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November 2014 - Test your knowledge in the quiz!

Which disorder underlies this unclear anaemia? Acute monoblastic leukaemia
B lymphoblastic leukaemia (B-ALL)
Dengue fever
Multiple myeloma


Online version of this month`s case:

THE CORRECT ANSWER TO NOVEMBER’S QUIZ IS:

Multiple myeloma

Scattergrams and microscopy

Patient history: a 52-year old woman with an unclear anaemia, thrombocytopenia and leukocytosis.

The large population of high-fluorescence mononuclear cells in the WDF scattergram (the green population positioned above the monocytes) indicated the presence of blasts or abnormal lymphocytes.
Nucleated red blood cells (NRBC) were detected in the WNR scattergram.
The presence of abnormal lymphocytes was apparent in the WPC scattergram and triggered the appearance of the flag ‘Abn Lympho?’.
The large population of lymphocytes with a high lipid content confirmed the presence of abnormal lymphocytes. Blasts were not detected.
Peripheral blood smear
Bone marrow smear

Table

Interpretation and Differential Diagnosis

The answer can be inferred from…

  • Lymphocytosis: increased LYMPH# and LYMPH %
  • Abnormal WDF scattergram: abnormal population present above the monocytes
  • Thrombocytopenia and anaemia: low PLT-I and PLT-F; low HGB
  • Presence of abnormal lymphocytes: ’Abn Lympho?’ flag

 

Case history

A 52-year old woman with fatigue, bone pain and recurrent infections was brought into the hospital. She suffered three bone fractures in the past twelve months. Blood was sent for analysis and then, based on the results, a bone marrow puncture was performed.

Case results

Blood analysis revealed an unclear normochromic anaemia (MCH and HYPO-He are normal) with thrombocytopenia and mild leukocytosis. The reticulocyte count was normal but NRBC were detected in the WNR scattergram. This reflected a bone marrow problem and already allowed exclusion of dengue fever (the reticulocyte count would have been high in case of a haemorrhagic fever with anaemia).

A large mononuclear population with high fluorescence was visible above the monocytes, resulting in a suspect flag ’Blasts/Abn Lympho?’ for abnormal lymphocytes or blasts in the WDF channel. This triggered a reflex measurement with the WPC channel. Blasts were not detected in the WPC channel (no cells visible in the blasts area of the WPC scattergrams) but an abnormal ratio of the two lymphocyte populations was visible in the SSC-FSC scattergram: the lymphocyte population with increased membrane lipids and low forward scatter was comparatively large and this indicated the presence of abnormal, neoplastic lymphocytes. The ’Abn Lympho?’ flag was therefore generated.

An acute monoblastic leukaemia or B-lymphoblastic leukaemia would have shown an abnormal WDF scattergram without having a separate mononuclear population above the monocytes, as visible here, but rather an abnormal population between the lymphocytes and monocytes. In case of acute monoblastic leukaemia the WPC channel would have shown a positive blast gate and in case of B-lymphoblastic leukaemia it would have shown an abnormal lymphocyte/blast population (with a bigger cellular volume) and a normal lymphocyte ratio in the FSC-SSC scattergram of the WPC channel.

The observed abnormal multiple myeloma (MM) cells have a highly-active cytoplasm, probably caused by antibody production, and this explains their high fluorescence. The presence of IG, NRBC, low platelet counts with low IPF, anaemia and low reticulocyte counts can be explained by bone marrow infiltration of neoplastic cells, which leads to suppression of normal haematopoiesis. The increased activation of neutrophils (high NEUT-SFL) can be a sign of a concurrent infection, which is frequently observed in suppressed bone marrow due to haematological malignancies.

In the peripheral blood and bone marrow smears, mononuclear cells with a large cytoplasm to nuclear ratio were seen, resembling plasma cells. High monoclonal immunoglobulin concentrations in blood and urine confirmed the MM diagnosis.

 

The following answers are incorrect for the described reasons

Acute monoblastic leukaemia

Acute monoblastic leukaemia is a myeloid leukaemia in which more than 80% of leukaemic cells are monoblasts. Patients usually present with common AML symptoms: fatigue, pallor and frequent infections. Normocytic, normochromic anaemia is common, as well as thrombocytopenia of various severities. Leukocytosis is observed and in the peripheral blood circulating blasts are present.

Samples from acute monoblastic leukaemia patients show an abnormality in the WDF channel between the lymphocyte and the monocyte populations, depending on the total amount of monoblasts, immature monocytes (promonocytes) and more mature monocytes. This is not observed in this case, which shows a separate population above the monocytes. Furthermore, the WPC measurement did not confirm the presence of blast cells (the blast gate was empty).

Monoblasts are large cells with abundant cytoplasm, but the cytoplasm to nucleus ratio is lower than in the cells seen in the peripheral blood of this patient.

 

B-lymphoblastic leukaemia

Acute B-lymphoblastic leukaemia (B-ALL) is one of the less common lymphoid neoplasms. It occurs most frequently in childhood, but can also be seen in adults. Patients with B-ALL typically present with symptoms related to anaemia, thrombocytopenia, and neutropenia due to infiltration of the bone marrow with tumour cells.

In the WDF scattergram, B-lymphoblasts appear as an abnormal population between the lymphocytes and monocytes. B-ALL samples always have a ’Blasts?’ flag in the WPC channel, triggered by the presence of the B-ALL lymphoblasts, which have a bigger cellular volume.

 

Dengue fever

Dengue fever is a mosquito-borne viral infection, widespread in tropical and subtropical regions.

The typical clinical manifestations of dengue range from self-limited dengue fever to dengue haemorrhagic fever with shock syndrome. The typical laboratory findings are leukopenia and thrombocytopenia. As a viral infection, it causes a specific immune response, characterised by reactive lymphocytosis, which would generate an ’Atypical Lympho?’ flag. In case of a haemorrhagic fever, the reticulocyte count would be high, but we do not observe it in this case.

The diagnosis of acute dengue virus infection is mainly a clinical one. In the presented case we can exclude dengue fever, because abnormal and not atypical lymphocytes were detected.

Underlying Disease

Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all heamatologic malignancies. It is an incurable disease with a five year survival rate of 45%. MM causes about 20% of deaths from heamatologic malignancy and 2% of deaths from all cancers. The peak age of onset of MM is 65 to 70 years of age, and men are affected more often than women.

MM arises from the malignant transformation of a post-germinal-centre precursor B-cell residing in a lymph node. The transformed B-cell progenitor migrates into the bone marrow, which provides the microenvironment necessary for terminal plasma cell differentiation. The resulting malignant plasma cells of MM have a low proliferative rate and the clone is restricted to the bone marrow. MM is diagnosed when plasma cells form multiple disseminated tumours located within the bone marrow and additionally end organ damage is observed, which includes lytic bone lesions, and renal dysfunction.

The malignant plasma cells secrete pathological monoclonal proteins, called M-proteins, and the presence of them in serum or urine is a major criterion for the diagnosis of MM. The malignant plasma cells can produce immunoglobulin heavy chains plus light chains, light chains alone, or in rare cases neither (non-secretory myeloma). The pathological proteins are detected by protein electrophoresis of the serum or urine and form a dense discrete band on the gel. In addition to the M-proteins, another type of pathological protein - beta-2-microglobulin, - may be secreted by malignant plasma cells.

The usual symptoms of MM are the following:

  • Frequent infections due to impaired function of the immune system.
  • Bone pain and bone fractions; plasma cells stimulate osteoclasts, which leads to bone lesions and increases their fragility.
  • Hypercalcemia due to bone resorption; hypercalcemia in turn impairs kidney function, which is also affected by M-proteins. In severe cases this may lead to kidney failure.
  • Fatigue due to anaemia, caused by infiltration of the bone marrow by malignant plasma cells.


The usual haematological findings are leukopenia and thrombocytopenia. Rouleaux formation of red blood cells is observed in the peripheral blood smear in more than 50% of cases, due to an increased serum protein concentration. In most cases MM is restricted to the bone marrow so malignant plasma cells are rarely seen in the peripheral blood. However, circulating malignant plasma cells (also defined as plasma cell leukaemia) can be detected in up to 10% of MM cases. These cases are characterised by mild leukocytosis, anaemia, thrombocytosis, and malignant plasma cells are detected as highly-fluorescent abnormal lymphocytes above the monocyte cloud in the WDF scattergram. The ’Abn Lympho?’ flag is generated after measurement with the WPC channel and circulating malignant plasma cells are associated with a poor prognosis in MM.

Literature

  1. Swerdlow SH, Campo E, Harris NL, et al. (2008): World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon
  2. Fuchs R and Thomalla J (2005): Manual of “Mikroskopierkurs Hämatologie”: 103-104
  3. Döhner H, Estey EH, Amadori S, et al. (2010): Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood; 115:453
  4. WHO. Dengue hemorrhagic fever: diagnosis, treatment, prevention, and control. 2nd ed. Geneva: World Health Organization, 1997.
  5. Teixeira MG, Baretto ML (2009): Diagnosis and management of dengue. BMJ, 339:b4338
  6. Rajkumar SV, Merlini G, San Miguel J. (2012): Haematological cancer: Redefining myeloma. Nat Rev Clin Oncol 9:494
  7. Kariyawasan CC, Hughes DA, Jayatillake MM, Mehta AB (2007): Multiple myeloma: causes and concequences of delay in diagnosis. QJM 100:636

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