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Diagnostics Histology, Training and education

Case of the Month

A 70-year-old woman underwent hysterectomy and salpingo-oophorectomy for endometrial adenocarcinoma. The left ovary was enlarged and showed the following macroscopic and microscopic appearance.

Which of the following immunostains would be most helpful to confirm the diagnosis?
a. Calretinin
b. p53
c. CK AE1/AE3
d. SMA

What are these tumors frequently associated with?
a. Paraneoplastic syndromes
b. Estrogenic changes
c. Meigs syndrome
d. Lynch syndrome

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B. More likely to obtain deep molecular response with imatinib therapy

Adult patients with CML are more likely to achieve remission with imatinib tyrosine kinase inhibitor (TKI) therapy. Whether children may respond better to second generation TKIs is under investigation. Pediatric patients presenting with CML tend to have a higher white blood cell count and are more likely to present in accelerated or blast phase than their adult counterparts. Both populations often present with splenomegaly, but it may be more noticeable in children.

CML is rare in the pediatric age group, accounting for 2 percent of childhood leukemias in children younger than 15 years and 9 percent of leukemias in adolescents between 15 and 19 years (1). The median age is 11 years, with an overall incidence of approximately 1–2 per million children per year (2). Pediatric patients tend to present with a higher white blood cell count (median ~250 x 109/L) compared with CML arising in the adult population (3) and have a more aggressive course. In addition, the proportion of pediatric patients diagnosed with advanced disease – accelerated or blast phase – is higher than seen in adult patients (1). They tend to show a different distribution of the breakpoint region, more similar to that seen in the adult population who develop BCR-ABL+ acute lymphoblastic leukemia (4). They may also have a lower rate of molecular remission with imatinib compared with adult patients, although response with second generation TKIs may be higher and remains under study.

Blast phase is defined as ≥ 20 percent blasts in the blood or bone marrow or the presence of extramedullary proliferations of blasts. In most of the cases the blasts are myeloid, but in 20–30 percent of cases, they are lymphoblasts. These are predominantly B lymphoblasts, but T and NK blast populations have also been reported (5).

In this case, it was also important to differentiate a lymphoid blast crisis arising from CML from B acute lymphoblastic leukemia/lymphoma (B-ALL), which also occurs in the pediatric population and can be associated with BCR-ABL1 fusion. However, the t(9;22)(q34.1;q11.2) BCR-ABL fusion is relatively rare in pediatric cases of B-ALL, accounting for only 2–4 percent of pediatric cases compared with 25 percent of adult B-ALL (5). Although there are increased immature myeloid elements in the peripheral blood, this may happen in the setting of any process in which the bone marrow is infiltrated. The presence of the BCR-ABL1 fusion in more differentiated myeloid elements favors CML as the underlying process. Mixed-phenotype acute leukemia may also occur de novo or arising from CML. Here, however, there was not an increased myeloid blast population. B-ALL with BCR-ABL1, blast or accelerated phase CML, and chronic phase CML all benefit from TKI therapy.

References

  1. N Hijiya et al., “Pediatric chronic myeloid leukemia is a unique disease that requires a different approach”, Blood, 127, 392 (2016). PMID: 26511135.
  2. J de la Fuente et al., “Managing children with chronic myeloid leukaemia (CML): recommendations for the management of CML in children and young people up to the age of 18 years”, Br J Haematol, 167, 33 (2014). PMID: 24976289.
  3. F Millot et al., “The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-PED-Study): objectives and preliminary results”, Blood, 120, 3741 (2012).
  4. M Krumbholz, “Genomic BCR-ABL1 breakpoints in pediatric chronic myeloid leukemia”, Genes Chromosomes Cancer, 51, 1045 (2012). PMID: 22887688.
  5. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. WHO: 2017.

Courtesy of PathologyOutlines.com. Case by K.V. Vinu Balraam and S. Venkatesan, Armed Forces Medical College, Pune, Maharashtra, India; discussion by Genevieve M. Crane, Weill Cornell Medicine, New York, USA.

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