéritier V., Béné MC., Lafage M., Macintyre E., Ifrah N., Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL). (2014) Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood, 2014,12;123(24):3739-49.
2. Bradford J. Siegele., Valentina Nardi. (2018). Laboratory testing in BCR-ABL1-like (Philadelphia-like) B-lymphoblastic leukemia/lymphoma. Am J Hematol, 2018(93):971–977.
3. Chao Gao., Shu-Guang Liu., Rui-Dong Zhang., Wei-Jing Li., Xiao-Xi Zhao., Lei Cui., Min-Yuan Wu., Hu-Yong Zheng and Zhi-Gang Li. (2014) NOTCH1 mutations are associated with favourable long-term prognosis in paediatric T-cell acute lymphoblastic leukaemia: a retrospective study of patients treated on BCH-2003 and CCLG-2008 protocol in China. Br J Haematol, 2014, 166(2):221-8. doi: 10.1111/bjh.12866
4. Elaine Coustan-Smith., Charles G Mullighan., Mihaela Onciu., Frederick G Behm., Susana C Raimondi., Deqing Pei., Cheng Cheng., Xiaoping Su., Jeff rey E Rubnitz., Giuseppe Basso., Andrea Biondi., Ching-Hon Pui., James R Downing., Dario Campana. (2009) Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.Lancet Oncol, 2009(10):147–56
5. Elizabeth A. Raetz and David T. Teachey. (2016) T-cell acute lymphoblastic leukemia. Am Soc Haemaetolo Educ Program, 2016(1), 580-588
6. Gökbuget N., Kneba M., Raff T., Trautmann H., Bartram CR., Arnold R., Fietkau R., Freund M., Ganser A., Ludwig WD., Maschmeyer G., Rieder H., Schwartz S., Serve H., Thiel E., Brüggemann M., Hoelzer D; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. (2012) Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood, 2012,120(9):1868-76.
7. Jacques J. M. van Dongen., Vincent H. J. van der Velden., Monika Br¨uggemann and Alberto Orfao. (2015) Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies.Blood, 2015;125(26):3996-4009
8. Marianne Ifversen., Dominik Turkiewicz., Hanne V. Marquart., Jacek Winiarski., Jochen Buechner., Karin Mellgren., Johan Arvidson., Jelena Rascon., Lenne-Triin Ko¨rgvee., Hans O. Madsen., Jonas Abrahamsson., Bendik Lund., Olafur G. Jonsson., Carsten Heilmann., Mats Heyman., Kjeld Schmiegelow., Kim Vettenranta. (2019) Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience. British Journal of Haematology, 2019(184): 982–993
9. Maude SL, Tasian SK, Vincent T, et al. (2012) Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Blood, 2012;120(17):3510-3518.
10. Monika Bru¨ ggemann and Michaela Kotrova. (2017) Minimal residual disease in adult ALL: technical aspects and implications for correct clinical interpretation. Hematology Am Soc Hematol Educ Program.2017(1):13-21. doi: 10.1182/asheducation-2017.1.13.
11. Nitin Jain., Audrey V. Lamb., Susan O’Brien., Farhad Ravandi., Marina Konopleva., Elias Jabbour., Zhuang Zuo., Jeffrey Jorgensen., Pei Lin., Sherry Pierce., Deborah Thomas., Michael Rytting., Gautam Borthakur., Tapan Kadia., Jorge Cortes., Hagop M. Kantarjian., Joseph D. Khoury. (2016) Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood, 2016;127(15):1863-1869
12. Paul, S., Kantarjian, H., & Jabbour, E. J. (2016). Adult Acute Lymphoblastic Leukemia. Mayo Clin Proc, 91(11), 1645-1666. doi:10.1016/j.mayocp.2016.09.010
13. Renato Bassan., Monika Brüggemann., Hoihen Radcliffe., Elizabeth Hartfield., Georg Kreuzbauer., Sally Wetten. (2019) A Systematic Literature Review And Meta-Analysis Of Minimal Residual Disease As A Prognostic Indicator In Adult B-Cell Acute Lymphoblastic Leukemia. Haematologica,2019 Mar 19. pii: haematol.2018.201053. doi: 0.3324/haematol.2018.201053.
14. Roberts KG. (2018) Genetics and prognosis of ALL in children vs adults. Hematology Am Soc Hematol Educ Program. 2018(1):137-145. doi: 10.1182/asheducation-2018.1.137.
15. Sergej Konoplev., Xinyan Lu., Marina Konopleva., Nitin Jain., Juan Ouyang., Maitrayee Goswami., Kathryn G. Roberts., Marc Valentine., Charles G. Mullighan., Carlos Bueso-Ramos., Patrick A. Zweidler-McKay., Jeffrey L. Jorgensen and Sa A. Wang. (2017) CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients: A Single-Institution Experience. Am J Clin Pathol, 2017(147):357-363
16. Stadt UZ., Escherich G., Indenbirken D., Alawi M., Adao M., Horstmann MA. (2016) Rapid Capture Next-Generation Sequencing in Clinical Diagnostics of Kinase Pathway Aberrations in B-Cell Precursor ALL. Pediatr Blood Cancer, 2016;63(7):1283-6. doi: 10.1002/pbc.25975
17. Tasian, S. K., Loh, M. L., & Hunger, S. P. (2017). Philadelphia chromosome-like acute lymphoblastic leukemia. Blood, 130(19), 2064-2072. doi:10.1182/blood-2017-06-743252
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Results of College Written Exam in Chemical Pathology & Clinical Microbiology and Infection 2019
 

EXAM NO.	RESULT
E19213	PASS
E19214	PASS
E19216	PASS
E19217	PASS

Candidates who failed in written exam cannot proceed further in Fellowship Assessment in 2019.
Passed candidates can proceed further in Membership or Fellowship Assessment in 2019.

Volume 28, Issue 2 (click here to download the full pdf version)

Message from the President

Dear Fellows and Members,

In this issue of College Newsletter, I have to bring very sad news to all Members and Fellows. Our Past President, Dr. Michael Suen passed away peacefully on 6 January 2020 after battling against cancer for over 2 years. Dr. Suen was a leader with traditional Chinese wisdom, an excellent practising pathologist, a resourceful and encouraging mentor, a good friend with whom you can share your feelings, a caring husband and father. He was a great role model for our community, College, trainees, colleagues and his family members. We will never forget his smiling face and warm words of encouragement, in particular, during times of difficulty. May Dr. Suen rest in peace.

On the other hand, there is a series of good news for our College in the past year. The breaking good news is the award of Professor Dennis Lo, Li Ka Shing Professor of Chemical Pathology, who was admitted as Honorary Fellow of The Hong Kong Academy of Medicine in December 2019 in recognition of his contribution to the field of cell-free plasma DNA for non-invasive prenatal and cancer diagnostics.

The second good news is the award of Distinguished Young Fellows 2019 to Dr. Elaine Au, Consultant Immunologist and Dr. David Christopher Lung, Consultant Microbiologist. They received the award from Professor CS Lau, Academy President, in September 2019.

The third good news is the successful Membership Examination and Fellowship Assessment for candidates in Anatomical Pathology, Chemical Pathology, Clinical Microbiology and Infection, Forensic Pathology as well as Haematology in August and September 2019.

The fourth good news is the successful completion of the First Fellow Assessment for candidates in Genetic and Genomic Pathology in October 2019. The College Examinations could not have been successfully conducted without the help of our External Examiners, Chief Examiners and Local Examiners. During the past months of social unrest, some of our External Examiners were not able to come to Hong Kong physically. Tele-communication was adopted to be the alternative option by the College and Academy. Thank you for the hard work and contributions from all examiners.

The fifth good news would be the award of The DS Nelson Trainee Oral Prize to Dr. Timothy Cheng, at the ‘Pathology Update 2019’ Conference in Melbourne. The title of his presentation was ‘Noninvasive Detection of Bladder Cancer by Shallow-Depth Genome-Wide Bisulfite Sequencing of Urinary Cell-Free DNA for Methylation and Copy Number Profiling’.

In this issue, the Topic Update was on “Recent Advances in Acute Lymphoblastic Leukaemia “ by Dr. Albert Sin, and the Out of the White Coat Interviewee was Dr. Clarence Lam, Consultant Haematologist.

The International Pathology Day Pre-Workshop was conducted to induce medical students to explore various disciplines of pathology in November 2019. Again due to social unrest, the International Pathology Day was postponed to a Saturday before Christmas when it was successfully conducted at the Pathology Teaching Laboratory of The Chinese University of Hong Kong, Prince of Wales Hospital.

Finally, let me wish all of you a Prosperous Chinese New Year of the Rat!

Dr. CHAN Ho Ming
President

Jan 2020

Volume 28, Issue 1 (click here to download the full pdf version)

Message from the President

This is the first issue of our College Newsletter in 2019. In 2018, College was busy with conducting the activities associated with the new training programme in Genetic and Genomic Pathology including the second open forum and First Fellow application. We are now processing numerous applications. An interview will be conducted in October 2019 to finalise the eligibility.

In 2018, the Hong Kong Academy of Medicine was also celebrating her 25th Anniversary with a series of fascinating events including the Congress of Medicine and Gala Dinner with an impressive drummer performance at the opening. Our Fellow, Prof. YUEN Kwok Yung was the Sir David Todd Orator in 2018. He presented his journey to becoming a renowned microbiologist with multiple showcases of Sherlock Holmes-style investigations for our community. In early 2019, the Academy also conducted a visit to Sichuan for our Young Fellows, so as to increase their understanding of the development of specialist care in Mainland China. Dr. MAK Siu Ming and Dr. CHENG Shui Ying, Ivy, represented our College to participate in this visit.

In March 2019, the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPA-QAP) held one of their 30th Anniversary Quality Symposia in the Pao Yue Kong Auditorium at the Hong Kong Academy of Medicine Jockey Club Building. Local and overseas speakers came to give talks and opinions on how quality can be exercised as well as the future of quality in pathology. What an enjoyable experience-sharing opportunity!

In the recent issue of Topical Update, Dr. CHONG Yeow Kuan, Calvin reviewed the technological development of biochemical genetics on three major categories of inherited metabolic diseases. With the introduction of expanded newborn screening using mass spectrometry, there is increasing awareness of these conditions in the community.

Last but not the least, Dr. CHAN Sheung Wai, Gavin will share his concept of modern mortuary development, with a life paradigm shift from just being a place for the dead to a decent environment of bereavement for the family.

I would like to thank all the above Fellows who have contributed so much to the build a positive image of pathologists. Hope you enjoy this issue of Pathologue!

Dr. CHAN Ho Ming
President

May 2019

Results of College Supplementary Autopsy Exam 2018 (Council Meeting 19 March 2019)

 

Exam No.	Result
ES18101	PASS