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Histopathologic Prognosis of Thymomas
Another Example of Medical Surrogacy
Mark R. Wick, MD
Particularly in anatomic pathology, the past 2 decades
have witnessed a proliferation of tests that are surrogates for
selected analytes of predictive or prognostic interest. Those
targets include such moieties as functional hormone receptor
proteins and the composition of genes that govern responses
to selected growth factors. Common respective examples of
those groups are estrogen and progesterone receptor proteins1
and the HER-2/neu, c-kit, and epidermal growth factor recep-
tor (EGFR) genes.2-8
Thousands of tests are done each year, predominantly
through immunohistochemical analysis, to assess the status
of such targets in malignant human neoplasms. And yet,
immunohistochemical analysis represents an imperfect
substitutive method in reference to the goal just mentioned.
Immunohistology does not necessarily detect functional
hormonal receptors (HRs),9 and it is suboptimally effec-
tive in separating HR-“positive” from HR-“negative”
tumors, when compared with the performance of tradi-
tional biochemical HR assays.10 General assumptions also
have been made (and accepted) that hold that the increased
cellular expression of the proteins related to the neu, c-kit,
and EGFR genes—as visualized by immunohistochemical
analysis—is an invariable reflection of gene amplification
or an activating mutation.11 Recent publications have dem-
onstrated the fallacy of those suppositions. Increasingly,
the published literature shows that fundamental, “first-
hand” laboratory tests are incontrovertibly superior to
immunohistochemical analysis as medical devices.8,12
Pertinent examples are the dextran-coated charcoal assay
(DCCA) for HRs13 and in situ hybridization or polymerase
chain reaction–based blotting techniques for the assess-
ment of gene structure.
This situation speaks to a common tendency that many
physicians have, that is, a propensity to exchange scientific
rigor—because it demands scrupulous attention to detail—
for expediency. If one assessment of prognosis is quicker,
cheaper, and less technologically intensive than another,
the first will be chosen by practitioners nearly every time.
Moreover, that paradigm applies even if the selected test is
statistically inferior to others, providing that seemingly con-
vincing rationalizations can be made for its use. Returning to
an assertion made in the previous paragraph, it has become
clear that the old-fashioned DCCA, if properly performed,
gives a more accurate depiction of the likelihood that breast
carcinomas will respond to hormonal modulation than does
immunohistochemical analysis.10,14,15 However, it is cum-
bersome to obtain aliquots of frozen tissue in each case of
breast cancer and equally problematic to transmit them under
controlled conditions to the laboratory. In addition, frozen-
section examination of the tissue aliquots is ideally necessary
before the DCCA is performed to ensure that tumoral—and
not nonneoplastic—material has been sampled for biochemi-
cal analysis. Hence, immunohistochemical analysis for HRs
in breast cancer is now the dominant method of pathologic
evaluation, principally because it is much less “needy” with
regard to tissue processing.
There are similar examples of “substitutionary” practice
in just about every area of medicine. One of them, concern-
ing the prognostication of thymomas, is touched on in an
article in this issue of the Journal by Moran and colleagues.16
This study clearly shows that spindle-cell thymoma (also
called “type-A” in the World Health Organization [WHO]
classification scheme) definitely has the ability for aggres-
sive clinical behavior. That conclusion flies in the face of
704 Am J Clin Pathol 2010;134:703-705
704 DOI: 10.1309/AJCPF4KT2PEXZUSD
© American Society for Clinical Pathology
Wick / Histopathologic Prognosis of Thymomas
counterassertions made in other published studies on thymic
tumors.17,18 For the most part, the latter analyses have claimed
that type-A thymoma was virtually always biologically
benign, with a low tumor-stage at diagnosis.19
Those articles substituted a histologic classification of
thymoma for formal clinical staging of that neoplasm, toward
the end of forecasting patient outcomes. As a consequence,
thoracic surgeons who embrace that approach currently may
eschew open thoracotomies and make treatment decisions that
are predicated on the results of imaging studies and WHO
schema–based descriptions of thymoma in small biopsy
specimens.20 With due respect to our colleagues in radiology,
even the most sophisticated procedures available to them are
no equal for intraoperative naked-eye inspection of anatomic
structures and appropriate tissue sampling of areas that appear
to be abnormal to the surgeon. Furthermore, tiny samples of
large tumors are quite likely to be poorly representative of the
The “story” behind the WHO categories for thymoma
makes the foregoing facts even more interesting. I was privi-
leged to be a member of the WHO committee whose work
eventually produced the document on thymic tumors that was
authored by Juan Rosai, MD (the committee chairperson), in
1999.22 Therefore, I was a witness to the discussions that had
considered which nosological terminology would be best for
such lesions and why. After many months of unproductive and
often-testy interactions in the late 1990s, the committee mem-
bers could not agree on a consensus scheme. Consequently,
Rosai made a “command decision” to construct the format
himself. His intent was, quite simply, to produce a workable
method for the histologic description of thymic tumors. There
was no associated suggestion that the resulting WHO classifi-
cation had, or could have, prognostic usefulness as well.
Despite that fact, articles began to appear shortly thereaf-
ter claiming that the Rosai-WHO scheme was, in fact, a prog-
nostic one.23,24 Such proposals held that the risk of aggressive
behavior predictably escalated as one moved from type A to
AB, B1, B2, and B3 tumors.
Those claims are still averred by WHO devotees.
However, the current article by Moran and colleagues16 is
one of several that have shown that the Rosai system is not,
in fact, a reliable surrogate prognostic construction.19,24-26 But
then again, it was not meant to be.
In my opinion, the WHO classification of thymomas can
be regarded as an “old man in a new set of clothes.” Almost
50 years ago, Bernatz et al27 advanced a system for categoriz-
ing thymomas that closely parallels the Rosai paradigm con-
ceptually, and the former of those schemes has likewise been
shown to lack prognostic usefulness.28
I, for one, prefer the straightforward construct advanced
by Suster and Moran,29 virtually contemporaneously with
the 1999 WHO publication. The former of those approaches
divides thymic tumors into 6 groups, integrating information
from surgical observation and histopathologic evaluation: thy-
moma (WHO types A, AB, B1, and B2 neoplasms), noninva-
sive and invasive; atypical thymoma (WHO type B3 tumors),
noninvasive and invasive; and thymic carcinoma (original
WHO type C lesions), noninvasive and invasive. The validity
of that model has recently been demonstrated convincingly by
Marchevsky et al25 and Kim and colleagues.26 Furthermore, it
is the stage of the tumors in each histopathologic cluster that
is the main determinant of outcome, not their morphologic
details. In that vein, Gupta and coworkers30 have shown that
the traditional 4-tiered Masaoka staging system for thymoma
also can be condensed into 3 strata, combining original stage
I and stage II as revised stage I lesions and retaining original
stages III and IV as revised stages II and III. Staging has once
again emerged from the fray as the dispositive piece of infor-
mation for the prognosis of thymomas, and, to reiterate a point
made earlier, I believe that formal thoracotomy is necessary to
the accuracy of that procedure.
Years ago, an often-shown television commercial assert-
ed that a particular investment firm made money the “old-
fashioned way”—they earned it. I believe that the same adage
applies to outcomes forecasting for thymic tumors; the most
direct and traditional methods are still the best.
From the Division of Surgical Pathology & Cytopathology,
University of Virginia Health System, Charlottesville.
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Am J Clin Pathol 2010;134:703-705 705 Download full-text
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AJCP / Editorial
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