Weatherly's Woes - Leukemia

LEUKEMIA

Blood cancer

Leukemia is a cancer of the bone marrow. You should suspect Leukemia when a patient presents with lymphadenopathy, vague symptoms (fatigue, malaise) and they have a wonky CBC. For example, a WBC is 50K (normal is 4K to 10K). As you look further into the CBC differential, expect to see more weirdness, such as one cell line being super dominant. Other times, the WBC will be very low. The gold standard diagnostic test for leukemia is to do a bone marrow biopsy. Now count the blasts. If over 20% of the marrow’s cells are blasts, then it’s "acute." And if it’s less than 20%, then it’s "chronic."

How does leukemia cause symptoms? By overcrowding the bone marrow. When too many cancerous cells occupy the marrow, there is no room left for the normal healthy blood cells. Patients get fatigued and tachycardic (from anemia). They have recurrent infections (from the leukopenia). They get bleeding or clotting (from the thrombocytopenia). They can even have bone pain (from the expanding pressure inside the bone marrow). The healthy blood cells are pushed into the spleen, lymph nodes and liver, causing hepatosplenomegaly and lymphadenopathy.

Acute leukemias are neoplasms of immature stem cells in the blood, aka "blast" cells. The word "acute" is used because the symptoms are severe and have a swift onset. Acute leukemia can kill in a matter of weeks.

Chronic leukemias are neoplasms of mature cell lines, for example T-cells. Chronic leukemias are often slow growing and insidious.

Myelodysplastic Syndrome is basically "pre-leukemia." Chronic Leukemia is defined as less than 10% of the nucleated cells in a bone marrow biopsy are blasts. Acute Leukemia is when there are over 20% blasts. So what about when the blasts are between 10% to 19%? It’s Myelodysplastic Syndrome! It can progress into cancer.

Myeloproliferative Disorder - neoplastic proliferation of mature myeloid cells (RBCs, granulocytes, monocytes, platelets) that results in a high WBC count with crowded bone marrow. All myeloid cell lineages will be increased, but the disorder will be named after the dominant cell line that is produced (usually one lineage outcompetes the other lineages, resulting in (say) a huge excess of RBCs versus a mild excess of granulocytes/monocytes/platelets). Although CML may technically fall into this category, it isn’t really considered a Myeloproliferative disorder.

ALL

Acute Lymphocytic Leukemia (ALL) is a cancer of immature lymphocytes in the bone marrow. There will be a crap load of pre-B-cells and/or pre-T-cells in the bone marrow (>20%). Typically affects children (in fact it is the most common cancer of childhood), but it can also affect adults (worse prognosis).

Forms?

B-cell ALL is the prototypical and most common variety of ALL. The prognosis of B-ALL has dramatically improved in the past several decades, especially if the patient has the t(12;21) translocation, as it confers a favorable outcome (90% remission). There is an excellent response to chemotherapy, although make sure to administer it to the CSF and scrotum as well as the blood (B-ALL likes the Brains and the Balls). B-ALL can be diagnosed with flow cytometry, it expresses CD10, CD19 and CD20. Note that the t(12;21) variant is quite common with Down Syndrome, as they have an extra 21st chromosome. Adults can get ALL, and are more likely to have a Philadelphia Chromosome t(9;21).

T-cell ALL is a less common variant that frequently pops up on test questions. Know that it usually occurs in Teenagers. Know that it causes a Thymoma (the thymus is a T-cell maturation organ). T-cells express CD2 - CD8.

Labs?

The most important test is the CBC. It typically shows a severe leukocytosis (at least 15K, often much higher). The differential will show high percentages of lymphoid lines and low levels of myeloid lineages (anemia, thrombocytopenia, neutropenia). There is a special test for ALL called TdT (an enzyme found in premature lymphocytes). Once you suspect ALL, confirm the diagnosis with a bone marrow biopsy, which would show that >20% of the cells were lymphoblasts.

AML

Acute Myeloid Leukemia is cancer of myeloid blasts in the bone marrow.

Risk factors

Down’s Syndrome (before age 5), radiation therapy and chemotherapy are the biggest risk factors.

Subtypes

There are a TON of subtypes. We’re currently in a transition period between the old classification scheme (M1, M2, M3…) and the new classification scheme (based on genetic markers). That makes AML confusing for students. So let's keep it simple, OK? You absolutely positively must learn about the Promyeloblast AML subtype (formerly M3). There are a ton of buzzwords with this one!

Auer rods are toothpick shaped inclusions inside the cancerous cells. They are pathognomonic for Promyeloblast AML.
Myeloperoxidase (MPO) is a stain that highlights neutrophils and pre-neutrophils. Recall that MPO is a weapon that neutrophils use to kill bugs. MPO will light up with Promyeloblast or Myeloblast AML.
The t(15:17) translocation results in the disruption of the retinoic acid receptor (the Vitamin A receptor). Without it, promyelocytes can’t mature. Instead of conventional chemo, give a vitamin A derivative called ATRA (all-trans retinoic acid), which is able to activate the wonky retinoic acid receptor, and helps all the cancerous immature cancer cells safely mature into adults. A revolutionary cure!
High risk for DIC if you give them conventional treatment, because Promyelocytes clot when lysed.

If you want to know about other subtypes, go right ahead, but they aren’t super high yield.

Gum infiltration is seen with Monoblast AML. MPO will not be positive.
Megakaryoblastic AML is seen in Down syndrome before the age of 5 (ALL caused cancer after the age of 5)

Labs

The CBC with AML will look pretty similar to ALL. The WBC is high, but the differential shows an incredibly high percentage of immature cell lines (of myeloid lineage for AML). The lymphocyte lineages will be especially low. Some of the myeloid lineages can also be low, due to crowding out of the bone marrow (anemia, thrombocytopenia). Non-Specific Esterase (NSE) is a special marker that will be positive for AML.

Auer rod (splintery inclusions in pre-granulocytes.

YOU MUST KNOW HOW TO RECOGNIZE AUER RODS ON A PICTURE.

CLL

Chronic Lymphoid Leukemia (CLL) is cancer of adult B-cells in the bone marrow. CLL is the most common leukemia. It is especially common in the elderly population. It’s often asymptomatic for many years (most patients die with CLL rather than from CLL). CLL is pretty benign, and treatment is often deferred, depending on how old the patient is. The most common symptom is generalized lymphadenopathy. Beware of the Richter transformation, which is a sudden jump from CLL to an aggressive lymphoma like DLBCL.

Under a microscope, lymphocytes are unfortunately bland looking. They all look like little dark circles. Thankfully, the lymphocytes of CLL have a tell-tale appearance! Look for smudge cells, or lymphocytes that get crushed during the preparation of the specimen for the microscope. Lymphoid cells are already pretty fragile, and they become especially fragile when they’re cancerous. Crushed Little Lymphocytes. If you did a bone marrow biopsy, you would see a lot of lymphocytes, but not a lot of lymphoblasts (less than 10% to be precise).

But in reality the diagnosis is based less on the microscope, and more on lab markers.

- - Really high WBC count. Like REALLY high. Like in the 100K range.
  - An abnormal flow cytometry, which will show B-cell markers (CD19, 20, 21 and 23). You don't have to know how to interpret flow cytometry results, it's very difficult and reserved for hematopathologists.

Smudge cells

CML

Chronic Myeloid Leukemia (CML) is a cancer of myeloid stem cells from the bone marrow. Now listen up. You have to know a buzzword with CML. It’s always associated with the presence of the Philadelphia Chromosome. The Philly Chromosome is a genetic mistake. It refers to a translocation of c9 onto c22, usually shorthanded as t(9;22). A chunk of c9 combines with a piece of c22. The tail end of the c9 chunk has the abl gene, and the c22 piece brings the bcr gene. When the two pieces meet, bcr fuses with abl, creating the evil bcr-abl gene, which will cause leukemia. It’s thought that the bcr-abl gene causes CML by increasing the activity of the oncogene Tyrosine Kinase. Note that CML can transform into AML or ALL (this is called a blast crisis).

The first test you should order is a CBC, looking for a ridiculously high WBC (over 50K). To see if this severe leukocytosis is cancerous in nature, order a Leukocyte Alk Phos (LAP) test, which is never elevated in cancer (CML LAcks the LAP ). The CBC will contain two additional clues. Elevated Basophils are pathognomonic for CML, and they may also have a lot of platelets (only leukemia with this). The diagnosis is confirmed with a bone marrow biopsy, which will show <10% blasts.

Treatment is with Imatinib, a TK inhibitor. This is a miracle drug that has revolutionized the treatment of CML.

HAIRY CELL LEUKEMIA

Memory B-cell Cancer

Hairy Cell Leukemia is cancer of memory B-cells. The name comes from the shaggy looking appearance of the cancerous cells. Recall that memory cells are almost exclusively found in the marrow. Thus it’s easy to see why patients develop marrow fibrosis and a resulting pancytopenia. The subsequent shift to extramedullary hematopoiesis results in severe splenomegaly. Memory B-cells are not found in lymph nodes, thus patients have no lymphadenopathy (spleen-lymph dissociation like this is pretty rare). It predominantly affects men (men are hairy after all). Memory B-cells are old lymphocytes (Old men are hairy).

There is a pathognomonic test for HCL, the TRAP stain (TRAPped in a hairy situation). TRAP stands for Tartrate-Resistant Acid Phosphatase. When you add TRAP, hairy cells will light up like a christmas tree. Apparently, it’s also associated with BRAF mutations. How lovely.

Treatment with new chemotherapeutic agents like Cladribine or Pentostatin have turned HCL from a death sentence to a very survival condition. The 5-year mortality rate is 85%.

So hairy

TRAP+

TUMOR LYSIS SYNDROME

Cell go “BOOM”

Tumor Lysis Syndrome is the shitstorm of cellular debris sometimes seen after chemotherapy / radiation. Here’s the deal - you successfully treat a patient’s cancer. But if you’re TOO successful, causing every cancer cell to immediately die (lyse), then all of the intracellular contents will spill out of the dead cells. Cells are filled with really high levels of K, Phosphate and Nucleic Acid. It’s very similar to Rhabdomyolysis in a lot of ways. But instead of dead muscle cells, it’s dead cancer cells. Of all the cancers, TLS occurs most commonly with heme cancers.