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Pⁿ Blog
The Pⁿ Blog is a forum for opinions, questions, controversies, and instructive discussions across the field of pathology and its relevant subspecialties.
Friday, April 18, 2014
While cruising through the Medscape Pathology and Lab Medicine web site (you need to register, but it's free). I came across some recent clinical studies on HPV in ENT carcinomas.  The most recent one, is a large series (n=1606) of patients from Denmark treated with radiation therapy for advanced stage squamous cell carcinoma of the head and neck.  HPV/p16 status was assessed.  For patients with oropharyngeal carcinomas, HPV status, as shown by others, was a significant prognostic factor.  HPV/p16+ tumors had significantly better locoregional control and 5-year disease-free survivals when compared to HPV/p16- patients.  However, for other anatomic sites in the ENT region, such as the larynx, the HPV/p16 status did not affect prognosis.  
This is an interesting and unexpected finding that needs verification in other studies.  Of course, outside of the oropharynx, only a small minority of ENT squamous cell carcinomas is related to HPV, in contrast to the high percentage of HPV+ oropharyngeal cases.  We also know that HPV status does not appear to affect the prognosis of HPV-associated non-squamous carcinomas in this region, including neuroendocrine carcinomas and adenocarcinomas.  However, the numbers of such cases are quite small and further study is clearly needed.
The second and slightly older article in Medscape  is a summary of a Lancet article from July 2013 examining the epidemiology of oral HPV infections in men.  The study followed 1626 men between the ages of 18 & 73 years.  The cohort was from Brazil, Mexico, and the United States.  Median follow-up was slightly over one year. During this time, 4.4% of the cohort developed an incidental oral HPV infection.  1.7% of these were with high-risk (oncogenic) HPV subtypes, mainly HPV-16 (0.6%).  Most of the infections appeared to be cleared in one year.  The method of detection was by oral rinse and gargle, which may have significantly underestimated infection rates.  There was a significant association between martial status and the risk of acquiring any oncogenic HPV infection. Men who were married or cohabiting were at significantly lower risk than men who were single, divorced, separated, or widowed.  ""Marital status seems to be more predictive of oral HPV acquisition than does lifetime number of sexual partners," the authors report.  However, these findings are in contrast with those from some previous studies, which found an association with the number of lifetime and recent partners, they note.  Smoking also appeared to increase the risk of infection. 
It is clear that the rate of HPV-related oropharyngeal carcinoma has increased dramatically in the last decade.  In fact, invasive HPV-related oropharyngeal carcinomas currently outnumber invasive uterine cervical carcinomas.  Epidemiologists continue to be perplexed by this dramatic rise.  Although there is some correlation, as shown above, with number of sexual partners, studies regarding specific sexual habits (oral sex rates) have shown inconsistent results.  In short, there is no evidence that there has been any dramatic change in sexual practices in the last few decades (hardly surprising!) to account for this dramatic increase in HPV-related oropharyngeal carcinomas.

Friday, April 04, 2014
When the human genome project announced in 2000 that the 3 billion base pairs of human DNA had been successfully mapped, the thinking was that major breakthroughs in medicine were right in front of us. Surely the cures for Alzheimers, diabetes, all sorts of genetic conditions, and, of course, cancer were just around the corner.  Well, as we now know, not quite.  Clinical advances based on our knowledge of the human genome have been, at best, modest in the last 14 years.   However, we may now be close to an inflection point in our utilization of this knowledge.  The original government-funded Human Genome Project cost 3 billion dollars and took 13 years.  It is now possible, with automated next generation sequencing to sequence an entire human genome for approximately $1000.  At that price, individualized whole genome sequencing becomes a viable clinical tool. 
Needless to say a LOT of venture capital is being thrown in this direction.  Craig Venter, one of the pioneers in the Human Genome Project has started a company known as Human Longevity with the goal of completely sequencing 40,000 human genomes per year.  This capability has considerable promise in a many medical fields.  Fetal testing for genetic anomalies, for example, will be far more sensitive and allow the detection of a virtually endless number of anomalies, rather than a select few of the more common ones, as is now the case.  Genetic components or predispositions will undoubted be found for many currently enigmatic diseases.  Identification of these predispositions will allow for targeted screening and, in many instances, the development of specific therapies. 
There will undoubtedly be major inroads in our understanding of cancer predispositions and targetted screenings in high risk populations.  The benefits to this approach are likely to be enormous.  Many cancers with specific mutations and a relatively stable genome may yield, at least initially, to targetted therapies.  Drugs directed at tumors with specific mutations will have great potential as first line therapies with little or no associated toxicity.  I remain skeptical, however, that targetted genetic therapy is going to result in dramatic long-term cure rates for many cancers, particularly those high-grade tumors with considerable genetic instability and the ability to "work around"  initial genetic road blocks.  GI stromal tumors (GISTs) are a case in point.  These tumors have dramatic initial responses to Gleevec therapy and yet many (most) ultimately acquire the proper mutations for a biochemical "work around" of the Gleevec road block and Gleevec-resistant recurrences develop several years later.  There may well be some biochemical road blocks for which work arounds aren't biologically possible, but cancer is, after all, "chaos" with entropy on its side and to paraphrase Jeff Goldblum in Jurassic Park, "life (even, or perhaps especially, malignant life) will find a way!"
The other looming issue on multiple levels is reimbursement!  Will insurance companies pay for whole genome sequencing?  Will they pay for enhanced screening based on detected predispositions?  Will they pay for the development and utilization of costly drugs to treat rare and in some cases patient-specific diseases?  At the moment reimbursement for molecular/genetic testing is in most cases a "loss leader" in medical centers.  This has the potential to get much worse as the complexity and expense of the testing increases.  Ultimately, market factors (read: patients demanding it), may lead to increased reimbursement in all these arenas, but only time will tell. 
There's no doubt about it.  We live in interesting times.

Friday, March 21, 2014
Is the Pap test dead?  Well, no but there is about to be a radical change in how it is used.  Last week an FDA advisory panel voted unanimously that the Pap smear should be replaced or at least supplemented by molecular tests for HPV DNA.  The story was reported in a recent issue of the New York Times. 
Up until now molecular testing was mainly done when the Pap smear was equivocal.  The new recommendations reverse the order, however, and advise the use of a molecular test as the front line screen, with Pap smears or biopsies utilized in HPV+ patients.  HPV testing has been widely reported to be more sensitive and more objective than a Pap smear.  Opponents note that many young women become infected with HPV but clear the infection and have no residual morphologic sequelae.  They fear that molecular testing may subject more women, particularly women under 30 years of age, to unnecessary examinations and biopsies.  Roche, a maker of one molecular test, notes that they only test for high-risk HPV types 16 and 18. 
The Pap smear is not dead; far from it.  But its use as THE primary screening technique for cervical dysplasias and carcinomas is going to undergo considerable change in the next few years.  The rapidity with which gynecologists switch from doing primary Pap smears to using HPV testing as their primary screen, or offering patients the choice will depend in large part on how soon their professional societies endorse the new FDA recommendations. Ultimately, though, high-volume Pap screening services looking at primarily low-risk patients are going to see a marked reduction in their volumes as molecular testing becomes the front line screen.  Institutions such as my own that see a high percentage of high-risk patients will see less dramatic changes in Pap smear utilization. 
The Pap smear has been and still is a fantastic tool for diagnosing pre-malignant cervical disease.  In countries where it has been utilized routinely, it has resulted in a marked reduction in cervical cancer mortality.  In the United States cervical cancer deaths decreased by 70% between 1955 and 1992.  Recently, however, the mortality rate, though remaining low, has stabilized with no further reductions.  Primary molecular screening, it is argued, is the next step in further lowering cervical cancer-related deaths.  Dr. George Papanicolaou would, I think, approve.

Tuesday, February 25, 2014
In the past I have discussed the problems with overdiagnosis and overtreatment of both mammary carcinoma in situ and prostatic adenocarcinoma.  A notable third example is the overdiagnosis and overtreatment of papillary thyroid carcinoma.  A recent article from JAMA Otolaryngology - Head & Neck Surgery, entitled "Current Thryoid Cancer Trends in the United States," and published online on February 20th details this problem. 
To review some findings in the article:
Since 1975, the incidence of thyroid cancer has nearly tripled, from 4.9 to 14.3 per 100,000 individuals  Virtually the entire increase is attributable to papillary thyroid cancer diagnoses. The absolute increase in thyroid cancer in women was almost 4 times greater than that of men. In spite of this dramatic increase, the mortality rate from thyroid cancer has remained stable between 1975 and 2009 (approximately 0.5 deaths per 100,000).
The authors conclude that there is an ongoing epidemic of thyroid cancer in the United States. The epidemiology of the increased incidence, however, suggests that it is not an epidemic of disease but rather an epidemic of diagnosis. The problem is particularly acute for women, who have lower autopsy prevalence of thyroid cancer than men but higher cancer detection rates by a 3:1 ratio.
That there is an epidemic of overdiagnosis and not of disease is based on the facts that: The increasingly detected cancers are highly unlikely to cause symptoms or death.  Despite a more than 2-fold increase in the rate of thyroid cancer detection, thyroid cancer mortality had remained stable.  Virtually all of the increase was confined to a type with the least aggressive histologic characteristics, namely papillary thyroid cancer. Finally, the bulk of the increase (87%) was explained by tumors 2 cm or smaller.
It is not surprising that women have bourne the brunt of this phenomenon.  Benign thyroid disease is more common in women, leading to fine needle aspirations, and surgical resections that uncover occult and largely harmless lesions.  Clinicians, the article suggests, are "looking too hard" for thyroid carcinomas.  Because the article is a large review based on SEER data, there is no discussion regarding what culpability pathologists might bear for this "epidemic." 
The article does not distinguish between conventional papillary carcinoma, a usually straightforward diagnosis, and the follicular variant, which, as any consultant reviewing such cases will attest, is often anything but straightforward.  Indeed, the latter diagnosis is associated with considerable interobserver variability and given the overall excellent prognosis, refining diagnostic criteria would require a huge database with tens of thousands of years of patient follow up.   
As mentioned above, a related issue that is discussed is the diagnosis of unequivocal but very small papillary carcinomas; lesions for which the term "microcarcinoma" has been used (and I also follow this practice). The authors raise the issue of whether such lesions should carry a designation other than "carcinoma," with all its associated connotations and emotional baggage.  At the very least, clinicians should share with patients the extremely indolent behavior of small papillary carcinomas, and suggest the possibility of watchful waiting as appropriate therapy.  After all, this is a tumor for which we have "magic bullet" therapy if needed.  The current statistic of 85% total thyroidectomy following a diagnosis of papillary carcinoma (of any type or size) is far too high.

Monday, February 10, 2014

Pathologists and clinicians have been taught for decades that atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH) of the breast are fundamentally different lesions.  ALH has been viewed as a marker for subsequent carcinoma of lesser predictive power than lobular carcinoma in situ (LCIS), and associated with increased risk of carcinoma in either breast (although Page and colleagues did show that 2/3rds of subsequent carcinomas occur in the ipsilateral breast). 

ADH has been viewed traditionally as a precursor lesion with more power than ALH to predict subsequent carcinoma, predominantly in the same breast.  Surgeons will often do reexcisions when ADH is present at the margin but almost all will ignore margins positive for ALH (or even LCIS). 

A recent article published in Cancer Prevention Research based on a large study from the Mayo Clinic calls these assumptions into question.  I recommend reading it and passing it on to your colleagues, both in pathology and the clinical specialties involved in breast disease management.  There are a LOT more data in the text than are briefly discussed here.
The study involved almost 700 women with atypical hyperplasias, 330 with ADH, 327 with ALH, and 32 with both.  This is by far the largest follow-up study in the literature on atypical hyperplasias of both types. To cut to the chase, the conclusion can be summarized in the following quote from the manuscript, "Our observations do not support present assumptions that ADH and ALH have substantively different behaviors.  More DCIS may occur in women with ADH than ALH (25% vs. 13%, p=0.07), but numbers are small and this was not statistically significant." 
Both ALH and ADH have features suggestive of precursor lesions and risk indicators.  When carcinoma arises (either in-situ or invasive) both are predominantly associated with ductal as opposed to lobular carcinomas (ALH -> 77% ductal, 17% lobular; ADH -> 78% ductal, 8% lobular).  Two-thirds of subsequent carcinomas arose in the ipsilateral breast in both ALH and ADH patients.  Both ALH and ADH showed a tendency for contralateral carcinomas to develop later in life. 
This is an valuable study that is packed with information, presented in a well-written format.  Table 2 is especially data dense. 
The authors conclude with the following:
"In summary, these findings underscore the importance of both ADH and ALH as premalignant lesions arising in an
altered tissue bed. The affected breast is at especially high risk for breast cancer in the first 5 years after diagnosis of breast cancer, with risk remaining elevated in both breasts long term. Both ADH and ALH portend risk for DCIS and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. These longitudinal data can help to inform clinical management strategies."
Although I think this is a very good study, I do have concerns that clinicians will interpret it to mean that ALH should treated more aggressively.   I would argue that it rather suggests that ADH be treated more like ALH.  The other problem(s), of course, are the distinctions between ALH & LCIS, and ADH & DCIS.  A topic we've dealt with before. 
About the Author

Stacey E. Mills, MD
Stacey E. Mills, MD, a graduate of University of Virginia (UVA) and the UVA Medical Center, has authored nearly 230 articles, 20+ books, atlases and monographs—including the renowned Sternberg's Diagnostic Surgical Pathology. He has been a practicing Professor and Staff Pathologist at UVA for 30+ years and is Director of Surgical Pathology and Cytopathology. His clinical specialty is general surgical pathology with emphasis on neoplasms and neoplasm-like lesions. Dr. Mills is also Editor-in-Chief of The American Journal of Surgical Pathology.