A sixty nine year old female who underwent right breast reconstruction about 13 years ago due to breast cancer presents to the doctor office with right breast pain and right breast enlargement over the last two months. She has lost some weight and does not recall any trauma to this area. She had a textured saline implant. Examination reveals no definite palpable masses. MRI of right breast showed intact saline implant with moderate amount of fluid surrounding the implant within the intact external capsule. No adenopathy was noted. Right breast implant was removed and complete capsulectomy was performed.
anaplastic large cell lymphoma.
Breast implant associated
anaplastic large cell lymphoma is a provisional entity that is morphologically
and immunophenotypically similar to ALK-negative anaplastic large cell lymphoma.
It arises primarily in association with a breast implant. It is a very rare
entity with an incidence of 1 in 500,000 to 3 million women with implants. Tumor
cells may be localized to the seroma cavity or may involve pericapsular fibrous
tissue. Sometimes it can form a mass lesion. Locoregional lymph node may be
involved. The mean patient age is 50 years. Most patient presents with
stage 1 disease, usually with peri-implant effusion. The mean interval from
implant placement to lymphoma diagnosis is 10.9 years. There is no association
with the type of implant. Histologic examination shows two different types of
proliferations. In patients with seroma, the proliferation is confined to the
fibrous capsule (“in situ” iALCL). However, the distribution of neoplastic
lymphocytes could be heterogeneous with some cellular areas with numerous large
pleomorphic cells of varying size and some fibrotic areas with rare atypical
lymphocytes. It is beneficial to look at the seroma fluid in addition to
capsule sections, because sometimes the neoplastic lymphocytes are
predominantly present in fluid (as in our case). Patients presenting with tumor
mass show more heterogeneous proliferations infiltrating surrounding tissues
(“infiltrative” iALCL). They consists of either sheets are clusters of large
neoplastic cells accompanied by a large number of eosinophils. By immunohistochemistry,
the tumor cells are strongly positive for CD30. CD2 and CD3 are more often
positive than CD5. CD43 is almost always expressed. Most cases are CD4 positive. The
prognosis is very good in patients with disease confined to the capsule.
The median overall survival is 12 years. However, patients with a tumor mass
could have a more aggressive clinical outcome.
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of
Haematopoetic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon
2. Jaffe, E , Arber, D, et al. Hematopathology (second edition) 2017.
-Junaid Baqai, MD, was born in Chicago, IL but spent most of his life in Karachi, Pakistan. He graduated from DOW Medical College in Pakistan and did his residency in anatomic and clinical pathology at Danbury Hospital, CT followed by hematopathology fellowship from William Beaumont Hospital, Michigan and oncologic-surgical pathology fellowship from Roswell Park Cancer Institute, New York. He currently serves as Medical Director of hematology, coagulation and flow cytometry at Memorial Medical Center and Medical Director of Laboratory at Taylorville Memorial Hospital.
76 year old man with a history of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with new anterior mediastinal mass and increasing lymphadenopathy.
Lymph Node Biopsy
Tissue sections show a diffuse atypical lymphoid infiltrate
that completely effaces the normal nodal architecture. The infiltrate is
composed of numerous small lymphocytes with round to mildly irregular nuclei,
clumped chromatin, inconspicuous nucleoli and scant cytoplasm. There are also
expanded pale areas that contain intermediate sized cells with more open
chromatin and distinct single to multiple nucleoli. These cells are most
consistent with prolymphocytes/paraimmunoblasts and form the proliferation
centers characteristic of CLL/SLL. Occasional centroblastic-type B-cells are
noted within these proliferation centers. In addition, there are scattered single
to multinucleated cells that have irregular nuclear membranes with pale,
vesicular chromatin and prominent inclusion-like, eosinophilic nucleoli. These
cells morphologically resemble Hodgkin cells, Reed-Sternberg cells, mummified
forms and other variants. These large cells are more evident in areas with a
histiocyte rich background and around foci of necrosis. Occasionally, apoptotic
bodies and mitotic figures are seen.
show that the vast majority of the small-intermediate lymphocytes express B-cell
markers CD20 (dim) and PAX5 and co-express CD5 and CD23 (subset). This is
consistent with a background of CLL/SLL. The large atypical cells are positive
for CD30, PAX5 and CD20 (variable). CD3 highlights numerous scattered
background small T-cells, which are increased in the areas with the large cells.
In situ hybridization for Epstein Barr viral RNA (EBER ISH) is mainly staining
the large atypical cells. By Ki-67, the proliferation fraction is overall
increased (40%) with increased uptake by the large atypical cells.
The morphologic and immunophenotypic findings are consistent
with involvement by the patient’s known small lymphocytic lymphoma/chronic
lymphocytic leukemia (SLL/CLL) with aggressive morphological features. The
aggressive features include expanded proliferation centers and an elevated
Ki-67 proliferative index (40%). Additionally there are histiocyte/T-cell rich
areas composed of multiple EBV positive large atypical cells with morphologic
and immunophenotypic features compatible with Hodgkin/ Reed-Sternberg cells.
These areas are most in keeping with evolving classic Hodgkin lymphoma. Sheets
of large cells indicative of large cell transformation are not seen, although
increased scattered large centroblastic-type B cells are present.
Lymph node involvement by CLL/SLL will typically show a
diffuse proliferation of small lymphocytes with effacement of the normal nodal
architecture. The small lymphocytes have
round nuclei, clumped chromatin and scant cytoplasm. Scattered paler areas
known as proliferation centers are characteristic of this entity. The
proliferation centers are composed of a mixture of cell types including small
lymphocytes, prolymphocytes and paraimmunoblasts. Prolymphocytes are small to
medium in size with relatively clumped chromatin, whereas paraimmunoblasts are
larger cells with round to oval nuclei, dispersed chromatin, eosinophilic
nucleoli and slightly basophilic cytoplasm. Some cases show increased and
enlarged proliferation centers with a higher proliferation rate. This must be
distinguished from large cell transformation.1
Aggressive features of CLL/SLL include proliferation centers
that are broader than a 20x field or becoming confluent. An increased Ki-67
proliferation >40% or >2.4 mitoses in the proliferation centers can also
portend a more aggressive course. These cases tend to have worse outcomes than
typical CLL/SLL and better outcomes than cases that have undergone Richter
transformation to diffuse large B-cell lymphoma (DLBCL). Transformation to
DLBCL occurs in 2-8% of patients with CLL/SLL. Less than 1% of patients with
CLL/SLL develop classic Hodgkin lymphoma (CHL). In order to diagnose CHL in the
setting of CLL/SLL, classic Reed-Sternberg cells need to be found in a
background appropriate for CHL, which includes a mixed inflammatory background.
The majority of these CHL cases will be positive for EBV.1
Richter’s transformation is defined as an aggressive
evolution of CLL. While the most common type of transformation is to a
high-grade B-cell Non-Hodgkin lymphoma, other histological transformations have
been described. This includes CHL, lymphoblastic lymphoma, hairy cell leukemia
and high-grade T-cell lymphomas. The prognosis for patients who present with
transformation to CHL is poor compared to de novo CHL.2
A large study from the M.D. Anderson Cancer Center described 4121 patients with
CLL/SLL and found that only 18 patients or 0.4% developed CHL. The median time
from CLL to CHL diagnosis was 4.6 years. Fourteen of the patients received
chemotherapy. The overall response rate was 44% with a complete response rate
of 19%. The median overall survival was 0.8 years and all patients eventually
died from disease recurrence or progressive disease.3 This dismal
prognosis is similar to patients with Richter transformation to DLBCL and much
worse than patients with de novo CHL, which is curable in >85% of cases.1
Swerdlow SH, Campo E, Harris NL, et al. WHO
Classification of Tumours of Haematopoetic and Lymphoid Tissues (Revised 4th
edition). IARC: Lyon 2017.
Janjetovic S, Bernd HW, Bokemeyer C, Fiedler W. Hodgkin’s
lymphoma as a rare variant of Richter’s transformation in chronic lymphocytic
leukemia: A case report and review of the literature. Mol Clin Oncol.
Tsimberidou, AM, O’Brien, S and Kantarjian, HM,
et. al. Hodgkin transformation of chronic lymphocytic leukemia. Cancer. 2006;107(6).doi.org/10.1002/cncr.22121.
–Chelsea Marcus, MD is a Hematopathology Fellow at Beth Israel
Deaconess Medical Center in Boston, MA. She has a particular interest in
High-grade B-Cell lymphomas and the genetic alterations of these
Last month, I wrote about some
projects I did while rotating through the pathology program at Danbury
Hospital in Connecticut. This month I’m in a more clinical setting with a
hematology/oncology clerkship at Northwell’s Staten Island University Hospital.
But, over the past few months of rotations (and arguably a lot longer before
medical school) I’ve been noticing a part of laboratory medicine which often
intersects with our clinical colleagues at the bedside. I’ve told you about the
pitfalls and successes in the relationships
between surgeons and anatomic pathologists before, where frozen sections
are critical and time is of the essence. And we’ve all seen collaboration
between the bench and bedside before—think microbiology and infectious disease,
blood bank and literally everyone, etc. Still, one collaborative effort sort of
happens behind the shadows, behind phone calls and lab reports, and sometimes
with no communication at all! So, what kind of vigilante medicine am I talking
about? Who is this Batman of medicine? It’s just our friends in hematology.
When you’re working the hematology bench in the lab, it’s
pretty commonplace for a physician on a hematology service to call and ask for
a peripheral smear to review. Many times, it’s for the purpose of teaching
residents, fellows, or medical students but more often than not it’s a
confirmatory exercise. See, when that hematologist asks to review a slide,
she’s probably coming down to the lab to look at the morphology of red cells
and white cells to help in their differential diagnosis. They might have a
patient with a suspected thalassemia or hemoglobinopathy and, before starting
the full work up of lab tests, just want to see if there are any RBC morphology
traits or target cells that stand out. Thrombocytopenia? Let’s make sure
there’s no platelet clumping. Maybe they’ve got a patient with some kind of
liver or kidney pathology and are on the hunt for acantho- or echinocytes. Or
better yet, someone went hiking, there’s an infectious etiology on their
differential—let’s go hunting for babesia, malaria, oh or even erlichia!
I know what you’re thinking. Wait—that’s our job as
medical laboratory scientists; our literal job. Our instruments, that we
validate, and correlate, and make sure work fantastically give us flags. We
investigate those flags and look at smears ourselves! We collaborate with other
lab techs, and with our pathologist colleagues and send out final lab results
with all kinds of helpful information: including platelet clumping,
microorganisms, RBC and WBC morphology, and loads more. What gives?
Hold on to your lab coats. I’ll get there in a minute.
Slide review and differential training in medical school
[This section intentionally left blank]
A Differential, Differential
So let me address the issue I brought up: why do
hematologists come down to the lab to look at the slides themselves, when
perfectly capable BOC certified, degree-holding medical laboratory scientists
and pathologists sign out validated differentials? It might not happen this way
at all hospitals, but I think the answer is a simple two-part problem.
First, as with the many things I’ve learned in medical
school, one of the lab-centric pieces of information that is well understood is
that, well, no one really knows what the lab does and how it operates.
Virtually nobody knows the depth and breadth of the testing that pathologists
manage, let alone the scientific precision and accuracy that instrument
validation requires. Learning that MLS techs are certified, can hold graduate
degrees, and even do their own research is often surprising to most of our
clinical colleagues. And—I will tell you for a fact—that pathology and
laboratory testing methodology is not covered in medical school the way you
might think. Pathology is more of a class of distinguishing the identifying
details of a disease, not understanding the interdisciplinary diagnostic
teamwork that goes into those CBC index results on a computer screen on the
Second, hematologists are specialists just like any other
practicing clinician. They know their stuff! They manage patient diagnosis,
treatment, and follow-up with the most up to date literature, national cancer
guidelines, and anything else available to better their patients’ outcomes. Despite
the notes in the CBC results that there are numerous macrocytes with
hypersegmented neutrophils, or 3+ schistocytes reported in a manual
differential—seeing is believing. It helps to see the slide yourself and get a
feel for the disease “state” with your own eyes. Moreso, it could be a learning
opportunity. It’s well within a clinicians’ scope to come down and look at a
peripheral smear, I actually encourage it. But it should come with a few
caveats…I’ll get to those too…
One of the places I was proud to hang my lab coat was
actually my first job as an assistant lab technician in the blood bank at Rush
University Medical Center in Chicago. Before I got my MLS and way before grad
school or med school, I was a blood bank “expediter.” Super fancy title, but
all I did was make sure specimens were logged in and blood products were up to
par with labels on their way out. Clerical but critical! (Let me have this,
please…haha) Anyway, part of the culture at that hospital has stayed with me
all these years. I’ve talked before about culture and the
way it permeates an institution’s practice like at the Mayo Clinic, but for
my first foray into clinical work their acronym was clutch: I CARE.
I for innovation
C for collaboration
A for accountability
R for respect and
E for excellence
Why am I telling you this? No, there are no royalties. I
just think it’s an easy way to remind ourselves about the meaning of
interdisciplinary medicine and they way we should work together across
specialties, and from bench to bedside. When we incorporate those values into
our work for the purpose of improving patient care and outcomes, everyone wins.
In this case, effective utilization of resources tells us that peripheral slide
review means different things to different people. In the setting of
hematologic work-ups, flags and review at the bench can signal something to the
clinician which could spark a conversation with the pathologist. All parts
contributing to a whole of patient care. Vigilante medicine is bad news.
Collaboration is key.
One place I was lucky enough to be a part of this
interdisciplinary collaboration was Swedish Covenant Hospital. One of the
hematology physicians would routinely call me and ask to look as peripheral
smears down in the lab, often as a group with med students, residents, and
fellows. I’d throw the image of his patients’ slides on a large flat screen and
go over what certain traits meant with regard to morphology and identification
from the lab setting. Dr. Cilley would add what this all meant clinically and
discuss treatment algorithms and next steps. That was collaboration at it’s
finest: lab tech working with pathologists, clinicians working with the lab,
and patient’s benefiting from all of it.
Teamwork makes the dream work
About those caveats for collaboration I mentioned earlier…
Let me put it briefly: it’s well within the scope of a clinician to come over
to the laboratory and get some information on their patient’s lab
results/testing. But why not consider the following:
If a physician calls to review a smear, offer
to go over it with them. Likewise, to our clinical friends: if you go to the
lab for a slide don’t be batman—ask the tech what they think!
Experienced techs are one of the hospital’s most valuable resources. Some
folks I’ve worked with have been looking at slides longer than I’ve been using
my eyes at all! They’ll save you and your residents the time when those
terrifying intracellular microorganisms are really just overlying platelets. I
mean, they’ve got a cute halo.
If you need help, just ask. This applies to
Talking with the tech about the slide is great start, but there’s more
resources in the lab than most people know what to do with! Clinical
physicians: check the shelves around the hematology microscope. Stuck on
something? Find a CAP atlas or a proficiency survey booklet guide. Easy to
read. Techs and pathologists: have someone who constantly comes down for slide
review despite your immaculate and detailed SOPs on CBC results reporting? Have
a quick chat about the work that goes into resulting those diffs—you might even
improve your heme TAT, who knows?
If it’s well within the right of a physician
to leave the unit and see a patient’s slide, logic says that maybe, just maybe,
it should be okay for a pathologist to leave the lab and see a patient at the
are full of never-ending rounding white coats, all asking patients questions,
and all contributing specialty notes to their charts. But its not only
to prevent patients from getting a decent nap. We’re all parts of a large
interdisciplinary patient team. A recent Medscape survey found that somewhere
around 3% of pathologists see patients, routinely! Got an interesting case in
the lab, someone who’s part of lots of tumor boards, someone with an
interesting case to write up, or even someone who nobody knows exactly what’s
going on with? Try walking over to 4 south and have a conversation with Mr.
Jones; it might help. At least he’ll know how many people are working on his
The bottom line: we’re in this together, and like the flag
on the ASCP ship says, we’re Stronger Together. Innovation,
collaboration, accountability, respect, and excellence are—and should be—simple
cornerstones of clinical medicine that translate across every discipline. When
we share information and expertise, everyone gets better at what they do.
Thanks for reading!
See you next time!
–Constantine E. Kanakis MSc, MLS (ASCP)CM graduated from Loyola
University Chicago with a BS in Molecular Biology and Bioethics and then
Rush University with an MS in Medical Laboratory Science. He is
currently a medical student actively involved in public health and
laboratory medicine, conducting clinicals at Bronx-Care Hospital Center
in New York City.
When a complete
blood count (CBC) and differential is ordered by a physician, most labs today
have instrumentation capable of performing an automated differential. Depending
on the instrument results and flags, we may need to perform a scan, review of
the slide, or a manual differential. However, the definition of a manual
differential today may be a bit different than the historical definition. A
typical manual differential, when I first started working as a technologist,
consisted of counting and differentiating 100 white blood cells under a
microscope, and performing a red blood cell morphology along with a platelet
estimate. Today, the 3 components of the manual differential have not changed,
but more and more labs are using an
automated digital counting device, such as CellaVision. Whether counting cells
under the microscope or scanning and verifying or reclassifying cells in CellaVision,
it is important to always address all 3 parts of the manual review.
CBC has flagged that abnormal RBC morphology may be present, a peripheral blood
smear should be reviewed. Reporting the red blood cell (RBC) morphology is an
important component of a differential. Evaluation and interpretation of RBC
morphology may provide the physician with important diagnostic information
regarding the underlying cause of a variety of disorders, including anemia and
systemic disease. Therefore, it is important to be able to accurately recognize and
identify RBC morphologic abnormalities.
Red blood cell
morphology can be subjective, and therefore inconsistent. Therefore, Laboratories
must have training and competency programs as well as procedures which dictate how they will report
RBC morphology. Some labs use a numbering system, 1+, 2+, 3+, and others
‘few’, moderate’ or ‘many’. Some morphological, such as rouleaux, can just be
reported as present, with no quantified. Any method is acceptable, as long as
there is consistency in reporting.
RBC morphology, these semi-quantitative
report formats for should be based on clinical significance. Some RBC
morphologies and inclusions are clinically significant,even when
they are present in very low numbers. Sickle cells are one of these
abnormalities that are significant even if only seen in very small numbers.
Malaria or other parasites are clinically significant in any number. Fragmented
cells such as schistocytes and helmet cells should also be noted if seen in any
number. Other abnormalities which can be clinically significant in very low
numbers are polychromasia, spherocytes and teardrop cells.
There are many
other abnormal RBC morphologies which are only clinically significant if seen
in larger numbers. Laboratories may choose to only report the presence of
ovalocytes, target cells, burr cells, macrocytes, microcytes or hypochromia
when greater than a defined percentage of cells exhibit these morphologies.
Other laboratories choose to not report macrocytes, microcytes and hypochromia
at all, instead relying on the physician to use the RBC indicies for their
indication. The 2 most important things to remember, whatever your procedures
are, is to be consistent, and not to ignore the:RBC morphology.
addition to performing RBC morphology, a manual differential also requires
platelet examination. A smear should be examined for a platelet estimate and
abnormalities. This is particularly important when platelet clumps or an
abnormal platelet scattergram are flagged on the CBC. If an instrument uses optical platelet
counts, large platelets can be missed. A fluorescent platelet count (PLT-F) ,
performed on Sysmex analyzers, will stain only platelets and give an accurate platelet
count. The fluorescent count eliminates interferences seen with other methods.
However, even when reporting a PLT-F, it may still required to review the smear
for a platelet estimate, particularly with a very low count, or with clumped
platelet flags. Clumped platelets are not an uncommon phenomenon, and an
accurate platelet count can not be reported if significant clumping is present.
The presence of giant platelets or hypogranular platelets, seen on the
slide, can also aid the physician in
diagnosis or patient management.
CellaVision users have the added benefit of automation which simplifies the process of performing manual differentials. The system automatically locates and takes digital images of cells, including white blood cells, red blood cells and platelets.This simplifies the process of performing a manual differential. White blood cells are pre-classified, RBC images are provided, and platelet images allow platelet estimates to be performed easily. The new advanced RBC application software can pre-classify RBCs. This makes it even easier than before to perform reliable, standardized RBC morphology. (Watch for my next Hematology blog about the new RBC software!)
disorders or abnormalities often involve characteristic changes to RBC
morphology “Assessment of RBC morphology can be the best tool for
laboratory hematology professionals to recommend clinical and laboratory follow‐up in a patient with anemia and to select the
right tests for definitive diagnosis.”1 Too
often, I have seen technologists perform a manual differential and either
superficially skim over the RBC and platelet components, or totally forget
them. Don’t forget
your RBC morphology and platelet estimate and morphology! With today’s
automated differential and autovalidation, 75-85% of CBCs are autovalidated.
This allows us to spend quality time on those manual reviews that need to be
done. Be sure to spend your time thoroughly reviewing the slides. A scan, slide
review or manual differential, whether done under the scope of with CellaVision,tells
the physician that we have looked at the slide or cells, which must include all
3 parts of manual review… WBCs , RBCs and platelets. Don’t sign it out until
J. Ford, Red Blood Cell Morphology.
International Journal of Laboratory Hematology. 2013
-Becky Socha, MS, MLS(ASCP)CM BB CM graduated from Merrimack College in N. Andover, Massachusetts with a BS in Medical Technology and completed her MS in Clinical Laboratory Sciences at the University of Massachusetts, Lowell. She has worked as a Medical Technologist for over 30 years. She’s worked in all areas of the clinical laboratory, but has a special interest in Hematology and Blood Banking. When she’s not busy being a mad scientist, she can be found outside riding her bicycle.
I will continue this month along the thread of last month’s
post, which addressed the controversy surrounding South African female
mid-distance runner Caster Semenya. Caster has won many international
mid-distance races (400-800m), but she has been suspected of naturally
producing higher levels of testosterone.
Since last month, I’ve learned the reason for the higher
testosterone is uncertain: it could be due to natural production
(hyperandrogenism) or rumors of her being intersex1. Regardless,
what I will discuss here is how the proposed actions of the International
Olympic Committee would be expected to affect Semenya’s performance.
Specifically, how would lowering testosterone levels affect her athletic
Last month, we saw that muscle mass might be expected to
decrease, but this may not affect athletic performance significantly.
Another important effect of testosterone is on red blood
cell levels including hemoglobin, which by carrying oxygen to muscle is a
central part of calculating VO2max. VO2max is maximal oxygen
consumption. This is strongly linked to performance in cardiovascular athletic
Mid-distance running requires a large cardiovascular
capacity. Maybe not the same level of Tour-de-France long distance bikers in
the Alps, but still substantial. As a runner that feels pretty proud at having
run a sub-3 minute 800m, I can say Caster’s feat of running it in less than 2
minutes is incomprehensible. From the burning feeling in my lungs and thudding,
maximum heart rate at the end of the half-mile, I can attest that this event
requires substantial cardiovascular efficiency.
Maximal oxygen consumption (VO2max) by exercising
skeletal muscle is principally limited most by cardiac output and
oxygen-carrying hemoglobin levels. This has been shown quite convincingly in a
series of experiments in the 1950’s-70’s2,3 that probably wouldn’t
be approved by the IRBs of today charged to protect research subject rights.
First, transfusing blood increased hemoglobin concentration
and similarly the VO2max and exercise endurance of participants. (This practice was exploited most notably later
on in the Tour de France). In other
studies3, blood was removed from participants before assessing their
exercise tolerance (10% loss of hemoglobin à
13% reduction in VO2max). Another study removed 400mL, 800mL and
1,200mL over several days, which decreased hemoglobin by 10%, 15%, and 18%
respectively. There was a concomitant decrease in endurance time (-13%, -21%,
-30%) and VO2max as well (-6%, -10%, -16%)3. A summary of blood transfusion and
hemodilution studies is shown in Figure 1 from Otto JM et al4.
In transgender women (gender incongruent with sex assigned
male at birth), hormone therapy to increase estrogen levels (oral estradiol)
and block testosterone (anti-androgen: spironolactone) reduces hemoglobin by 9%
on average (from 15.2 g/dL to 13.9 g/dL)5. I would expect a smaller
decrease for Semenya as she will likely not get a full dose hormone regimen
used for transgender transition and because her testosterone levels wouldn’t be
as high as biologic males’. However, she
would still be expected to have lower hemoglobin- similar to donating a half or
whole unit of blood. If hemoglobin decreased even just 5%, that could affect
her performance substantially when the difference between competitors boils
down to seconds in mid-distance races.
Arguably, forced blood donation could produce the same
effects as testosterone-lowering therapy. But it would be far too dramatic to
suggest something like bloodletting by the International Olympic Committee.
In the end, I don’t feel qualified to say what should be
done in this case. All I can say is that I don’t think lowering Caster
Semanya’s testosterone levels will have the intended effect of decreasing
muscle mass. On the other hand, it would decrease hemoglobin levels tempering
her performance. But who should determine the point where her hormone levels
should be? There is such a strong biologic connection between hormone levels
and physiology that manipulating them for athletic fairness could be akin to
North, Anna. ““I am a woman and I am fast”: what Caster Semenya’s story says about gender and race in sports” Vox. May 3, 2019
BALKE B, GRILLO GP, KONECCI EB, LUFT UC. Work capacity after blood donation. J Appl Physiol. 1954 Nov; 7(3):231-8.
Ekblom B, Goldbarg AN, Gullbring B. Response to exercise after blood loss and reinfusion. J Appl Physiol. 1972 Aug; 33(2):175-80.
Otto JM, Montgomery HE, Richards T. Haemoglobin concentration and mass as determinants of exercise performance and of surgical outcome. Extrem Physiol Med. 2013; 2: 33.
SoRelle JA, Jiao R, Gao E et al. Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clin Chem. 2019; 65(1): 170-179.
-Jeff SoRelle, MD is a Molecular Genetic Pathology fellow at the
University of Texas Southwestern Medical Center in Dallas, TX. His
clinical research interests include understanding how the lab intersects
with transgender healthcare and advancing quality in molecular
The patient is a 77 year old man with a longstanding history of increased white blood cell (WBC) count who presented with a new rash and increasing absolute lymphocytosis.
Peripheral Blood Smear
Peripheral blood smear shows small to medium-sized
lymphocytes with basophilic cytoplasm, cytoplasmic protrusions or blebs, round
to oval nuclei with indented nuclear contours and some cells with prominent
Bone Marrow Biopsy
marrow aspirate (top left) shows increased lymphocytes with similar features to
those seen in the peripheral blood. The core biopsy (top right) shows an
abnormal lymphocytic infiltrate. By immunohistochemistry, CD3 highlights
markedly increased interstitial T-lymphocytes (30-40%) that predominantly
express CD4. CD8 highlights only few scattered T-cells.
Concurrent flow cytometry identifies an expanded population
of lymphocytes comprising 73% of the total cellularity. Of the lymphocytes, 98%
are T-cells. The T-cell population is almost entirely composed of CD4 positive
cells (CD4/8 ratio = 301). The T-cells show expression of TCR (a/b), normal
T-cell antigens CD3, CD2, CD5 and CD7 and express CD52 (bright).
Concurrent chromosome analysis shows that 90% of the
metaphase bone marrow cells examined have a complex abnormal karyotype with a
paracentric inversion of chromosome 14 that results in the TRA/D/TCL1 gene
rearrangement. There is also a rearrangement resulting in three copies of 8q
with partial loss of 8p as well as other chromosome aberrations.
Altogether, the presence of an abnormal CD4 positive and
CD52 (bright) lymphocyte population with the characteristic cytogenetic finding
of inv(14), is diagnostic of T-cell prolymphocytic leukemia (T-PLL). This patient’s
course is unusual in that he initially presented with indolent disease that ultimately
progressed. The lymphocyte morphology was also somewhat atypical in that only
occasional cells had prominent nucleoli. This is consistent with the “small
cell variant” of T-PLL.
T-PLL is generally an aggressive disorder characterized by
small to medium sized mature T-cells that are found in the peripheral blood,
bone marrow, lymph nodes, spleen, liver and sometimes skin. T-PLL is rare and
occurs in adults usually over 30 years old. The clinical presentation includes
a lymphocytosis, often >100 x 10^9/L, hepatosplenomegaly and
lymphadenopathy. Serous effusions and skin infiltration can be seen in a subset
of cases. On microscopy, the cells are usually small to medium in size with
basophilic cytoplasm, round to irregular nuclei and visible nucleoli.
Characteristic cytoplasmic blebs or protrusions are a common feature. The
immunophenotype is of a mature T-cell and cells are positive for CD2, CD3, CD5
and CD7. They are negative for TdT and CD1a. Another characteristic feature is
bright expression of CD52. Sixty percent of cases are positive for CD4, while
25% show double expression of CD4 and CD8. The most frequent chromosome abnormality
is inversion of chromosome 14 at q11 and q32, which is seen in 80% of patients.
Translocations involving chromosome X and 14 are also seen, as well as
abnormalities of chromosome 8. The overall prognosis is generally poor with a
median survival of 1-2 years. Patients with expression of CD52 may respond well
to the monoclonal anti-CD52 antibody alemtuzumab, but other treatment options
The small cell variant (SV) of T-cell prolymphocytic
leukemia was once referred to as T-cell chronic lymphocytic leukemia due to a
predominant population of small lymphocytes with condensed chromatin and lack
of conspicuous nucleoli. In addition, unlike the aggressive course seen in most
patients with T-PLL, patients with this morphology tended to have an indolent
or more chronic disease course. Eventually, it became clear that this was
merely a variant of T-PLL due to similar immunophenotypic and cytogenetic
findings. Ultimately, the term T-cell CLL was retired from use.2
In a comparison of patients with SV T-PLL to three large
studies of classic T-PLL patients, the SV patients were found to have a higher
frequency of a normal karyotype and increased double negative (CD4-/CD8)
immunophenotype. Interestingly, 38% of the SV patients did not receive
treatment for the entire duration of follow-up, while 19% required treatment
after initially just being observed. This time period ranged between 2 months
to 3 years. The remaining patients were treated at diagnosis. Most of the
patients ultimately progressed and the cause of death was disease progression
in 86% of the patients who died during follow-up. Overall, SV T-PLL tended to
show less aggressive clinical behavior than classic T-PLL, however many
aggressive cases of patients with the small cell variant have been seen.
Likewise, more indolent cases of classic T-PLL featuring cells with larger
nuclei with prominent nucleoli have also been described.2
While cases of SV T-PLL may initially present with more
indolent disease, they almost always progress to a similarly aggressive disease
course as seen in classic T-PLL. T-PLL is generally resistant to most
conventional chemotherapies. As mentioned earlier, cases of T-PLL tend to
express bright CD52, which is a glycoprotein present on the surface of mature
lymphocytes. CAMPATH-1H is an anti-CD52 monoclonal antibody that may result in
complement-mediated lysis and antibody-dependent cellular cytotoxicity. In a
study by Dearden et. al., thirty-nine patients with T-PLL received CAMPATH-1H
treatments. The overall response rate was 76% with 60% achieving complete
remission. These rates are significantly higher than those reported for
conventional therapies like CHOP. Unfortunately, almost all of the patients
ultimately progressed and all but 2 had relapsed following 1 year of therapy.
This indicates that CAMPATH-1H is good for first line therapy, but is not a
curative treatment for this aggressive and most often deadly disease. 3
Swerdlow SH, Campo E, Harris NL, et al. WHO
Classification of Tumours of Haematopoetic and Lymphoid Tissues (Revised 4th
edition). IARC: Lyon 2017.
Rashidi and S. Fisher. T-cell chronic lymphocytic leukemia or small-cell
variant of T-cell prolymphocytic leukemia: a historical perspective and search
for consensus. European Journal of
Haematology. 2015(Vol 95).
Dearden, E. Matutes and B. Cazin, et. al. High remission rate in T-cell
prolymphocytic leukemia with CAMPATH-1H. Blood.
–Chelsea Marcus, MD is a Hematopathology Fellow at Beth Israel
Deaconess Medical Center in Boston, MA. She has a particular interest in
High-grade B-Cell lymphomas and the genetic alterations of these
A 71 year old man with a history of multiple myeloma
presented with urinary incontinence and confusion and was found to have
hyperkalemia with renal failure. Imaging showed extensive inguinal
lymphadenopathy with concern for new lymphoma.
Excisional Lymph Node Biopsy
show an enlarged lymph node with complete effacement of the normal lymph node
architecture by sheets of medium and large plasmablastic cells. The cells have
round nuclear contours, large prominent nucleoli and moderate amounts of
amphophilic cytoplasm. Frequent apoptotic cells and scattered mitoses are seen.
Immunohistochemical stains show that the neoplastic cells
are immunoreactive for CD138, CD38, CD19 (dim) and MUM1. They are negative for
CD20, which highlights only small admixed B-cells. The cells are kappa
restricted by kappa and lambda immunostain. The Ki-67 proliferation index is
greater than 90%.
Taken together, the morphologic and immunophenotypic
features are of a high grade plasmablastic neoplasm. The differential diagnosis
includes plasmablastic myeloma and a plasmablastic lymphoma. Given the
patient’s history of a kappa restricted plasma cell dyscrasia, plasmablastic
myeloma is favored.
Multiple myeloma is a neoplasm of clonal plasma cells that
accounts for 10% of all hematologic malignancies. It is most commonly seen in
adult and elderly patients with a male predominance. Plasma cells are generally
characterized by the presence of a “clockface” nuclei and distinct perinuclear
Hof or clearing of the cytoplasm containing a large number of Golgi bodies. The
morphology of plasma cell tumors can range from small mature plasma cells to
anaplastic or plasmablastic morphology. In this case, the cells showed
plasmablastic (PB) morphology, which is characterized by a large nucleus, large
nucleolus, fine reticular nuclear chromatin pattern, lack of nuclear Hof and
less abundant cytoplasm than typical plasma cells.1
The differential diagnosis for cases with this morphology primarily
includes PB lymphoma and PB myeloma with extramedullary involvement. PB
lymphoma is seen more commonly in HIV positive patients or patients with other
causes of immunodeficiency. It typically occurs in adults and has a male
predominance. The tumor generally presents outside of nodes and is most
frequently seen in the oral cavity/jaw. Patients tend to present with advanced
stage and bone marrow involvement. While PB lymphoma is categorized as a
distinct subtype of diffuse large B-cell lymphoma, PB myeloma is considered an
atypical morphologic variant of multiple myeloma and is treated with therapy
geared towards plasma cell neoplasms. 2
Making the distinction between these entities is difficult due to similarities in morphology and immunophenotype. Ultimately, the diagnosis is generally made based on the clinical context. In one series of “plasmablastic” neoplasms by Ahn, et. al., 6 out of 11 cases were called PB lymphoma, 2 out of 11 were called multiple myeloma and 3 were called indeterminate. Among the PB lymphoma patients, 4 were either HIV positive or had a history of immunosuppression. All 6 cases were positive for CD138 and negative for CD20 with EBV in situ hybridization positivity in 3 out of 6 cases. The multiple myeloma cases had evidence of end organ damage without lymphadenopathy. One indeterminate case had peritoneal nodules, lytic lesions and an EBV positive neoplasm in the bone marrow, which precluded a definitive diagnosis. 3
The immunophenotypic pattern seen in this case is typical of
these neoplasms and is characterized by the expression of plasma cell antigens (CD138,
CD38, MUM1) with either weak or negative expression of B-cell antigens (CD20). A
study by Vega et. al. looked at the immunophenotypic profiles in nine cases of
PB lymphoma and seven cases of PB myeloma. They found that the profiles were
nearly identical. All cases were
positive for MUM1/IRF4, CD138 and CD38 and negative for CD20, consistent with a
plasma cell immunophenotype. PAX5 and BCL6 were weakly positive in 2/9 and 1/5
PB lymphomas and were negative in all PB myelomas. A high Ki-67, overexpression
of P53 and loss of p16 and p27 were present in both tumors. There was no
evidence of HHV8 detected in either neoplasm. The presence of EBV-encoded RNA,
was seen in all PB lymphoma cases tested and negative in all plasma cell
myeloma cases. This was found to be statistically significant. 4
Unfortunately, both PB lymphoma and PB myeloma are aggressive
high grade neoplasms with a poor prognosis. A study conducted by Greipp et. al.
assessed the prognostic significance of plasmablastic morphology in a cohort of
patients from the Eastern Cooperative Oncology Group Myeloma Trial E9486. They
looked at bone marrow aspirates from 453 newly diagnosed multiple myeloma cases
in a 5 year period. Of the 453 aspirates, 8.2% were classified as PB
morphology. The overall survival of
patients with PB morphology was significantly shorter than patients with non-PB
morphology with a median of 1.9 years compared to 3.7 years. There did not
appear to be a relationship between PB morphology to other clinical or
laboratory features such as age, sex, bone lesions or type of M-protein. 5
M Srija, P Zachariah, V Unni, et. al.
Plasmablastic myeloma presenting as rapidly progressive renal failure in a
young adult, Indian Journal of Nephrology,
Volume 24(1): 2014, Page 41-44.
JJ Castillo, M Bibas, RN Miranda, The biology
and treatment of plasmablastic lymphoma, Blood,
Volume 125, 2015, Page 2323-2330.
J Ahn, R Okal, J Vos, et. al. Plasmablastic
Lymphoma vs Myeloma With Plasmablastic Morphology: An Ongoing Diagnostic
Dilemma, American Journal of Clinical Pathology,
Volume 144(2): 2015, Page A125.
F Vega, CC Chang, LJ Medeiros, et. al.
Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly
identical immunophenotypic profiles. Modern
Pathology, Volume 18: 2005, Page 806-815.
PR Greipp, T Leong, J Bennett, et. al. Plasmablastic Morphology – An
Independent Prognostic Factor With Clinical and Laboratory Correlates: Eastern
Cooperative Oncology Group (ECOG) Myeloma Trial 39486 Report by the ECOG
Myeloma Laboratory Group, Blood, Volume 91: 1998, Page 2501-2507.
–Chelsea Marcus, MD is a Hematopathology Fellow at Beth Israel Deaconess Medical Center in Boston, MA. She has a particular interest in High-grade B-Cell lymphomas and the genetic alterations of these lymphomas.