What is cancer and what is a malignant cell? Is it something
that has already spread to other organs or something which has the potential or
capacity to spread? This note is an analysis of the issues associated with
diagnosis of pre-cancerous lesions including carcinoma in situ. The intent is
to examine the broad set of diagnosis of these types and whether they merit the
description of being a carcinoma. This issue has become more relevant as we
have seen increasing diagnosis of "cancers" and many of them being
early stage confined cellular lesions. We fundamentally ask the question: is
here a bright line between abnormal growth and cancers? Unlike many of our
other notes this one poses a multiplicity of questions which may beg for
answers. As usual, any and all comments are welcome.
Before addressing the full question let us first address the
meaning of capacity or potential. The reason for doing so is to better
understand what we mean by "carcinoma in situ" or that the cells are
cancerous but they are not malignant to the extent that they are moving about,
only that their local presence looks ominous. We see this construct in many
cases such as the prostate, the breast, the thyroid and the skin. Namely, when
the cells take on certain characteristics which we perceive as a potentially
malignant process, yet not quite there. Thus, a great deal rests upon our
understanding of potential or capacity to do something.
Our focus herein is with what is called "carcinoma in
situ" or CIS. As we shall note later, CIS has the characteristic of having
the "capacity" or "potential" to become a full-blown cancer,
including metastatic growth. The fundamental question is; what do we mean by
capacity or potential? Does a pigeon have the potential to become an eagle? No.
Does a pigeon egg have the potential to become a pigeon that can fly? Yes,
possibly. Thus, capacity or potential is a statement that is not deductive but
rather inductive. Can we say a HGPIN in the prostate will inevitably become a
metastatic carcinoma? No. In fact we know that HGPINs may actually disappear
and never become anything at all. Thus, our first challenge is to address the
meaning of capacity or potential. This may be a bit afield for a paper on
cancer, but for a patient, hearing the word "cancer" can evoke all
sorts of negative effects.
Let us start with Aristotle and his handling of the concept
of capacity or potential in his work, The Metaphysics[1]:
Potentialities as a whole we can divide into:
the in-born, such as the senses,
the acquired by practice, such as that for flute-playing,
and
the acquired by learning, such as that for skills.
The last two of these groups are to be had on the basis
of previous actualization, the potentialities, that is, that are conditioned by
habituation and the grasp of an account. But such previous actualization is not
required for those potentialities which, not of this kind, are conditioned
merely by the bearer’s undergoing a certain affection.
Although Aristotle is here describing human potential it is
not difficult to expand this to cells. For a cell to have the potentiality to
be cancerous is can be divided into:
i.
the genetic in-born, namely
the cell has an innate genetic makeup that predisposes it
ii.
the acquired by mutation,
such as what we would find in irradiated cells or cells resulting from reactive
oxygen species interference
iii.
the acquired my
environment, such as would be the case where the cell receives signalling or
epigenetic changes that incite cancerous changes
Aristotle continues[2]:
Potentiality (is defined as):
(i) The principle
of process and change, either in another thing or in the same thing qua other.
The art, for instance, of building is not present in what
is built, whereas with the art of medicine, it may, since it is a Capacity, be
present in the person being healed, but not qua a person being healed. So, what
is a principle of change or process in this way is said to be a Capacity,
whether in something else or in the thing itself qua something else.
(ii) Also, a principle of change or process through the
agency of something else or of the thing itself qua something else. After all,
it is by dint of the principle by which something affected is affected in some
way that we say that the thing affected has a Capacity for being affected, and
this sometimes merely if it is affected at all, sometimes not with regard to
its each and every affection but only if it is affected for the better.
(iii) The Capacity for performing the given function well
or in an intentionally guided manner. For instance, on occasion one says of
those who can just about walk or talk but not do so well that they do not have
the Capacity to talk or walk. …
Given that there is this plurality of accounts of
Capacity, in one way the account of the potential will correspondingly be of
something that has a principle of process and change (given that what can
induce stasis is also a sort of potential) in something else or in the same
thing qua something else.
Aristotle has laid out three meanings. Note the first,
wherein he argues that the "art of medicine" may be included in the
"person being healed". There is a nexus between the art and the
person but not qua the person. This first definition tris to have a clear
continuum between cause and effect. The second definition is via a separate
agency this allowing the cause and effect to be separate from one another
unlike the art of medicine and the involvement of the patient. The third is a
bit obscure in that it relates to the potential but of something which cannot
fully carry out the desired effects. Perhaps here we can have a CIS? He
continues;
Another account has it that a thing is potential if
something else has a Capacity of … over it, and another is that it is potential
if it has the Capacity to change into something of whatever sort, whether for
worse or for better. Indeed, even what is destroyed is held to be potentially
destructible, since it would not have been destroyed if it had no potential for
it. In fact, however, what is destroyed has a certain disposition, a cause and
principle of an affection of this sort, this being held sometimes because it is
thought to have some state and sometimes because it is thought to have been
deprived of it.
If, then, a privation is in a way a state, then everything
would be deemed to be potential, potential by dint of having a certain state,
and, if not, then by homonymy, with the result that things are potential both
by dint of having a certain state and a principle and by having the privation
of this – assuming one can be said to have a privation. Yet another account is
that something is potential by dint of the fact that neither any other thing
nor itself qua other thing has a Capacity to destroy it. Now, also all these
cases are examples of Capacity either by dint of the fact that the event in
question might or might not turn out to happen or by dint of the fact that it
might do so either well or badly...
He then poses the issue of the contrary to potential as
follows:
As for non-potentiality and incapacity, this is
the corresponding privation to this kind of potentiality, and so every
potentiality is of the same thing under the same aspect as the corresponding
non-potentiality. There are, though, a plurality of accounts of privation, as
follows:
(i) that which does not have f;
(ii) that whose nature is to have f, if it does not in
fact have f (either at all or at a time when it would be natural for it to have
f, and either in a particular way, as, say, completely or to some extent or
other);
(iii) in some cases, things constituted to have f and
lacking it through force, are said to be deprived.
Thus incapacity is more simply based upon; (i) not having
the necessary fundamental elements by its very nature to accomplish the task, a
dog with no wings, (ii) being fundamentally of the nature to fly but not having
the essential element to accomplish it, such as a bird born with no wings,
(iii) an entity being fundamentally of its nature but having been exogenously
deprived of them, a bird whose wings were cut off. How then does this apply to
CIS. In case (i) we would argue that the cells by their nature, genetic etc.
makeup, are unable to metastasize, in (ii) the cells may possess the genetic
faults but they are blocked by other similar faults, and (iii) the cells may
possess the genetic faults but some factor such as an epigenetic blockage
prevents it from operating.
This is a long but essential discussion. If we assert some
form of capacity or potentiality, we must be asserting it on one of two bases. First,
there is in the cells an inherent and identifiable set well defined and
determined elements, which is activated as they would be in the natural course
of the cell's life, lead to a cancer as we understand that to be. Namely, we
can identify and assert a causality. If the genes or whatever in the cells are
in some state X, we know that state X inevitably goes to state Y. This is the
deductive approach. Second, on the other hand, we can assert that by multiple
observations we have a fairly his probability that if we see cells in state X
that they may most likely become cells in state Y. This is the inductive
approach.
Just where are we today? Unfortunately, we do not have the
genetic or similar certainty that X becomes Y because the genes are in state S.
We have a great many good guesses but alas no certainty. What we do have is
some reasonable approach to the inductive case. Yet even here we are lacking
certainty. The lacking of certainty leads to questionable assertions regarding
capacity or potentiality.
We can now extend this discussion of classical concepts to
our understanding of what a cancer is. As Al-Saleem has noted:
The diagnosis of “cancer” is a very traumatic and is
usually associated with huge psychological, social and economic burdens to most
patients and their families. It is obvious that a “modern” definition of
“cancer” may not improve research and management of this rather complex disease
only, but will also reduce the burden of cancer diagnosis and improve the
patient-provider communications and clarify the diagnostic and therapeutic
decisions. So, what is the present definition of “cancer”? This seems to be an
absurd question from a person who has spent more than half a century diagnosing
and researching cancer, like myself.
Indeed, it is not. Definitions should reflect what we know
and the definition should not necessarily remain fixed in time if knowledge is
continuously being added. For example, in the field of systematics, as we have
obtained more detailed information based upon the genetics of those things we
are classifying we find the trees which have been used for centuries do change
and sometime dramatically. Thus, it should be the case with cancer that we
should modify its classification as we progress in knowledge and understanding.
The author continues:
The National Cancer Institute (NCI) defines cancer as
follows “cancerous tumors are malignant, which means they can spread into, or
invade, nearby tissues. In addition, as these tumors grow, some cancer cells
can break off and travel to distant places in the body through the blood or the
lymph system and form new tumors far from the original tumor”.
Similarly, The World Health Organization (WHO) states: “a
malignant tumor of potentially unlimited growth that expands locally by
invasion and systemically by metastasis”. Do all lesions we call “cancer”
satisfy these definitions of invasion and metastasis?
The last sentence is the most compelling. Perhaps we have
been a bit too aggressive in our assertion of what is malignant and a cancer.
For example, take a thyroid lesion which histologically is identified as a
FVPTC, a malignant cancer. Yet it may be circumscribed and without any
vasculature. But more importantly it has no fusions or genetic changes. From
the genetic perspective it is perfectly normal, namely looks genetically like
every other normal cell. So, do we allow genetics to trump histology? That will
be the challenge we will face now.
We now focus on some definitions. The definitions are
critical because as we learn more about small lesions with limited to no change
of metastasis, we may have to re-examine the overall nature of cancers.
Moreover, we may have the opportunity to better understand the relationship
between morphological changes and the genetic underpinnings.
Cancer has been with humans most likely since the beginning.
As Papavramidou et al have noted some of the early understandings including
that of Galen as below:
Cancer appears in medical history as early as 1600 BC in
the Edwin Smith papyrus, where the oldest description of the illness exists.
However, the origin of the word ‘‘cancer’’ is credited to the Hippocratic
physicians, who used the terms karkinos and karkinoma in order to describe
tumors. Karkinos was used for any nonhealing swelling or ulcerous formation,
even hemorrhoids, whereas karkinoma was reserved for nonhealing ‘‘cancer.’’
The physicians of antiquity generally used remedies and
plasters for local treatment of tumors, as well as cauterization, which was
used even by the Hippocratic physicians for treatment of cancer of the pharynx.
Nonetheless, in this Editorial, an attempt is made to describe ancient surgical
methods that include excision of the tumor and to correlate them with modern
medical practice, providing possible explanations for the surgical choices made
by ancient authors. Such references were traced in the texts of the Hippocratic
physicians, of Archigenes of Apamea, of Galen, of Leonides of Alexandria, and
of Paulus Aegineta, ranging from the 5th century BC to the 7th century AD.
They continue with a discussion of the approach of Galen:
Almost contemporary to Archigenes, but strongly
criticizing him at any given opportunity, Galen, who made a detailed
categorization of abnormal growths (he even wrote a treatise named On tumors
against nature), believed that cancer may appear in any part of the body, but
he had seen it more often occurring in the breasts of women whose menstruation
was either abnormal or inexistent. He believed that the cause of this disease
is the accumulation of ‘‘residues of black bile formed in the liver during
hematosis and left aside by the cleaning process taking place in the spleen.’’
These residues are created when the liver is weak, when
the diet is of the nature that produces a large amount of thick blood and the
spleen is weakly attracting the humor. Such a procedure produces a very thick
and mud-like blood that accumulates in the veins. This is how Galen explains
the appearance of black veins around the cancerous part that looks like a crab:
‘‘as the crab has legs spreading around its body, in the same way are the veins
in this illness; they are spread by the abnormal tumor in a shape of crab.’’
This comparison of the cancerous tumor to a crab is
actually the reason for the name of the disease, since karkinos (cancer) means
crab in Greek. Additionally, Galen notes that, when such tumors ulcerate, they
discharge a dark-reddish and foul-smelling secretion, suggesting that the cause
of the illness is black bile. As for treatment of cancer, Galen suggests that
it is only curable at its commencement, otherwise surgery should take place.
A round incision should be made around the tumor, so that
the entirety of the growth is excised. He advises the surgeon to be extremely
careful because there is great danger that hemorrhage will occur and the
attempt to restrain it with ligatures may affect neighboring parts with cancer.
He also mentions the use of cauterization for burning of the roots of the
tumor, which is a process that may also prove to be dangerous. Finally, he
suggests that the physician should try to ‘‘thin’’ the blood first, with the
aid of purgative medicaments and then proceed to the operation.
For centuries we have been battling this disease. Admittedly
shorter life span mitigated against many cancers, especially those of older
age. Now from the NCI we have the following more current definition for malignancy[3]:
A term for diseases in which abnormal cells divide
without control and can invade nearby tissues.
Note first that the cells must be abnormal. Just because a
cell is abnormal may or may not make is a malignant cell. The second element is
dividing without control. Many "in situ" lesions divide up to a
point. However, we may not really know their lifetime states. Perhaps, as if
found in HGPIN, they may regress. Invasion is the third criteria. Thus, are the
abnormal cells of a larger number than usual are not invading but are
circumscribed, what does that mean?
Malignant cells can also spread to other parts of the
body through the blood and lymph systems.
Here we have the Aristotelean concept of capability or
potential. The cell may spread, but we do not know that unless they really have
spread.
There are several main types of malignancy. Carcinoma is
a malignancy that begins in the skin or in tissues that line or cover internal
organs. Sarcoma is a malignancy that begins in bone, cartilage, fat, muscle,
blood vessels, or other connective or supportive tissue. Leukemia is a
malignancy that starts in blood-forming tissue, such as the bone marrow, and
causes large numbers of abnormal blood cells to be produced and enter the
blood. Lymphoma and multiple myeloma are malignancies that begin in the cells
of the immune system. Central nervous system cancers are malignancies that
begin in the tissues of the brain and spinal cord. Also called cancer.
Now we consider the definition of cancer from NCI[4]:
Cancer cells differ from normal cells in many ways that
allow them to grow out of control and become invasive. One important difference
is that cancer cells are less specialized than normal cells. That is, whereas
normal cells mature into very distinct cell types with specific functions,
cancer cells do not.
This is a difficult one. For example, thyroid malignancy
results in thyroid like cells that go off under metastasis to other organs. Yet
they still have thyroid like functions producing thyroglobulin. This is a
hormone produced in search of a colloid to generate T3 and T4. Melanocytes
retain much of their functions producing melanosomes and thus a met to the
brain can be so identified. Thus, this claim is not dispositive.
This is one reason that, unlike normal cells, cancer
cells continue to divide without stopping. In addition, cancer cells are able
to ignore signals that normally tell cells to stop dividing or that begin a
process known as programmed cell death, or apoptosis, which the body uses to get
rid of unneeded cells.
Cancer cells may be able to influence the normal cells,
molecules, and blood vessels that surround and feed a tumor—an area known as
the microenvironment. For instance, cancer cells can induce nearby normal cells
to form blood vessels that supply tumors with oxygen and nutrients, which they
need to grow. These blood vessels also remove waste products from tumors.
How can this assertion be shown in a localized lesion?
Again, we can consider HGPIN or NIFTP. Oftentimes what we observe is a slight
proliferation and possible cellular abnormalities. Are the cell abnormalities
induced endogenously or exogenously? That is a challenge in a localized lesion.
Adenomas are also classic examples. They are a proliferation of cells with some
possible cellular abnormalities. For example, we may see mitotic events,
enlargement of a nucleus, enlargement of the nucleolus. Are these alone
dispositive for a cancer?
Cancer cells are also often able to evade the immune
system, a network of organs, tissues, and specialized cells that protects the
body from infections and other conditions. Although the immune system normally
removes damaged or abnormal cells from the body, some cancer cells are able to
“hide” from the immune system. Tumors can also use the immune system to stay
alive and grow. For example, with the help of certain immune system cells that
normally prevent a runaway immune response, cancer cells can actually keep the
immune system from killing cancer cells.
The immune response effects are of interest. Much of current
immunotherapy is based upon the recognition that cancer cells can protect
themselves despite the fact that they can be determined to be attacked by the
immune system[5].
As Hanahan and Weinberg have noted:
Arguably the most fundamental trait of cancer cells
involves their ability to sustain chronic proliferation. Normal tissues
carefully control the production and release of growth-promoting signals that
instruct entry into and progression through the cell growth and division cycle,
thereby ensuring a homeostasis of cell number and thus maintenance of normal
tissue architecture and function.
Cancer cells, by deregulating these signals, become
masters of their own destinies. The enabling signals are conveyed in large part
by growth factors that bind cell-surface receptors, typically containing
intracellular tyrosine kinase domains. The latter proceed to emit signals via
branched intracellular signaling pathways that regulate progression through the
cell cycle as well as cell growth (that is, increases in cell size); often
these signals influence yet other cell-biological properties, such as cell
survival and energy metabolism.
Nice, but how do we apply this principle? Must we wait until
the cells proliferate, chronically? There are many cancers in what is
considered the in-situ state where at best one has some morphological
identification. Are these delimited non proliferated calls which exhibit
morphological changes really cancers?
Cancer for the most part is a genetic disorder. Homeostasis
of normal cells means that there is a place for everything and everything in
its place. When cells no longer follow the "rules" then we consider
this to be a cancer, most of the time. For example, a wart is often the hyperplasia
that results from some viral infection. But the hyperplasia is localized. A
breast cancer is a lesion where the cells are growing as a result of some
failed genetic mechanism. However, in a myelodysplastic syndrome, MDS, the
cells proliferate aberrantly due to an epigenetic defect, methylation. Is MDS
also a genetic defect as BRCA is in the breast cancers?
The reasons why we ask these questions is driven by the
explosions of some "cancers" which are really carcinoma in situ and
may never metastasize. Thus, as asked by Al-Saleem have our abilities to
identify more and more led us to an over exuberance? Or perhaps as I have
suggested, the histological diagnosis must be aligned with the genomic
assessment for an integrated diagnosis[6].
It is also worthwhile to examine some of the perspectives on
cancer in an historical context. In the 1938 book on Cancer by Cutler and
Buschke we see that at that time there was a categorization with diagnosis
occurring only after the lesions were clearly noticeable. The approach was
treatment after the fact. For example, their discussion on prostate cancer had
suggested rectal exams as a new technique and surgery or radiation as the
treatment. The discussion on biopsies was paltry to say the least. In fact they
suggested that for the most part biopsies were unnecessary since the disease
was at the time of recognition obviously self-evident.
There has been a trend in many cancers of increasing
incidence but stead mortality. Incidence is changing because of improved
surveillance and mortality remaining constant or even decreasing due to
improved treatment. But that does not appear to tell the whole story. As Welch
and Black have noted:
…the phenomenon of cancer overdiagnosis—the diagnosis of
a “cancer” that would otherwise not go on to cause symptoms or death. We
describe the two prerequisites for cancer overdiagnosis to occur: the existence
of a silent disease reservoir and activities leading to its detection
(particularly cancer screening).
We estimated the magnitude of overdiagnosis from
randomized trials: about 25% of mammographically detected breast cancers, 50%
of chest x-ray and/or sputum-detected lung cancers, and 60% of
prostate-specific antigen–detected prostate cancers. We also review data from
observational studies and population-based cancer statistics suggesting
overdiagnosis in computed tomography–detected lung cancer, neuroblastoma,
thyroid cancer, melanoma, and kidney cancer. To address the problem, patients
must be adequately informed of the nature and the magnitude of the trade-off
involved with early cancer detection.
Equally important, researchers need to work to develop better
estimates of the magnitude of overdiagnosis and develop clinical strategies to
help minimize it.
We now consider some of the recent observations regarding a
collection of cancers in their early stages which may or may not ever become a
true malignancy, namely an entity which has metastasized. The figures from
Welch and Black and tell an interesting tale, albeit a bit problematic.
The Figures of Jun show the following:
1. New diagnoses are increasing over time
2. Mortality is remaining constant
3. The reasons for this may be at least twofold. First,
medicine has advanced to mitigate against mortality, a reasonable conclusion.
Second, earlier stage cancer are being caught and resulting in lower mortality.
Third, "cancers" are being identified which would never have resulted
in mortality.
Welch and Black conclude:
Overdiagnosis—along with the subsequent unneeded
treatment with its attendant risks—is arguably the most important harm
associated with early cancer detection. The impact of false-positive test
results is largely transitory, but the impact of overdiagnosis can be life-long
and affects patients’ sense of well-being, their ability to get health
insurance, their physical health, and even their life expectancy.
For clinicians and patients, overdiagnosis adds
complexity to informed decision making: Whereas early detection may well help
some, it undoubtedly hurts others. In general, there is no right answer for the
resulting trade-off—between the potential to avert a cancer death and the risk
of overdiagnosis. Instead, the particular situation and personal choice have to
be considered. Often, the decision about whether or not to pursue early cancer
detection involves a delicate balance between benefits and harms—different
individuals, even in the same situation, might reasonably make different
choices.
To address overdiagnosis, it is important to ensure that
patients are adequately informed of the nature and the magnitude of the
trade-off involved with early detection. This kind of discussion has been
widely advocated as part of PSA screening but is nevertheless challenging for
patients. They must first clearly understand the nature of the trade-off that
although early diagnosis may offer the opportunity to reduce the risk of cancer
death, it also can lead one to be diagnosed and treated for a “cancer” that is
not destined to cause problems. Then, they must understand the magnitude of the
trade-off. Each idea will be foreign and difficult, so they must be presented
very clearly. We believe that this is best done through the construction of
simple one-page balance sheets that frame the trade-off. We have provided one
such example for screening mammography
We now will examine several of the CIS that are prevalent.
As Al-Saleem notes the current confusion regarding the
definition of CIS:
Atypical epithelial proliferations called “carcinoma
in-situ” may not qualify for the name “cancer”; the lowest-grade ductal
carcinoma in situ lesions behave more like atypia, with risks for invasive
cancer at 10 years in patients with low-grade lesions similar to risks in
patients diagnosed with atypia. The so-called lobular carcinoma in situ is
generally considered a marker of higher risk of developing mammary carcinoma
rather than a non-invasive malignancy itself. The low grade non-invasive
papillary urothelial “carcinoma” rarely if ever invades the lamina propria and
may never metastasize; still we call it “cancer”.
In certain organs, e.g. gastrointestinal tract, the term
carcinoma-in situ was abandoned in favor of “high grade dysplasia” without
obvious effect on the rigorous management and/or follow up as needed. HPV
associated squamous lesion that used to be called carcinoma in-situ of the
cervix is now named “grade III cervical intraepithelial neoplasia. Yet, a
morphologically and etiologically similar lesion in the oral cavity or
oropharynx is still called “carcinoma in situ”!
Thus, we ask, just what is CIS? Is it a misnomer and why do
we call it CIS in some cases and not in others? One may even ask if this is
done for legalistic or billing purposes, albeit placing many patients in
considerable discomfort not truly understanding their condition. We consider
four cases and try to obtain some insight as to this issue.
Prostate cancer, PCa, is a very common malignancy amongst
men, and often approaches 100% in men in their 90s. It has generally two forms,
albeit based on some clinical evidence only. One form, the dominant, is very
slow growing and generally indolent. This form may represent up to 95% of all
PCa. The second form is highly aggressive and with very high mortality and is
represented by about 5% of the cases[7].
HGPIN is represented by morphological changes in prostate
cells in the acinar or glandular locations. It generally is a complex set of
growth patterns of new cells whose morphological appearance is similar to but
not identical to the existing cells in the gland. The new cells clearly have
form and shape that demonstrates pre-malignant morphology, with enlarge and
prominent nucleoli.
From the paper by Putzi and DeMarzo we have:
The high-grade form of prostatic
intraepithelial neoplasia (PIN) has been postulated to be the precursor to
peripheral zone carcinoma of the prostate. This is based on zonal
co-localization, morphologic transitions, and phenotypic and molecular genetic
similarities between high-grade PIN and carcinoma. Although high-grade PIN is
thought to arise from low-grade PIN, which in turn is thought to arise in
normal or “active” epithelium, little is
known whether truly normal epithelium gives rise to PIN or whether some other
lesion may be involved.
Focal atrophy of the
prostate, which includes both simple atrophy and postatrophic hyperplasia, is
often associated with chronic, and less frequently, acute inflammation. Unlike
the type of prostatic atrophy associated with androgen withdrawal/ blockade (hormonal
atrophy), epithelial cells in simple atrophy/postatrophic hyperplasia have a
low frequency of apoptosis and are highly proliferative. In addition, hormonal
atrophy occurs diffusely throughout the gland and is not usually associated
with inflammation.
To simplify
terminology and to account for the frequent association with inflammation and a
high proliferative index in focal atrophy of the prostate, we introduced the
term “proliferative inflammatory atrophy” (PIA).
In a similar manner in a review paper by O’Shaughnessy et al
on multiple intraepithelial neoplasia the authors state the following regarding
HGPIN:
The evidence that PIN
is a morphological and genetic precursor to prostate cancer is extensive and
conclusive ...
When examined microscopically,
PIN lesions are characterized by collections of proliferative prostatic
epithelial cells confined within prostatic ducts that exhibit many
morphological features of prostate cancer cells, including architectural
disorganization, enlarged cell nuclei and nucleoli. …
In addition to the
similarity of the cellular morphologies of HGPIN and invasive lesions, evidence
that HGPIN is a precursor of prostatic adenocarcinoma includes the
multifocality of both lesions and the presence of carcinoma in foci of PIN;
among older men, foci of PIN are found in 82% of prostates with carcinoma but
in only 43% of normal prostates.
PIN is frequently
located in the peripheral zone of the prostate, the site at which 70% of
prostatic carcinomas occur. Additional similarities include enhanced
proliferative activity of both PIN and carcinoma (3-fold that of benign
tissue), cytokeratin immunoreactivity, lectin binding, and loss of blood group
antigen with both PIN and carcinoma.
Prevalence of PIN and
its temporal association with invasive cancer are illustrated by the known
40–50% PIN incidence in men 40–60 years of age, evolving into the 40–50%
incidence of prostate cancer in men 80 years of age. Autopsy data reveal that
PIN lesions appear in the prostates of men in their 20s and 30s in the United
States, preceding the appearance of prostate cancer lesions by as many as 10
years …
African-American men, who are at higher risk
of prostate cancer mortality, appear to have a greater extent of PIN at any
given age. PIN and prostate cancer lesions share a number of somatic genome
abnormalities, including loss of DNA sequences at 8p and increased GSTP1 CpG island DNA methylation,
among others.
Finally, transgenic
mouse strains prone to developing prostate cancers typically develop PIN
lesions in advance of the appearance of invasive cancer. PIN lesions are always
asymptomatic and cannot currently be diagnosed or detected by any reliable
means other than examination of prostate tissue histologically. In autopsy
studies, the incidence and extent of PIN increases with age, as does the
incidence of prostate cancer.
Notwithstanding the correlation, there does not seem to be
causality. In addition, the authors do indicate that HGPIN can be reduced but
they seem to fail to speak to the issue of total remission without any
treatment. The question is therefore, is PIN a precursor of PCa? If it is or is
not, is PIN the result of a genetic change as has been postulated by many? It
would seem clear that the existence of remission of PIN would imply that it is
not at all necessarily a precursor and furthermore that it is not necessarily a
genetic change for all PIN. That is can there be a morphological PIN that is
genetic and not remissionable and one which is remissionable. Remissionable
implies the existence of apoptosis, that is a natural cell death or perhaps a
cell death due to some immune response.
Noe let us consider Welch and Black who note:
Let us consider the data of two investigators who made
age- specific estimates of the reservoir of prostate cancer from autopsies…
examined the prostate glands of 525 American men who died in an accident; …
examined 212 Greek men who died of other causes and were not found to have
palpable prostate cancer. Because additional estimates based on specimens
obtained by radical cystectomy are similarly variable, it is clear that the
reservoir of potentially detectable prostate cancer is highly age dependent and
The above comments demonstrate several factors. First the
prostate cells are still in a glandular fashion and the fundamental structure
remains. Second, the prostate composed of basal and luminal cells has a
proliferation of the luminal cells. Third, the papillary forms show some papilla
of curved growth as compared to the more uniform structure. Fourth, HGPIN
generally is diagnosed via the cell proliferation and does not include detailed
single cell forms.
Melanoma is a highly aggressive cancer of the skin and it
metastasizes rapidly. Recently many types of immunotherapy can abate the cancer
and place it into remission. However it can often be so aggressive that one is
as of yet unable to mitigate it in any manner[8].
Welch and Black note:
For melanoma, the rate of diagnosis has almost tripled
(from 7.9 per 100 000 to 21.5 per 100 000). Again, the rate of death is
generally stable (little change in the past 15 years). Although there may be an
element of a true increase in clinically significant melanoma, these data suggest
that most of the increase in diagnosis reflects overdiagnosis. The issue of
overdiagnosis is well known to dermatologists. Because almost all the new
diagnoses are localized (or in situ) melanomas and because their appearance
almost perfectly tracks the increase in population skin biopsy rates,
overdiagnosis is likely the predominant explanation for the rise.
If we look at single cells, the melanocytes, and we see
changes in the cell itself. If we then we look at cells in a more grouped
manner as shown below. Normally the melanocytes reman at the basal layer of the
epidermis. However, they can start moving upward and this is indicated in the
figure below. The lack of stable location can be genetically related to loss of
E cadherin.
Breast cancer (BCa) is the alter ego of prostate cancer. It
occurs in women at a younger age than PCa in men but has many elements in
common.
From Hanna et al:
Ductal carcinoma in situ (DCIS) is a neoplastic proliferation
of mammary ductal epithelial cells confined to the ductal-lobular system, and a
non-obligate precursor of invasive disease. While there has been a significant
increase in the diagnosis of DCIS in recent years due to uptake of mammography
screening, there has been little change in the rate of invasive recurrence,
indicating that a large proportion of patients diagnosed with DCIS will never
develop invasive disease.
The main issue for clinicians is how to reliably predict
the prognosis of DCIS in order to individualize patient treatment, especially
as treatment ranges from surveillance only, breast-conserving surgery only, to
breast-conserving surgery plus radiotherapy and/or hormonal therapy, and
mastectomy with or without radiotherapy. We conducted a semi-structured
literature review to address the above issues relating to “pure” DCIS.
Here we discuss the pathology of DCIS, risk factors for
recurrence, biomarkers and molecular signatures, and disease management.
Potential mechanisms of progression from DCIS to invasive cancer and problems
faced by clinicians and pathologists in diagnosing and treating this disease
are also discussed. Despite the tremendous research efforts to identify
accurate risk stratification predictors of invasive recurrence and response to
radiotherapy and endocrine therapy, to date there is no simple, well-validated
marker or group of variables for risk estimation, particularly in the setting
of adjuvant treatment after breast-conserving surgery.
Thus, the standard of care to date remains
breast-conserving surgery plus radiotherapy, with or without hormonal therapy.
Emerging tools, such as pathologic or biologic markers, may soon change such
practice.
As shown, the CIS consisted of localized proliferation along
with putative changes in the cells. To best understand the cellular changes one
must examine the cells independently. As Berg notes in an Editorial on this
topic:
The diagnosis and management of ductal carcinoma in situ
(DCIS) is controversial. With widespread mammography screening, diagnosis of
DCIS became more prevalent. Some are uncertain whether this has translated into
a decrease in invasive cancer and a subsequent decline in breast cancer
mortality. Part of the concern has been that frequently the treatments of DCIS
are as extensive as for invasive cancer with a similar panoply of risks. A
straightforward approach to selecting the optimum therapy— defined here as the
minimum needed to avoid recurrence, particularly with an invasive component—is
needed.
Many solutions have been proposed, but none has gained
wide acceptance. For example, the Van Nuys Prognostic Index has been in common
use for decades. Several randomized clinical trials have compared lumpectomy
alone to lumpectomy followed by radiation treatment, but no subset analysis of
these results has found a group that does not benefit from radiation with a
lower in-breast recurrence risk.
We can examine some of the related genomic issues of DCIS.
As Russnes et al have noted:
Complex rearrangements as defined by CAAI occurred in all
subgroups, and CAAI had a strong prognostic impact independent of other
factors, even if it only occurred on one chromosomal arm. The mechanisms behind
complex rearrangements are not completely understood, but one type can be
explained by breakage-fusion-bridge cycles because of double-strand repair
defects resulting in high-level amplicons with intermittent deletions. Because
high-level amplicons are seen even in DCIS and in diploid tumors, this opens
the possibility for a distinct subtype of carcinomas having complex alterations
at an early stage of progression (“de novo complexity”).
Lari and Kuerer note:
Understanding of the biology and clinical behavior of
ductal carcinoma in situ (DCIS) is currently inadequate. The aim of this
comprehensive review was to identify important molecular biological markers
associated with DCIS and candidate markers associated with in-creased risk of
ipsilateral recurrence after diagnosis of DCIS.
A comprehensive systematic review was performed to
identify studies published in the past 10 years that investigated biological
markers in DCIS. To be included in this review, studies that investigated the
rate of biological expression of markers had to report on at least 30 patients;
studies that analyzed the recurrence risk associated with biomarker expression
had to report on at least 50 patients.
There were 6,252 patients altogether in our review.
Biological markers evaluated included steroid receptors, proliferation markers,
cell cycle regulation and apoptotic markers, angiogenesis-related proteins,
epidermal growth factor receptor family receptors, extracellular matrix-related
proteins, and COX-2. Although the studies in this review provide valuable preliminary
information regarding the expression and prognostic significance of biomarkers
in DCIS, common limitations of published studies (case-series, cohort, and
case-control studies) were that they were limited to small patient cohorts in
which the extent of surgery and use of radiotherapy or endocrine therapy varied
from patient to patient, and variable methods of determining biomarker
expression. These constraints made it difficult to interpret the ab-solute
effect of expression of various biomarkers on risk of local recurrence.
No prospective validation studies were identified. As the
study of biomarkers are in their relative infancy in DCIS compared with
invasive breast cancer, key significant prognostic and predictive markers
associated with invasive breast cancer have not been adequately studied in
DCIS. There is a critical need for prospective analyses of novel and other
known breast cancer molecular markers in large cohorts of patient with DCIS to
differentiate indolent from aggressive DCIS and better tailor the need and
extent of current therapies.
The authors of the above have provided an extensive review
of a multiple set of putative genetic markers but their conclusion is limited
as noted in the following:
It was difficult to elucidate the prognostic importance
of the biomarkers investigated in this comprehensive review because of
heterogeneous treatment approaches and often conflicting results. Although the
studies in this review provide valuable information on the diagnostic and
prognostic significance of the studied markers, another factor that limits our
ability to draw conclusions on the basis of the information in this review is
the fact that many of the studies reviewed included only small numbers of
patients. Other studies included groups of patients treated with different
therapies, and in some studies the treatment was inconsistent. In addition,
several studies included patients who had received endocrine therapy or
radiotherapy, while other studies did not. This heterogeneous treatment makes
it hard to assess clinical outcome. In conclusion, novel and key breast cancer
biological markers need to be studied prospectively in large cohorts of patient
to differentiate indolent from aggressive DCIS and tailor the need and extent
of therapies.
However, there is no definitive set to be examined. A
similar paper by Vincent-Salomon et al discusses the same issue as follows:
In conclusion, our data show that DCIS already displays
the molecular diversity observed in IDC and, therefore, can be classified
according to molecular criteria distinguishing ERBB2- amplified DCIS, usually
high-grade, ER negative with frequent TP53 mutations, from luminal DCIS
corresponding to low/ intermediate-grade, ER positive with a very low rate of
TP53 mutations.
In our series, only three cases were classified as triple
negative and only one was classified as basal-like DCIS, which confirms that
this last entity is rare among DCIS. Further studies are needed to define
whether a classification of DCIS based on molecular markers may help to more
accurately define cases associated with a higher risk of recurrence. And
finally, genomic/transcriptomic correlations represent a promising tool to
identify new genes and pathways important in early breast carcinogenesis.
The search goes on with DCIS.
Thyroid cancer is substantially less than prostate or breast
and comes in a variety of forms. It generally has a higher incidence in females
and at a younger age. In older adults it is less frequent and may be of limited
aggressiveness if contained. On the other hand, it can be highly aggressive and
lethal if undetected before it becomes anaplastic. The anaplastic variety,
albeit quite rare, is lethal in months[9].
Welch and Black note:
Harach et al. systematically examined the thyroid gland
in 101 autopsies. They examined slices of thyroid tissue taken every 2.5 mm and
found at least one papillary carcinoma in 36% of Finnish adults. Because many
of the cancers were smaller than the width of the slices, they reasoned that they
were missing some. Given the number of small cancers they did find and the
number that they estimated they had missed (which was a function of size), Harach
et al. concluded that the prevalence of histologically verifiable papillary
carcinoma would be close to, if not equal to, 100% if one could look at thin
enough slices of the gland.
Another variant is the NIFTP. Shrestha et al have
characterized it as:
The re-naming of noninvasive follicular variant papillary
thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid
neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of
malignancy rates, thereby affecting mutation frequency in papillary thyroid
cancer. Preoperative assessment of such nodules could affect management in the
future. The original publications following the designation of the new
nomenclature have been extensively reviewed.
With the adoption of NIFTP terminology, a reduction in
the follicular variant of papillary thyroid cancer (FVPTC) prevalence is
anticipated, as is a modest reduction of papillary thyroid cancer (PTC)
prevalence that would be distributed mainly across indeterminate thyroid
nodules.
Identifying NIFTP preoperatively remains challenging. RAS
mutations are predominant but the presence of BRAF V600E mutation has been
observed and could indicate inclusion of the classical PTC. The histological
diagnosis of NIFTP to designate low-risk encapsulated follicular variant
papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby
altering the mutation prevalence. The histopathologic criteria have recently
been refined with an exclusion of well-formed papillae. The preoperative
identification of NIFTP using cytomorphology and gene testing remains challenging.
They go on to characterize it specifically as:
Encapsulation or clear demarcation
Nuclear score 2–3
No vascular or capsular invasion
No tumor necrosis
No high mitotic activity<1 2018="" bodies="" criteria="" growth="" i="" in="" insular="" modified="" no="" papillae="" pattern="" psammoma="" solid="" to="" trabecular="" well-formed="">
Thus, if one sees a micro FVPTC, fully encapsulated, no
vascularization, and a singular lesion with no nodes, and no expression of
fusion or genetic mutations, is this a carcinoma? Is morphology of the cells
the telling sign, is the genetic profile more compelling, or what? We now
examine some histological factors.
The analysis is from Jug. The nuclear score is a cell by
cell analysis to ascertain if the cells meet the three general specifications;
(i) size and shape, (ii) membrane irregularities, (iii) chromatin
characteristics. For each, if there is a sufficient number, then a measure is
recorded. As we have noted previously this is a complicated and highly
professional task on the part of the pathologist. It also appears to be
independent of the genomic artifacts which may exist.
The authors note on the Figure above the following:
Growth patterns of noninvasive follicular thyroid
neoplasm with papillary-like nuclear features (NIFTP). The tumor may
be composed uniformly of very small
(A) or small- to normal-sized
(B) follicles or demonstrate a wide variability in the
size of follicles with mostly very large follicles intermixed with focal areas
composed of small follicles
(C). Small areas of solid growth are seen in this tumor
(D), which comprises <30 and="" criterion="" does="" exclusion="" for="" i="" niftp.="" not="" of="" the="" therefore="" trigger="" tumor="" volume="">
Jug et al note on the above Figures as follows:
H&E images of NIFTP: (a) low-power (2x) view
demonstrating a well-circumscribed lesion with follicular architecture. No
vascular or capsular invasion is present. (b, c, d) High-power (40x) images
demonstrating nuclear enlargement, crowding, optical clearing, and grooves[11]
We have discussed the genetic elements previously as noted.
The argument here is; is there a genetic set of markers which will indicate a
causative driver for proliferation and metastatic change. Should we remove all
NIFTP lesions, should we remove all FVPTC lesions not fully meeting NIFTP
criteria?
Clearly there must be some addressing of just what is a
cancer and what is not. We present several observations and some possible
suggestions. As is usual, these are at best suggestive.
Some eighty years ago as we have noted there was little
biopsy results performed. In the past two decades there has been monumental
growth in understanding the genetic structure of many cancers. In between we
have classic histology in examining cells and clusters of cells and determining
their malignant potential. The next step must be the correlation between
histology and genetic makeup. As of this time the results are somewhat
orthogonal.
The above depicts many dimensions. Clearly, we have
histological. We have had for ages the gross anatomic descriptions dating to
Galen and before, the genomic we are in the midst of, the exomic describes the
signals sent out by the cells, and the epigenetic which can represent a whole
new dimension in cancer understanding.
Many histological determinations assert the lesion to be a
CIS. That means the cells histologically present artifacts consistent with a
mass which has metastatic potential or capacity. Yet we do not know if that is
really the case.
The NCI defines CIS as follows[12]:
A group of abnormal cells that remain in the place where
they first formed. They have not spread. These abnormal cells may become cancer
and spread into nearby normal tissue. Also called stage 0 disease.
The above definition has the following elements:
1. Abnormal cells: this is a broad statement because
from time to time there may appear abnormal cells which in turn may disappear.
We have seen this in HGPIN where sometimes there is substantial amounts and
then upon a set of re-biopsies, they disappear[13].
2. Remain in Place…have not spread: An adenoma
of the colon can be suspicious but for the most part it remains in place.
Lipomas remain in place, yet the cells are less abnormal than other alleged
CIS.
3. May become cancer: Here the definition uses the
transition to cancer in its own definition. Recall our earlier definition from
NCI on what a cancer is.
4. Spread into nearby normal tissue: Spreading
entails two elements. First movement from point A to other points. Second a
proliferation of cells associated with the new locations. But one must ask if
it is just limited to nearby cells? Consider melanoma in situ. The melanocytes
move, and they may proliferate but all is done in the epidermal layers. Is this
a non-spreading but not remaining in place lesion?
At no point in the definition do we see the term capacity or
potential. We do see the term "may become". One wonders if that is a
mere softening for the public or a reflection of uncertainty of potentiality.
The question is a critical one in that we can see a
proliferation of cells in a prostate gland, namely a multiplication of luminal
cells overlaying one another. Is that equivalent to an adenoma in the colon?
Currently it is a CIS. Also, for a melanocyte, if there are a collection at the
rete, a collection up among the keratinocytes? Is even a collection a
dispositive measure?
This seems to be a tug of a between histological
descriptives and genomic markers. Are the histological markers such as
characteristics of nuclei enough? The same for genomic markers. BRAF V600 is
seen in many cells and is a known marker but not quite pathognomonic.
Stem cells have been
acknowledged as the sources of and drivers of many cancers. We have examined
these in many cancers[14],
[15].
Now in assessing CIS, is it also essential to identify a stem cell as well? If
so then do we need stem cells to assert a carcinoma?
When does a CIS become a
cancer? This seems to be a significant question. Is it inevitable? Have we
"caught it just in time" type of question? Namely to be able to give
an adequate answer we need to have some dividing point established.
As we noted at the beginning, what we call something has
effects. This is especially true for a patient. Patients are not the best
listeners, if the hear a word which incites fear then perhaps all that follows
gets blocked. Thus, we should be concerned about the words, and the words must
reflect the facts. Medieval physicians such as Gadsden, Mondino, Gordon, and
others often relied as much on grammar, logic, and rhetoric in dealing with
patients. They knew that what a patient heard and how they responded was as
powerful as the limited medical arts they had available to them.
1. Ackerknecht, A Short History of Medicine, Hopkins, 1982
2. Al-Saleem, What Is “Cancer”? Is There A Need for New Terminologies?
Journal of Cancer Prevention & Current Research, 2016
3. Aristotle. The Metaphysics (Penguin Classics) Penguin Books Ltd.
Kindle Edition
4. Berg, Resolving the Ductal Carcinoma In Situ Treatment Conundrum,
JNCI Vol. 105, Issue 10 May 15, 2013
5. Boerner, Biopsy Interpretation of the Thyroid, Wolters Kluwer,
2018
6. Brinster et al, Dermatopathology, Elsevier, 2011
7. Crowson et al, Biopsy Interpretation of the Skin, Wolters
Kluwer, 2010
8. Cutler and Buschke, Cancer, Saunders, 1938
9. Elston and Ferringer, Dermatopathology, Saunders, 2009
10. Epstein and Netto, Biopsy Interpretation of the Prostate,
Wolters Kluwer, 2002
11. Habif, Clinical Dermatology, Mosby, 2010
12. Hanahan and Weinberg, Hallmarks of Cancer: The Next Generation, Cell
144, March 4, 2011
13. Hanna et al, Ductal carcinoma in situ of the breast: an update
for the pathologist in the era of individualized risk assessment and tailored
therapies, Modern Pathology, Feb 2019 https://www.nature.com/articles/s41379-019-0204-1
14. Jug and Jiang, Noninvasive Follicular Thyroid Neoplasm with
Papillary-Like Nuclear Features: An Evidence-Based Nomenclature Change,
Pathology Research International Volume 2017
15. Jug R, Poller D, Jiang X. Noninvasive follicular thyroid neoplasm
with papillary-like nuclear features (NIFTP). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/thyroidglandNIFTP.html
.
16. Lari and Kuerer, Biological Markers in DCIS and Risk of Breast
Recurrence: A Systematic Review, Journal of Cancer 2011, 2
17. Mattern, Prince of Medicine, Oxford, 2013
18. Nikiforov et al, Diagnostic Pathology and Molecular Genetics of
the Thyroid, Wolters Kluwer, 2020
19. O'Shaughnessy, J., et al, Treatment and Prevention of
Intraepithelial Neoplasia, Clin Cancer Res, V 8, 2002, pp 314-346.
20. Papavramidou et al, Ancient Greek and Greco–Roman Methods in
Modern Surgical Treatment of Cancer, Ann Surg Oncol (2010) 17:665–667
21. Putzi, M., A. De Marzo, Morphologic Transitions Between
Proliferative Inflammatory Atrophy and High Grade Prostatic Intraepithelial
Neoplasia, Adult Uro 2000 pp 828-832.
22. Russnes et al, Genomic Architecture Characterizes Tumor
Progression Paths and Fate in Breast Cancer Patients, ScienceTranslationalMedicine
30 June 2010 Vol 2 Issue 38
23. Shrestha et al, Cytomorphology of Noninvasive Follicular Thyroid
Neoplasm with Papillary-Like Nuclear Features and the Impact of New
Nomenclature on Molecular Testing, Med. Sci. 2019, 7, 15
24. Su, Early Diagnosis and Treatment of Prostate Cancer, Saunders
2010
25. Vincent-Salomon et al, Integrated Genomic and Transcriptomic
Analysis of Ductal Carcinoma In situ of the Breast, Clin Cancer Res 2008;
26. Wallis, Medieval Medicine, Toronto, 2010
27. Welch and Black, Overdiagnosis in Cancer, JNCI, Review, 605,
2010
28. Yang, Early Diagnosis and Treatment of Breast Cancer, Saunders
2011
[1] Aristotle.
The Metaphysics (Penguin Classics) (pp. 263-264). Penguin Books Ltd. Kindle
Edition.
[2] Aristotle.
The Metaphysics (Penguin Classics) (p. 131). Penguin Books Ltd. Kindle Edition.
[10]
We shall be discussing this metric shortly.
[11]
From Jug et al
[13] https://www.researchgate.net/publication/325047485_PROSTATIC_INTRAEPITHELIAL_NEOPLASIA_PROGRESSION_REGRESSION_A_MODEL_FOR_PROSTATE_CANCER
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