CASE HISTORY: Burton L.
Mr. L. is a married 40-year-old man, who presented at the ER with a complaint of large amounts
of bright red blood in his stool.
He reported a gradual onset of fatigue over the last several weeks, as well as numerous small
red dots on his skin the day before. PE revealed a well-developed man in no acute distress.
Significant physical findings were tachycardia (P 104), tachypnea (R 27), orthostatic
hypotension, pallor of skin and mucous membranes, and numerous petechiae. Blood work
showed the following laboratory values:
Hemoglobin (Hb) 6.5 g/dL
Hematocrit (Hct) 17.9%
White Blood Cells (WBC) 2,200/mm3
Platelets (Plt) 4,000/mm3
Prothrombin time (PT) 14.6 sec
Partial thromboplastin time (PTT) 42.4 sec
Fibrinogen 118 mg/dL (ref. range 190 - 400)
D-dimer 7.8 µg/mL (nl 95%) immature cells with very little residual adipose. (This will be seen in the
lesson.)
13. Is emergency treatment indicated? What and how?
Because he isn't in “acute distress,” you might think rapid treatment is not an issue.
However, his platelet count is so low that he is at real risk for hemorrhage into the
brain and other vital organs.
Ordinary anemia is treated with transfusion of packed RBC. But his pancytopenia
requires fresh whole blood (if available) or recent whole blood plus platelets. Each unit
raises the Hb about 1 gm/dL and he needs to get up to 10 gm, so 4 units are indicated.
This would be a tremendous cardiac burden if given quickly, so give the first unit over
one hour, and the others each over 3-4 hours max, with an interval up to 8 hours
between the last units, if his cardiac status appears threatened.
AML Marrow
This patient’s marrow was obscured by over 95% promyelocytes with copious granular, purple
cytoplasm with occasional Auer rods, and a few cells with bilobed nuclei. The normal level of
50% adipose tissue is largely gone.
He has Acute Promyelocytic Leukemia, a type that accounts for 7% of all AMLs.
Promyelocytes are daughter cells of the even less differentiated promyeloblast. Promyelocytes
are the first step in differentiation of the myelocytic series that produces various kinds of
granulocytes.
They can be binucleate or have a bilobed nucleus. The cytoplasm, especially in cases of
myelogenous leukemia, has many large granules with some Auer rods, indicated by the arrow.
The Auer rod is of uncertain origin, and is found in immature myelocytes. There is some
thought that they may be abnormal lysosomes, since they're known to contain peroxidase and
acid phosphatase enzymes.
Acute Promyelocytic Leukemia
These cells are the first step in differentiation of the myelocytic series that would become
granulocytes (neutrophil, baso, eosinophil, mono, platelet, erythrocyte). They can be
binucleate or have a bilobed nucleus. The cytoplasm has many large granules with some Auer
rods (cell touched by small, dark cell.). This is Fig 14-29A, page 694.
Cytogenetic Analysis Reveals translocation t (15;17)
This translocation results in rearrangement of the retinoic acid alpha receptor gene on
chromosome 15 with the PML gene on chromosome 15.
Retinoic acid (Vit A) is important for granulocyte maturation; hence if that is interrupted the
cells become arrested at the promyelocyte stage.
Treatment with all-tran retinoic acid overcomes the block, allowing the “tumor” cells to mature
to adult forms, and restores the WBC Diff and platelets.
Conventional chemotherapy is still required to remove the “tumor” cells to prevent relapse.
Acute Myelogenous vs Lymphocytic Leukemia and Lymphoma
Because treatment is so different, it is important to distinguish between AML and ALL. AML
cells have abundant granular cytoplasm, and may have Auer rods (left); while ALL cells show
very little cytoplasm (right). Leukemias involve peripheral blood, marrow, liver, and spleen.
Lymphomas do not involve peripheral blood.
Enzymes and Antigens
Selected enzymes are active in each cell type. Myeloperoxidase (left) and CD13, 14, 15, and 33
are found in myelocyte precursors; while TdT and CD10, 19, 20, and 22 are found on flow
cytometry in lymphocytes (right.) Cluster designation (CD) antigens in single digits (CD4, CD8,
etc.) have been reserved for T cell lymphs.
World Health Organization Classification of AML
The last 70 years have seen many attempts at classification of leukemias and lymphomas. This
initially was needed for consistent labeling, but recently it's become even more important as a
guide for treatment and prognosis.
The emergence of enzyme-based stains and CD antigens has enabled fine tuning and
challenging tables of classification. In the 1980s leukemias were often described as either
"large" or "small cell" with "cleaved" or "non-cleaved nuclei." With only 4 classes, this made
things easy for pathologists. But we now readily concede that further differentiation of classes
is indicated, because of the 30% chance of a cure.
FAB Classification of AML
MO: Minimally differentiated, 2-3%, identifiable by EM only
M1: AML by peroxidase only, 20% of AML cases
M2: AML with maturation through granulocytes, 35%, Auer rods present, t(8;21)
favorable prognosis
M3: Acute PML, 5-10%, many Auer rods, young adults, often develop DIC, t(15;17) is
characteristic
M4: Acute myelomonocytic leukemia, 15-20%
M5: Acute monocytic leukemia, 10%, monoblasts and promonocytes in marrow and
blood, organomegaly
M6: Acute erythroleukemia, 5%, dysplastic erythroids. 1% of de novo AML in patients
>60 years old; 20% treated AML
M7: Acute megakaryocytic leukemia, 1%, myelofibrosis
Leukemia Classifications
The last 70 years have seen many attempts at classification of leukemias and lymphomas,
initially for consistent labeling, recently for guidance toward treatment and prognosis.
Emergence of enzyme stains and CD antigens has enabled fine tuning and challenging tables of
classification like Table 14-4 on page 671.
In the 1980s leukemias were often described as either "large" or "small cell" with "cleaved" or
"non-cleaved" nuclei. Only 4 classes made things easy for pathologists. We now readily concede
further differentiation is indicated because of the 30% chance of a cure.
Degrees of Differentiation
These two images have show types of AML at increasing and variable patterns of differentiation
The percentage of AML cases each type represents is shown in parentheses. Each is associated
with specific chromosomal anomalies, which often explain the mechanism of onset and give a
rationale for therapy.
This is an example of AML that's minimally differentiated (2%) in #1. It's shown at higher
magnification in without (20%); and in #3 with maturation and Auer rods (35%).
Myelomonocytic AML is shown in #1A and 1B (20%); Monocytic in #2 (10%), Erythrocytic in #3
(5%), and Megakaryocytic AML in #4 (1%).
These forms account for 93%, if you add up the numbers: the remaining 7% falls into the
promyelocytic form, which Mr. L. has.
Whereas highly lethal in the past, 60% of AMLs are now treatable (half for a cure). They are
AML with maturation t(8;21), promyelocytic leukemia t(15;17), and myelomonocytic leukemia
inv(16).
Prognosis
AML with maturation and t(8;21), or acute myelomonocytic leukemia with inv(16) respond well
to traditional chemotherapy. Patients with acute promyelocytic leukemia with t(15;17) quick
get relief from ATRA (all-tran retinoic acid) and lose tumor cells with conventional
chemotherapy or arsenic trioxide.
Patients with AML from prior genotoxic therapy or myelodysplastic syndrome (MDS) or relapse
from any type of AML fare poorly. These are now being treated with allogeneic bone marrow
transplantation.
Chronic Myeloproliferative Disorders (MPD)
There are four types:
o Chronic myelogenous leukemia
o Polycythemia vera
o Essential thrombocytosis
o Myelofibrosis with myeloid metaplasia
All have stem cells migrate to spleen, producing splenomegaly up to 3 kg (normal 150 gm).
Tumor cells replace normal marrow progenitors but initially differentiate to give an elevated
RBC (polycythemia), platelets (thrombocytosis), etc.
All can change to acute leukemia, especially CML
Chronic Myelogenous Leukemia (CML)
Affects adults age 25-60 (mostly 30-50)
Has the "Philadelphia chromosome" with t(9;22)(q34;q11) of BCR gene on 9 and ABL gene
on 22
M arrow is 100% cellular with increased granulocyte precursors and sea-blue histiocytes
WBC may reach 100,000 with neutrophils, metamyelocytes, myelocytes, and myeloblasts
Symptoms are fatigue, weakness, weight loss, and anorexia progressing over about 3
years
Can progress to blast crisis with circulating myeloblasts
May require bone marrow transplant in younger adults
This smear is an example of CML: it shows an excessive number of WBCs, including mature and
band neutrophils, metamyelocytes, and one myelocyte.
Polycythemia Vera (PV)
This condition arises in a myeloid stem cell around age 60. The patient shows increased RBC,
megakaryocytes, and granulocytes, a Hgb to 28, Hct to 70, WBC 12-50,000, platelets > 400,000.
Spleen and liver initially enlarge from congestion, then from in situ hematopoiesis to
compensate for marrow loss. The bone marrow becomes 90% cellular, and develops fibrosis
over about 10 years, eventually no longer producing cells. Blood is so thick it thromboses in
veins and delivers oxygen poorly. PV can cause DVT, stroke, MI, epistaxis. Clinical signs are
headache, dizziness, hypertension, GI ulcers from excessive basophil histamine, high BUN from
cell turnover, and 10% of patients have gout. Treatment is weekly phlebotomy until Hct is
normal.
In this gross specimen from a PV patient, the rule spans 5 cm; therefore this is either a liver
twice its normal size, or a spleen 20 times normal size. It is in fact a spleen: extramedullary
hematopoiesis has resulted in its weighing 3020 grams. A spleen this size squeezes the
stomach, creating a feeling of "fullness" and tenderness in the left upper quadrant of the
abdomen.
Essential Thrombocytosis
All MPDs have high platelet counts, so this is a diagnosis of exclusion, i.e., purely
thrombocytosis. It is the least common MPD. The bone marrow shows increases in only large
megakaryocytes and reticulin fibrils. The peripheral smear shows large platelets. Clinical signs
are thrombosis from so many platelets, or hemorrhage because of faulty platelets! Survival is
10-15 years.
The peripheral smear shows a large amount of "debris" created by a high number of platelets
of normal size. There also are very large platelets about the size of adjacent RBCs (7 microns).
Primary Myelofibrosis
This condition presents after age 60, following Polycythemia Vera or Chronic Myelogenous
Lymphoma; or spontaneously with fatigue, weight loss, night sweats from increased
metabolism, and Left Upper Quadrant fullness from spleen enlargement to 4 kg. It is thought
that megakaryocytes (mkc) put out too much PDGF and TGF- � , both fibroblast mitogens. The
bone marrow has large, dysplastic, clustered mkc and increasing fibrosis or osteosclerosis.
Peripheral blood may show leukoerythrocytosis with erythroid and granular precursors. Spleen,
liver, and nodes may show hematopoiesis.
In smears, several RBCs are teardrop-shaped (dacryocytes) from distortion in the fibrotic
marrow. Nucleated erythroid precursors have escaped from the spleen or liver for
leukoerythroblastosis. Immature myeloid cells are in other fields.
Myelodysplastic Syndromes (MDS)
This is a group of clonal stem cell disorders characterized by maturation defects associated
with ineffective hematopoiesis and an increased risk of transformation to acute
myelogenous leukemia.
There are two main types:
1. Idiopathic or primary, developing insidiously after age 50; and
2. Therapy related MDS (t-MDS) occurring 2-8 yr after genotoxic drug or radiation therapy.
Both types occur with monosomy 5 or 7, deletions of 5q plus 7q or 20q, or with trisomy 8
MDS Morphology
Myelodysplastic Syndrome morphology affects all non-lymphoid lineages in the marrow.
The erythroid series will have ringed sideroblasts with iron-laden mitochondria.
Megaloblastoid differentiation resembles folate and Vitamin B-12 deficiency anemias.
Neutrophils may have no nuclear segmentation or be bilobed (pseudo Pelger-Huet cells) and
have fewer secondary or toxic granulations, and/or Dohle bodies.
Megakaryocytes may have single nuclear lobes or multiple, separate, smaller nuclei ("pawn
ball" megakaryocytes).
Myeloblasts may be increased up to 20%. Peripheral blood often has pseudo-Pelger-Huet cells,
giant platelets, macrocytes, poikilocytes, monocytosis.
In this image, A demonstrates the morphology of the Pelger-Huet cell, B that of the giant
platelet; C is an example of a dysplastic megakaryocyte, and D shows a lobulated erythroid cell.
MDS Clinical Course
MDS usually present after age 60 as weakness, infections, and hemorrhages due to
pancytopenia. The higher the percent of blasts present, the greater the likelihood of severe
cytopenia,eventual progression to AML, and the worse the prognosis.
Survival in primary MDS is 9 to 29 months, with some patients surviving 5 years. Progression to
AML occurs in 25% of cases. In t-MDS, progression to AML is rapid and survival is only 4 to 8
months. Young patients get bone marrow transplants; older patients get transfusions,
antibiotics, and supportive therapy.
OK, Doctor: What's Your Diagnosis On This One?
Bob H. is a 92-year-old man who has an apartment in an assisted-living facility. He presents at
his doctor with a 3-year history of progressive weakness and fatigue. All his lab reports are
normal for his age, except he has a Hb of 8.5, Hct 26, BUN 36, and Creat 2.0. His BP is 135/85
and he's on antihypertensive medication which controls his blood pressure.
His past history includes a mitral valve prolapse from age 55 to age 80; at 80 rupture of the
anterior papillary muscle caused acute heart failure, necessitating surgical intervention to
correct both these problems.
He also had a localized colon cancer removed at age 86. His vision in the right eye is
deteriorating from macular degeneration.
What is the most likely diagnosis and treatment? Stop and think!
"You know my methods, Watson: apply them. When the impossible has been eliminated,
whatever remains, however improbable, must be the truth"
— Sir Arthur Conan Doyle (1859-1930)
"The Sign of Four" ( 1890)
The onset over a period of years is far too slow for AML. It's possiblethis could be
chronic lymphocytic leukemia, but the blood profile is too pure (RBC) for CLL, other
leukemias, or for MDS.
It could be chronic blood loss from a colon cancer, but Bob denies having dark stools
and there is no palpable mass. It could be an iron deficiency (but he has normal Fe,
TIBC, and ferritin values).
The next best bet is a chronic, low-grade, hypertensive vascular sclerosis with renal
ischemia, and deficient production of erythropoietin (EPO). A serum test for EPO is
indicated.
Give him erythropoietin and let him get his money's worth from Medicare at $1,000 per
shot per month for the rest of his life! (Get him started with two shots two weeks apart
in the first month.)