In the midst of talking about career choices with other residents and faculty, it seems that certain generalizations are made about choosing one specialty over another.  Plenty of generalizations could be made about pathologist personalities compared with those in other fields of medicine.  I would have to emphasize that many are clearly untrue, of course.

But perhaps there is some truth to generalizing what types of residents and fellows are looking for hematopathology, versus dermatopathology, versus general surgical pathology, versus microbiology, etc.  One generalization I heard was that hematopathologists like things well-ordered and relatively black and white.  On the other end of the spectrum would be dermatopathologists who are more tolerant of flexible diagnoses.  And surgical pathologists somewhere in between.  I am clearly a literal person who prefers the ‘black and white’ distinctions in life.  I focus well on one subject at a time.  Thus pathology fits me well and perhaps hematopathology fits me the best.

What are your thoughts on specialty choices and personality types?  Any truths to help guide searching students or residents?

So, to start off with, the 5% “unclassified cells” were myeloid blasts without Auer rods.  In addition, the peripheral smear shows mostly granulocytes in varying stages of maturation.  The mature bands and neutrophils do not show toxic granulation or vacuolation or Dohle bodies.  Only 2% of the cells were basophils, but this still qualifies as an absolute basophilia.

Given these finidings, this is very suspicious for a leukemia, especially given the high serum LDH and the extreme leukocytosis. Leukemoid reaction is certainly in the differential – by pure virtue of its name, “leukemoid”, it mimics a leukemia.  However, leukemoid reaction rarely attains leukocyte counts of >100,000/ul and usually shows toxic changes in the granulocytes (vacuolation, granulation, cytoplasmic Dohle bodies).  Without any other history of infection and the man’s mild symptoms, a leukemia must be considered.  The 5% blast level would also be unlikely in a leukemoid reaction.  The low hemoglobin and platelet counts are also in favor of a process in the bone marrow that is “bullying” the other cell lineages.

These were the “unclassified cells” we counted as blasts.

The differential diagnosis could also include chronic myelomonocytic leukemia (more monocytes) a myeloproliferative neoplasm with PDGFRalpha/beta rearrangements or FGFR1 abnormalities (unlikely), or a myeloproliferative neoplasm, unclassified (or atypical CML).

I spoke with the Heme/Onc fellow who also reviewed the slide and my hematopathology attending and everyone was on the same page that this was likely CML.  A bone marrow had been done already.  The treating team started hydroxyurea, allopurinol, and hydration immediately and Gleevec (imatinib) was started the following day.

The bone marrow showed a typical picture of CML: a very hypercellular marrow with an immature shift of granulocytes, small and hypolobated megakaryocytes, and decreased erythroid precursors.  FISH for the t(9;22) BCR-ABL fusion gene showed the fusion in 98% of cells analyzed and the conventional karyotype showed the Philadelphia chromosome in all 20 cells.

The patient is doing well despite persistent mild fatigue and is due for his 3 month follow-up marrow in September.  He will also get bone marrows at 6 months and 12 months.  The most sensitive methods of follow-up, though, are by cytogenetic and molecular testing for BCR-ABL.  CML is one of the success stories in medicine, as a once fatal disease now sees 85% of patients alive and disease free at 7 years while on Gleevec.  Alternative tyrosine kinase inhibitors (e.g. dasatinib) are available should patients fail this regimen.

Here’s a Hemepath case I had on-call a few weeks ago:

I was called on Friday night at 6:30pm by our Hematology lab to evaluate a peripheral blood smear with “unclassified cells” on a 45 year-old man who had a complete blood count showing 165,000 WBCs/microliter.  Surprisingly he felt ok overall, except for slight malaise.  His labs were as follows:

WBC 165k/ul

Manual differential: 5% unclassified cells, 39% neutrophils, 10% bands, 9% metamyelocytes, 13% myelocytes, 1% promyelocytes, 10% lymphocytes, 8% monocytes, 3% eosinophils, 2% basophils

Hgb 10.2 (normocytic, normochromic);

Plt 137

Creatinine 0.79

LDH 737 (ref range 100-190)

The peripheral smear that I reviewed looked like this:

For any beginning residents in the audience, how would you handle the case at this point?

After I triaged the case that night with my attending, we looked at the bone marrow on Saturday and signed out the flow cytometry on Monday.

Examination of the bone marrow showed 95% cellularity, decreased and small, hypolobated megas, decreased erythroids, and an immature shift of granulocytes.

Flow cytometric analysis showed 91% granulocytes, 4.5% monocytes, 1.1% T cells, 1.0% erythroids, 0.71% immunophenotypically unremarkable myeloid blasts, 0.21% NK cells, a subset of granulocytes and monocytes CD56+, and maturation disruption of granulocytes based on the CD11b/CD16.

How should this case be signed out?

In our case, the presentation was quite classic as described in the literature and was recognized quickly by our hepatologist.  Her ceruloplasmin level (the copper carrying protein) was slightly low but was likely elevated due to an acute phase reaction.  Her urine and plasma copper were quite high (24 hour urine collection was 27180 mcg [normal 3-35 mcg]).  She underwent 4 consectutive days of plasma exchange with FFP as the replacement product and underwent an uncomplicated liver transplantation.  The following chart shows the drop in creatinine following plasmapheresis (extending the span of the red bracket) and the date of liver transplant (black arrow).

Her INR and bilirubin dropped similarly, although not quite back to normal before the transplant.  Because the clinical team suspected ongoing hemolysis and coagulopathy, she received a new liver when one became available.  As you can see in the H&E and trichrome stains of the native liver, there is clear cirrhosis.  Her hepatic parenchymal copper content (by ICP/MS) was 1103 mcg/g dry weight, which is “strongly suggestive of Wilson’s disease.”  A level of <40-50 mcg/g dry weight almost always excludes the disease.

I came into contact with this case on my Blood Bank rotation because we were asked in consultation to assess her for plasmapheresis.  Wilson’s disease is not included as an indication in the ASFA (American Society for Apheresis)’s recommendations for therapeutic apheresis, but a few case series have shown its effectiveness, especially in cases showing fulminant liver failure and hemolytic anemia.  Thus, it should probably be a category III indication (diseases with anecdotal benefit but for which there is limited data or conflicting results from published clinical trials).  The thought is that excessive copper accumulates in hepatocytes due to inherited autosomal recessive mutations in a copper transport gene, ATP7B, that codes for a P-type ATPase.  When this accumulation reaches some threshold, the liver begins to fail as hepatocytes die and release copper into the circulation, which damages erythrocytes through membrane damage or enzyme disruption.  This is thought to be the mechansim behind the hemolysis partly because of the strong, direct association of levels of serum copper and the severity of hemolysis.

Plasmapheresis effectively removes the toxic levels of copper in the circulation to disrupt the hemolytic cycle, most importantly sparing the kidneys of irreversible damage.  In some cases in the literature, plasmapheresis has been used effectively to obviate the need for liver transplantation, but in most of the cases it serves as a bridge to stabilize the patient in anticipation of a donor liver.  Many of these patients are female and have fit into an age range of 16-21, as was true in our case.

Random fact:  if you are looking for copper in your diet, you may find it in these foods: shellfish, nuts, chocolate, mushrooms, organ meats…among others.  See, you learn something new every day!

For my first post I’ll share an interesting case that my Blood Bank team last month was involved with, but is interesting from an Anatomic Pathology point-of-view too.  It’s identical to my post on my original blog (geniculating.blogspot.com) but I still haven’t posted the answer.  I’ve also changed some of the information to protect the patient’s privacy.

Case:

A 21-year-old female presented with a 5 week history of fatigue, anorexia, and mild jaundice. She was previously healthy with no past medical history, no medications, and no drug or medication use. The initial workup showed a normochromic, normocytic anemia (Hgb 11.5) and increased liver function tests and was negative for infectious mononucleosis and viral hepatitis. Just a few days after this basic workup her course worsened and she became more severely jaundiced and developed dark urine and right upper quadrant pain. She was admitted to a referring institution before being transferred to Milwaukee and the workup showed the following:

Afebrile and vital signs stable
Scleral icterus, jaundice, splenomegaly, and RUQ pain on exam

WBC: 13.5 H
Hgb: 6.5 L
Plt: 178
Creatinine: 2.2 H

ALT: 13
AST: 147 H
Alk phos: 17 L
Tbili: 42.9 H
Dbili: 12.6 H

INR: 3.1 H
Albumin: 2.3 L

LDH: 659 H
Haptoglobin: undetectable L
Retic: 11.79 H
Direct antiglobulin: neg.
Blood type: O+, Ab screen neg.

Peripheral smear: see image

ANA: within normal limits
Serum pregnancy test: neg.

Does anyone have a diagnosis? I’ll say that the peripheral smear is just of interest, not crucial to the diagnosis.  I thought it was just nice to see an image associated with the case.  I’ll post the diagnosis in a week with follow up photos in a new post and/or comment.

B-cell IgH PCR revealed a clonal B-cell population, and the diagnosis of extranodal marginal-zone lymphoma was made. After treatment with antibiotics, repeat biopsy showed persistent lymphoma, and she underwent radiation therapy. After radiation, further biopsies demonstrated complete histological remission of the lymphoma.

Follow Up
After an interval of twenty months, she was found to have an incidental parathyroid adenoma, for which she underwent a parathyroidectomy and partial thyroidectomy.

The morphological and immnuohistochemical findings in the thyroid seemed more consistent with Hashimoto thyroiditis than with lymphoma. However, given her history, B-cell IgH PCR was performed on the thyroid tissue. A clonal B-cell population was detected, with the same immunoglobulin gene rearrangement size as the previous clonal population detected in the patient’s gastric MALToma. FISH for t(11;18) showed that the translocation was present in both the gastric and thyroid samples.

Discussion
This case raises some interesting questions about the significance of clonality in lymphomagenesis. Though clonality is usually strong evidence for hematopoietic malignancy, a growing body of literature shows that clonality may be found in various benign hematopoietic cell populations.¹ In gastric MALT lymphoma, the malignant behavior of the B-cell clone is believed to be driven by continual antigenic stimulation by H. pylori antigens, which is why antibiotic treatment is frequently curative, and why persistent clonal B-cell populations can sometimes be found in cases of complete histological lymphoma regression.^2-3 There is also evidence that patients with autoimmune disease have a decreased response to H. pylori eradication therapy.⁴ The presence of t(11;18) typically indicates a more aggressive course with a diminished response to antibiotic treatment, which also raises questions about prognosis and about the significance of the possible autoimmune stimulus in the thyroid. To date, this patient has no clinical evidence of further malignant behavior of the B-cell clone, in the thyroid or elsewhere. What do you think? Could the clonal cells in the thyroid be thyroid benign, or will her lymphoma progress?

1. Torlakovic E, Cherwitz DL, Jessurun J, Scholes J, McGlennen R. B-cell gene rearrangement in benign and malignant lymphoid proliferations of mucosa-associated lymphoid tissue and lymph nodes. Human pathology. 1997 Feb;28(2):166-73.
2. Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet. 1993 Sep 4;342(8871):571-4.
3. Fishleder A, Tubbs R, Hesse B, Levine H. Uniform detection of immunoglobulin-gene rearrangement in benign lymphoepithelial lesions. The New England journal of medicine. 1987 Apr 30;316(18):1118-21.
4. Raderer M, Osterreicher C, Machold K, Formanek M, Fiebiger W, Penz M, et al. Impaired response of gastric MALT-lymphoma to Helicobacter pylori eradication in patients with autoimmune disease. Ann Oncol. 2001 Jul;12(7):937-9.