You Make the Diagnosis

A 42-year-old male presents with fever and fatigue. A CBC shows the following:

Hgb 14.2 g/dL (normal = 13.5 – 17.5 g/dL)
WBC 18 x 109/L (normal = 4.5 – 11 x 109/L)
Platelet count 320 x 109/L (normal = 150 – 450 x 109/L)

Differential:

  • Neutrophils and precursors: 80%
  • Lymphocytes: 16%
  • Monocytes: 2.5%
  • Eosinophils: 1.4%
  • Basophils: 0.1%

A review of the blood smear shows a slight left shift in the neutrophil series, with occasional metamyelocytes and rare myelocytes present. Several cells similar to the one shown below are noted.

toxic-gran

Which of the following is the most likely diagnosis?

A.  Acute myeloid leukemia
B. Chronic myeloid leukemia
C. Bacterial infection
D. Viral infection
E. Parasitic infection

The answer in this case is C, bacterial infection. The cell shown in the photo is a slightly immature neutrophil showing toxic granulation (heavy, dark azurophilic cytoplasmic granules), a morphologic sign seen most commonly in severe bacterial infections. The elevated neutrophil count with a left shift supports the diagnosis of bacterial infection.

Toxic granulation is thought to be a result of the bone marrow’s response to the need for neutrophils in the peripheral tissues. Promyelocytes are the last dividing stage of the neutrophil series (once a cell reaches the myelocyte stage, it can no longer divide, but only mature). Normally, as promyelocytes divide, their azurophilic granules are dispersed into daughter cells, the end result being a mature neutrophil with few azurophilic granules.

If there is an urgent need for increased numbers of neutrophils, like there is in a severe bacterial infection, promyelocytes may opt to simply mature, rather than divide. As a result, the azurophilic granules are not diluted among daughter cells, but retained in the maturing neutrophil, the end result being a mature neutrophil with many more azurophilic granules than usual.

The normal red cell and platelet count, as well as the lack of a significant number of very immature myeloid cells, rules out the presence of acute myeloid leukemia (AML). In AML, at least 20% of the nucleated cells in the blood or bone marrow must be composed of blast or blast equivalents.

Chronic myeloid leukemia (CML) is often a consideration in patients with an elevated neutrophil count and a left shift. In CML, however, the neutrophil count is usually quite high, and there is a marked left shift, with a particularly large number of myelocytes. In addition, a basophilia is almost always present.

Viral infection often presents with a lymphocytosis, sometimes with reactive changes in the lymphocytes. Finally, some parasitic infections present with an eosinophilia (but not a neutrophilia).

 

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Name That Cytogenetic Abnormality

A 36-year-old male presents with recurrent epistaxis and fatigue of several days’ duration. Physical examination reveals numerous ecchymoses scattered over his limbs and trunk. A CBC shows the following:

  • Hgb 9.2 g/dL (normal = 13.5 – 17.5 g/dL)
  • WBC 31×109/L (normal = 4.5 – 11 x 109/L)
  • Platelet count 23 x 109/L (normal = 150 – 450 x 109/L)

Review of the blood smear shows numerous hypergranulated immature myeloid cells. Rare cells like the cell below are also present.

auer-rod

What cytogenetic abnormality is most likely present in the abnormal cells?

  1. inv(16)
  2. t(8;21)
  3. t(14;18)
  4. t(15;17)
  5. t(11;14)

The answer is D, t(15;17). This is a case of acute promyelocytic leukemia (or AML-M3 in the old FAB classification). The key to the diagnosis is the cell in the image above, which is an immature myeloid cell containing innumerable Auer rods. This cell is called a faggot cell because the Auer rods resemble a bundle of sticks (or faggot). Faggot cells are specific for acute promyelocytic leukemia; they are not seen in any other hematologic malignancy.

Other clues to the diagnosis which are not entirely specific for acute promyelocytic leukemia include the anemia and thrombocytopenia (which point towards bone marrow failure), and the leukocytosis (which presumably is comprised mostly of the hypergranular myeloid cells noted on the blood smear).

Acute promyelocytic leukemia (APL) is a type of acute leukemia in which the predominant cell type is the promyelocyte. The malignant promyelocytes in APL have a distinctive appearance which is different from that of normal promyelocytes. In most cases, the malignant promyelocytes in APL contain innumerable small azurophilic granules – but in rare cases, the promyelocytes are hypogranular.

The characteristic morphologic finding in APL is the faggot cell, as shown above. When you see faggot cells, you can make the diagnosis of APL based on morphology alone, without waiting for molecular or cytogenetic studies (which will show the characteristic t(15;17) of APL – but which take some time to perform).

Making an immediate, morphologic diagnosis is critical in cases of APL, because patients with APL cannot be given routine acute myeloid leukemia chemotherapeutic agents. The granules in the malignant promyelocytes contain substances which quickly activate the coagulation system. Traditional chemotherapeutic agents cause cell lysis and release of the procoagulant substances, which puts the patient at high risk for disseminated intravascular coagulation (DIC).

Patients with APL are given a drug called all-trans retinoic acid (ATRA) that overcomes the maturation block caused by the translocation between chromosomes 15 and 17. Following ATRA therapy, the malignant promyelocytes mature into segmented neutrophils, and the risk of DIC diminishes.

The other cytogenetic translocations in this question are seen in different disorders: inv(16) is seen in some cases of acute myelomonocytic leukemia (AML-M4); t(8;21) is seen in some cases of acute myeloblastic leukemia with maturation (AML-M2); t(14;18) is seen in follicular lymphoma; and t(11;14) is seen in mantle cell lymphoma.

Krafts

-Kristine Krafts, MD, is an Assistant Professor of Pathology at the University of Minnesota School of Medicine and School of Dentistry and the founder of the educational website Pathology Student.

Heparin-Induced Thrombocytopenia

The fine folks over at The Poison Review discuss a paper about heparin-induced thrombocytopenia that is relevant to your interests. The paper appeared in the journal Clinical Toxicology and is geared toward that audience, but even so it serves as a nice refresher for technologists working in coagulation and hematology.

The Importance of Manual Urine Microscopy

Research presented today at the National Kidney Foundation spring clinical meeting indicates that manual microscopy surpasses automated analyzers when assessing kidney injury. The abstract is titled “Manual Microscopy: Not a Lost Art” and says, in part: “In this study, we examined if a significant difference exists between the reported ranges of granular and muddy brown casts using manual microscopy as compared to an automated urine analyzer in an acute kidney injury cohort.”

According to one of the abstract’s authors, Dr. Sharda, “What our research has been able to show so far is that the automated system under reported the value of granular casts in our patient cohort of acute kidney injury. The automated system still has utility as a screening test, but manual microscopy should be done in all cases of abnormal kidney function, as accurate quantification of casts could have some prognostic benefit to patients.”

The poster is available online. The authors are currently writing a paper on their research; their contact information is here.

On the Lab Medicine Website

In case you’ve missed it, here is the table of contents for the current issue of Lab Medicine. New articles are uploaded regularly, so be sure to check back often.

Theoretical knowledge helps troubleshoot wonky results, but unfortunately that knowledge is easy to forget if it’s not used every day. If you’ve worked the chemistry bench long enough to have forgotten some of theory behind the analytes, check out this series of articles to refresh your memory.

In the latest edition of our podcast series, Dr. Alex Thurman walks listeners through diagnosing a new acute leukemia in the middle of the night.

ASCP Call for Abstracts

Do you want to present your research at a national meeting? The American Society for Clinical Pathology is currently accepting abstract submissions for their Annual Meeting. This year it’s in October in Tampa, Florida. Soak up the sun while presenting your work and networking with your peers.