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ORIGINAL ARTICLE
Year : 2020  |  Volume : 23  |  Issue : 1  |  Page : 33-40

Evaluation of laboratory investigative methods of diagnosing clonal hematological disorders in a resource-poor setting


1 Department of Hematology and Immunology, College of Medicine, University of Nigeria, Ituku/Ozalla Campus, Enugu, Nigeria
2 Department of Hematology and Immunology, College of Medicine, Chukwuemeka Odumegwu Ojukwu University, Awka Campus, Awka, Nigeria
3 Department of Hematology and Immunology, College of Medicine, University of Port Harcourt, Nigeria

Date of Submission16-Nov-2018
Date of Acceptance04-Sep-2019
Date of Web Publication10-Jan-2020

Correspondence Address:
Dr. C C Efobi
Department of Hematology and Immunology, College of Medicine, Chukwuemeka Odumegwu Ojukwu University, Anambra
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_580_18

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   Abstract 


Background: The successful treatment of patients with clonal hematological disorders (CHDs) depends largely on making an accurate diagnosis, which is, in turn, is dependent on performing specific diagnostic tests that are necessary. Objectives: This study assessed the laboratory investigative methods of diagnosing CHDs with regard to the specific required tests (SRTs) that were needed to make a final diagnosis in a center with limited resources. Methods: This is a descriptive hospital-based retrospective study. For the study, data about laboratory investigation details of adults diagnosed with CHDs from 1995 to 2015 were retrieved. The SRTs were determined and data analyzed using SPSS version 20. Results: A total of 129 case notes of adults in the age range of 18–80 years, diagnosed with CHDs, were used. Out of the 671 SRTs needed for diagnosis, only 304 (45.3%) were conducted. When an SRT was requested to be done within the treatment facility, the patients were significantly more likely to do it in comparison with when they were requested to get it done from an external referral laboratory. All the patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) had all (100%) their SRTs done while patients with non-Hodgkin's lymphoma (NHL) had the least (15.3%) of their SRTs done. Full blood count (FBC) was the most frequently used (n = 129; 100%) SRT for diagnosis while immunophenotyping (IMPT) was the least (n = 4; 8.3%) used SRT. Conclusion: Most of our patients had CHD diagnosis without the complete SRT, and this may cast doubt on the accuracy of diagnosis. Therefore, there is a crucial need for availability of more comprehensive laboratory services, especially in government-owned hospitals.

Keywords: Assessment, hematological cancers, laboratory tests, low-income country


How to cite this article:
Okoye H C, Efobi C C, Korubo K. Evaluation of laboratory investigative methods of diagnosing clonal hematological disorders in a resource-poor setting. Niger J Clin Pract 2020;23:33-40

How to cite this URL:
Okoye H C, Efobi C C, Korubo K. Evaluation of laboratory investigative methods of diagnosing clonal hematological disorders in a resource-poor setting. Niger J Clin Pract [serial online] 2020 [cited 2020 Jul 14];23:33-40. Available from: http://www.njcponline.com/text.asp?2020/23/1/33/275627




   Introduction Top


Clonal hematological disorders (CHDs) include both premalignant and malignant disorders. The premalignant disorders include aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS) while the malignant disorders include acute leukemia (AL), myeloproliferative neoplasms, lymphomas, and multiple myelomas (MM).[1–3] These clonal disorders require both diagnostic and supportive investigative procedures performed at the time of making a diagnosis and during monitoring of therapy; however, in a resource-poor setting, this poses a challenge.[4] Over the years there has been progress in diagnosing these disorders, increasing the accuracy of diagnosis. Some routine hematological investigations, such as full blood count (FBC), peripheral blood film (PBF), and bone marrow examination, are readily available and relatively affordable, and they are crucial in the diagnosis of certain disorders, such as leukemia. On the other hand, highly specialized tests, such as karyotyping, immunophenotyping (IMPT), and molecular methods, increase the accuracy and specificity of diagnosis, but they are not readily available and are expensive. These specialized tests are important in confirming the diagnosis of a clonal disorder,[5],[6] especially in AL and lymphoid malignancies, where FBC findings and morphology of the peripheral blood and bone marrow may be insufficient.[7] The aim of this study was to assess the laboratory methods of investigating CHDs with respect to the specific required tests (SRTs) that were performed during diagnosis in a center with limited resources.


   Methods Top


The study was a hospital-based, retrospective study conducted at the University of Port Harcourt Teaching Hospital, which is an 800-bed tertiary center in the Southern region of Nigeria. The hospital also serves as a referral center for neighboring states.

Ethical approval was received from the hospital's ethical committee. The case notes of adult patients (18 years and above), who had been diagnosed with any of the CHDs within a 20-year period, from September 1995 to August 2015, were retrieved from the department of hematology/blood transfusion and medical records unit of the hospital. Data on patients' biodata and sociodemographic were collected. Also, retrieved were data on the definitive diagnosis and details of the investigations used in arriving at the definitive diagnosis, including SRTs and where the tests were done, whether it was within the hospital or elsewhere. Case notes with incomplete data, for example, inconclusive diagnosis, incomplete biodata, and investigation results required to make a diagnosis were excluded. SRT was defined as the specific investigation required in making a diagnosis for each of the clonal disorders. The tests will be specific to a particular disorder; hence, they will differ from one clonal hematological disorder to the other. Data were collected and recorded into Microsoft Excel® worksheets while analysis was done using SPSS version 20. Using descriptive statistics, results were expressed numerically as frequencies and means and a P < 0.05 was considered significant.


   Results Top


There was a total of 129 patients with CHDs whose case notes were used for the study, 74 (57.4%) were males while 55 (42.6%) were females. The median age was 46 years (range 18–80 years). [Figure 1] shows the distribution of the various CHDs diagnosed. Of all the CHDs, FBC was required for diagnosis in 63 cases (48.8%), lymph node (LN) biopsy (n = 23; 17.8%), bone marrow aspiration/bone marrow biopsy (BMA/BMB) (n = 22; 17.1%), serum protein electrophoresis (SPEP) (n = 14; 10.9%), BCR/ABL analysis (n = 5; 3.9%), Philadelphia chromosome (Ph) karyotyping (n = 4; 3.1%), IMPT (n = 4; 3.1%), and serum-free light chains (sFLC) (n = 2; 1.6%).
Figure 1: Distribution of the clonal haematological disorders in patients Key: PNH = Paroxysmal nocturnal hemoglobinuria, MDS = Myelodysplastic syndrome, MPN = Myeloproliferative neoplasm, MM = Multiple myeloma, NHL = non-Hodgkinfs lymphoma, H =. Hodgkinfs lymphoma, CML = Chronic myeloid leukaemia, CLL = Chronic lymphocytic leukaemia

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The SRTs were the specific investigations required to make a diagnosis for each clonal disorder. AL, non-Hodgkin lymphoma (NHL), and MM had the highest number of SRTs (n = 7). AL required FBC, PBF, bone marrow examination, cytochemistry, IMPT, cytogenetics, and molecular analysis. The NHLs required LN or tissue biopsy and immunohistochemistry (IHC); however, an FBC was not required for diagnosis. In MM, the SRTs included FBC, bone marrow examination, renal function test, SPEP, SFLC, and skeletal survey. [Table 1] shows the full list of the SRTs required for making the diagnosis of each clonal disorder while [Table 2] gives a summary of the SRTs performed by the patients in order of frequency. The laboratory investigations that were done within the hospital included FBC, PBF, hemoglobinuria, serum calcium, S/E/U/Cr skeletal survey, LN and tissue biopsy, BMA/BMB, and cytochemistry. Whereas, the ones performed in referral laboratories were SPEP, JAK2, FLC, BCR-ABL, Ph+ karyotype, IMPT, cytogenetics, molecular genetics, IHC, Mpl, and CALR. The most common investigation was FBC, which was done by all patients, while the least common was IMPT done by only 4 (8.3%) of those requiring it for their diagnosis.
Table 1: List of required investigations required for the diagnosis of clonal disorders

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Table 2: SRTs performed by patients in order of frequency

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Altogether, the 129 patients required 671 SRTs, but only 304 were performed, giving a 45.3% rate of performing the SRT across the various CHDs. The various SRTs were performed both within the hospital (nine SRTs) and outside the hospital at external referral laboratories (11 SRTs) (see [Table 2]). Within the hospital, 354 SRTs were requested to be performed, of which 268 (75.7%) were done. While, 317 SRTs were requested to be performed at an external referral laboratory, of which 36 (11.4%) were done. Therefore, the proportion of SRTs requested and those actually performed within the hospital were significantly higher than those requested but actually performed at an external referral laboratory (75.7% vs. 11.4%; P < 0.0001). The six patients with AA and single patient with PNH had all their SRTs done. Patients with MM and MDS on an average had 75.7% and 75% of their SRTs done, respectively. Patients with NHL had the least mean number of SRTs done, with an average of 15.3% of SRTs. [Table 3] shows the various SRTs required for each clonal disorder, with the mean number performed by patients in each group of CHDs.
Table 3: Mean number (%) of SRTs done by patients per disorder

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   Discussion Top


In this study, we reported that 129 patients required 671 SRTs, but only 304 SRTs were performed, giving a rate of performance of 45.3% across the various CHDs. The proportion of SRTs requested and actually performed within the hospital were significantly higher than those requested but actually performed at an external referral laboratory. The most common investigation was FBC, which was done by all patients, while the least common was IMPT, done by only 4 (8.3%) of those requiring it for their diagnosis.

Usually, the primary evaluation of a CHD begins with the use of basic hematological tests, such as the FBC and PBF. The FBC and PBF are readily available in most centers, affordable, and frequently performed together.[8] Therefore, it is unsurprising that FBC was done for all the patients while the majority had a PBF review. Although the FBC and PBF are essential basic tests, they have their limitations and, most of the time, they require further investigations for making a final diagnosis. The PBF is an informative and accessible piece of investigation, which is very useful, especially in our resource-limited center. The PBF can distinguish between chronic and AL, indicate the presence of blasts or dysplasia, differentiate between myeloid and lymphoid cells (especially in the mature forms), detect lymphomas with a leukemic spill, etc.[9] Based on the findings of the FBC and PBF, a bone marrow examination may be requested. Although the PBF or BM examination have their limitations and are prone to interobserver errors in diagnosing CHDs, they are still very important in the preliminary workup of patients and help to determine what further definitive tests are required. In recent times, with the availability of highly specialized investigations, the diagnostic criteria for several CHDs (such as lymphomas, MPNs, and AL) keep on being modified to include these novel tests.[10],[11]

To make an accurate diagnosis of AL, the mandatory investigations are FBC, morphologic analysis of the peripheral blood and/or bone marrow to demonstrate the presence of blasts >20%, IMPT (to determine presence/absence of specific cellular markers), and cytogenetic and molecular analysis (to determine the presence of chromosomal mutations).[12–14] In our patients, the diagnosis of AL was mostly based on morphology alone (from peripheral blood and bone marrow); IMPT was done for only one patient. Morphology may sometimes clearly distinguish the specific type of AL, e.g. in using the French–America–British (FAB) classification acute lymphoblastic leukemia (ALL) L3 subtype and acute myeloid leukemia (AML) M3 subtypes are easy to differentiate because of multiple cytoplasmic vacuoles and  Auer rods More Details, respectively.[15],[16] However, the limitation of the FAB classification is that in AL, blasts may resemble each other and cannot be distinguished using morphology alone, e.g. AML M0 and ALL L1 or L2 may appear similar because these blasts do not usually have granules. It is also important to note that a few cases of ALL exhibit granules in the lymphoblasts, which may be confused morphologically as myoblasts.[17–20] Moreover, haematogones, which are benign lymphoid precursors, are morphologically indistinguishable from lymphoblasts.[21] Accurate diagnosis determines specific therapy given to patients because none of our patients with AL had cytogenetic studies done, those who may have had recurrent chromosomal abnormalities, such as t (15:17) in AML-PML/RARA or BCR/ABL positive ALL would have been missed and this will directly affect outcome in these patients as these mutations have targeted therapy.[22],[23] Therefore, it is difficult to determine the accuracy of our diagnoses of AL in these patients as patients with AML may have been diagnosed as ALL or vice versa, and this would have affected treatment given to these patients. Although our study did not follow-up patients in terms of response to treatment given, if the wrong diagnosis was made and, therefore, wrong treatment was given, it would adversely affect the outcome in the patient. Being a resource-poor center, facilities for IMPT and cytogenetic and molecular studies are largely unavailable in government institutions like ours,[4],[9] but these tests can be done in some privately managed/external referral laboratories. Although these specialized tests were requested for our patients, most of them were not able to afford the cost of running these tests; therefore, they were not done.

The NHLs are a broad group of clonal lymphoid disorders, some of which have specific genetic mutations and characteristics warranting specific diagnostic criteria as recommended by the 2016 World Health Organization (WHO) classification of lymphoid neoplasms. Diagnostic investigations for NHL include excisional LN biopsy for histology and IHC, IMPT by flow cytometry, molecular analysis, and fluorescent in situ hybridization.[24] In our study, patients with NHL had the least number of SRTs performed. Although a majority of our NHL cases had LN biopsies, there were still a few cases with high index of suspicion who did not have LN biopsies done due to financial constraints; however, BMB made a histological diagnosis of lymphoma in those cases which were included in this study. IMPT may be done by IHC or flow cytometry. Only a couple of our cases had IMPT done by flow cytometry, but none of them had IHC. In as much as histological diagnosis informed our decision to manage as NHL, histological diagnosis limited the classification of NHL into the various subtypes.[13],[25] With regard to Hodgkin's Lymphoma (HL), the diagnosis can be made by the demonstration of Hodgkin and Reed–Sternberg cells on histology and confirmation of the characteristic immunophenotype by IHC.[26–28] All our HL patients had LN biopsy, and although IHC was not performed for anyone of them, the diagnosis of HL in our patients may be more accurate, unlike those diagnosed with NHL, because the histology of HL is more informative in terms of classification of HL into specific subtypes as compared to NHL, which requires further testing than histology for a final diagnosis.

The accurate diagnosis of chronic lymphocytic leukemia (CLL) requires a combination of lymphocyte morphology, presence of >5 × 109/L of circulating clonal lymphocytes and demonstration of the characteristic immunophenotypic pattern to differentiate CLL from other mature B-cell neoplasms, which have a similar morphologic appearance.[29],[30] Therefore, flow cytometry is essential in diagnosing CLL to demonstrate clonality and confirm diagnosis. A CLL score was developed to differentiate CLL from other monoclonal B-cell neoplasms (MBCNs).[31],[32] As with most of the other CHDs diagnosed in our patients, FBC and PBF formed the basis of our patients' diagnosis of CLL. On the other hand, many of our CML patients had karyotype for Ph+ chromosome and molecular testing for the BCR-ABL mutation performed to make a definitive diagnosis of CML.[32] Most of the patients who did not have karyotyping or molecular testing done were patients who were managed prior to the availability of tyrosine kinase inhibitors (TKIs) for the treatment of CML in our environment. The requirement for BCR-ABL positivity for treatment with TKIs may have contributed to the number of our patients who had the molecular testing for CML done despite the cost of the test. The myeloproliferative neoplasms (MPNs) are characterized by the presence of specific genetic mutations, such as the JAK2, CALR, and MPL, in addition to the FBC and bone marrow findings.[12] These molecular tests are not available yet at our facility and were all performed at an external referral laboratory for the patients who could afford the tests.

According to the International Myeloma Working Group (IMWG), the diagnosis of MM requires the presence of ≥10% clonal plasmacytosis or plasmacytoma; a monoclonal protein with any of the features of myeloma defining events, which include hypercalcemia, renal impairment, anemia, and bone disease (CRAB); abnormal SFLC ratio; ≥60% bone marrow plasmacytosis; or magnetic resonance imaging (MRI) scan findings of lytic lesions.[33] Therefore, the tests used in the diagnosis include the FBC, bone marrow examination, X-rays or MRI for a skeletal survey, serum creatinine (to detect renal impairment), calcium assay, SPEP (to detect monoclonal proteins), and SFLC. Majority of these tests were available at our center; however, SPEP and SFLC requested for the patients had to be done at an external referral laboratory. While majority of our patients had SPEP done, the SFLC was only done for a minority. The cost of SFLC is about three times the cost of SPEP, and this may have played a significant role in limiting those who could access the service. Over two-thirds of our MM patients had their SRTs done, and as diagnosis may be made with bone marrow findings and presence of features of CRAB, this aided the diagnosis even in those who were unable to afford SPEP and SFLC, making MM the third most accurately diagnosed CHD in our patients (after AA and PNH).

For a suspected case of PNH, patients can be screened for hemoglobinuria, using urinalysis, while IMPT done by flow cytometry, which shows the lack of expression of GPI-anchored proteins (CD55 and CD59), confirms the diagnosis.[34],[35] We had only one case of PNH. Urinalysis is an easy-to-perform and inexpensive test that is capable of detecting hemoglobinuria in urine samples, if present, explaining why it was promptly done for the case of PNH. The diagnosis was confirmed by flow cytometry that, fortunately, the particular patient involved was able to afford. AA is a diagnosis made from the FBC (including reticulocyte count) and bone marrow examination,[36] and because these tests are readily available and affordable at our center, it is unsurprising that all the patients with AA had all their SRTs performed. Diagnosis of MDS is established by blood count cytopenias, dysplasia on bone marrow morphology and cytogenetic studies to demonstrate the presence of recurrent genetic mutations that occur in MDS.[12],[37] Our patients with MDS were diagnosed based on blood counts and morphology alone as none of them had cytogenetic studies done but this may have been sufficient in making a diagnosis in our low-income setting as cytopenia and morphology together are the cornerstone for the diagnosis and classification of MDS.[38]

From our study, the majority of CHDs in our patients were diagnosed using basic hematological tests while only a minority of cases was fully diagnosed using novel highly specialized tests. The accuracy in diagnosing these CHDs in our patients is questionable especially in disorders which require highly specialized tests to arrive at a final diagnosis, such as in the AL and lymphoid neoplasms. These molecular tests are also important in making early diagnosis even before the onset of symptoms but this was not the cases in our patients as no patient who had any form of molecular testing was asymptomatic at diagnosis. Tests such as the flow cytometry are also important in cell count. For example, our patients with MDS may have been wrongly classified based on their blast count using morphology alone; therefore, proper risk stratification was not achieved in these patients. Risk stratification is also done using cytogenetic studies for disorders like AL and MM, but this was also not achievable in our patients. Our center did not have the facility for many of the specialized tests required to make a diagnosis; therefore, for such investigation requests, patients were sent to an external referral laboratory.

In 2016, a national survey carried out on management of bleeding disorders reported that majority of the government-owned institutions were not well-equipped to make molecular/genetic diagnosis, and the few centers that had the facilities rarely performed the required tests.[9] Specialized hematological tests, such as molecular tests, are expensive due to the cost of the machines, such as the polymerase chain reaction (PCR) equipment; technical skill; and length of time involved for these tests. Many patients were not able to perform these tests due to financial constraints. It is possible that if these investigations are made available within the hospital they will cost much less due to government funding; they will also be more readily available and accessible to the patients requiring them as was seen in our study, where a majority of the investigations that were done were those performed within the hospital.

In conclusion, the diagnosis of CHDs in most of our patients was done using basic laboratory tests, such as the FBC, morphology of the blood, or bone marrow and tissue histology, but highly specialized tests like cytogenetics, IMPT were generally lacking. Updated diagnostic criteria for most of the CHDs require several of these highly specialized tests, which casts doubt on the accuracy of diagnosis of CHDs in our patients. Adequate funding of the tertiary health facilities by the government and stakeholders will go a long way to bridge the technological gap and increase the accuracy of diagnosis in patients. This will go a long way in impacting proper prognostication and therapeutic outcomes in patients diagnosed with CHDs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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