The Cross-Sterilization of Disciplines, redux
Primum non nocereJack Leissring, Santa Rosa, CA
I had a restless night, last night. Almost ten years after quitting my pathology practice, I was reminded of some of the reasons for my decision. The reminder came in the form of a request made by a friend who recently was assigned a diagnosis of breast “cancer.” I was asked to be present during her consultation with the surgeon and the nurse practitioner who was acting the role of coordinator for this patient’s journey into the realm of cancer therapy.
During these meetings, which took place over an approximately two hour period, I was impressed by the care with which the explanations were made and the obvious atmosphere of compassion and feeling.
I was given a copy of the pathology report and was immediately brought back to the days I presented my own views to our hospital’s “tumor board,” or committee. The diagnosis made for my friend was DCIS, “Ductal Carcinoma In Situ,” a diagnostic term with which I had a great deal of concern, for it contained a word–carcinoma–commonly associated with, and felt to be synonymous with “cancer.” Cancer is an abnormal growth of malignant cells and malignant cells are characterized by uncontrollable growth with metastatic potential. I hold that if a diagnosis of carcinoma is made, it should possess the malignant features above or, if not, the process should be renamed and recategorized as a potentially pre-malignant condition, akin to a dysplasia, an abnormal growth. Statistically, it is suspected that DCIS may be a precursor of truly invasive carcinoma–invasive of the tissues surrounding the “basement” membrane of the breast duct--thus, a properly defined malignancy. This approach is taken in diseases of a variety of other organs exemplified by the uterine cervix and skin, but for some odd historical reason there has not been sufficient complaint by thoughtful investigators to right this error.
This is a diagnostic epithet which relates more to the effect upon the patient than it does to colloquy among medical practitioners and supporting staff. A diagnosis of ‘cancer’ must be one of the major stress-generating causes in the life of an individual and family. Such a stressful response surely played outduring my experience. In the spirit of the Hippocratic Oath, we should take necessary steps to change at least this element of medicine.
The report by the pathologists also asserted, in keeping with the importance of nomenclature here, that the “tumor,” had been transected in several margins. In the first place, no tumor as such exists, for the definition of that word requires a mass-like abnormal growth, generally something feel-able or discernable “grossly.” Secondly, the interpretation of the microscopic examination of the tissue generated the assertion that the abnormal zones were “transected” is open to question. I wish to stress that I am NOT questioning the observer’s ability, only that, based upon my own experience, such a statement may not be accurate or valid, for reasons I shall describe.
About ten or more years ago, I became concerned with the methods my associates and I were using for the study of “lump-ectomy” specimens (literally removal of a lump of tissue) from patients undergoing breast biopsies. During the forty years I was in practice, I personally examined many thousands of breast specimens. There is a wide variety of expression; breasts differ in character quite widely and range from those having a rich fibrous tissue supporting component to those with very loosely-arranged adipose lobules, specimens that almost fell apart when examined. Some of our early experiments, as we attempted to identify putative surgical margins as reproducibly and accurately as possible, generated a wide variety of outcomes. Unless mordanted, with a picric acid solution, a trick we learned from the laboratory at Stanford, the India ink we used disbursed itself very widely within the interstices of the tissue. In a series of cases I presented to the hospital tumor committee, I demonstrated just how it was there could never be a clear-cut way to prove a surgical margin. I photographed many blocks prepared after serially cutting the marked specimen at 2.5 mm intervals. The breast specimens with a “fatty” character were commonly sodden with ink throughout the block, although the ink was supposedly placed on the surface of the specimen. It became clear to me that in making a subsequent diagnosis based upon the resultant microscopic slide, the most one might do is state that “there is ink adjacent to the abnormal tissue,” followed by a disclaimer at the bottom of the report. I also found that the dye or ink often followed the pathof the localization needle, and thus found its way, not unexpectedly, adjacent to the zone of microcalcifications and thus, often to the site of the lesion. Furthermore, the knife used to slice the specimen can bring dye or ink with it as it cuts through the tissue from perimeter to perimeter.
After finding this to be the case, I began approaching these biopsies in a completely different manner: to the best of my ability, I shaved the exterior surface of the undyed or un-inked biopsy–akin to peeling a potato--(as received from the surgeon or radiologist), to a depth of approximately 2 mm on the entire surface of the specimen, laying this tissue flat in the tissue cassette. In this way, I thought, one had a much less opportunity for dye contamination and the site of any residual abnormality within those 2 mm zones could be localized by the position-labeled block. Of course, very large numbers of blocks were required; the tissue remaining after this peel was subsequently mordanted with picric acid solution after immersion into India ink, and the remainder serially sectioned as usual.
Based upon my experience, I would have to conclude that the only thing one can say with certainty about a dye or ink-marked breast specimen is that there is or is not dye or ink at a certain place on the microscopic slide; this is NOT the same thing as saying this dye or ink is actually a surgical margin as hoped for and provided by the surgeon.
Michael Lagios has been a major contributor to the understanding of premalignant and malignant breast disease. He correctly, I believe, describes DCIS as follows: “Ductal carcinoma in situ is a noninvasive carcinoma that is unlikely to recur if completely excised.” [Correctly, because it is unlikely to recur, although still demonstrating the problem of definition of carcinoma.] In a 1999 paper, Silverstein, Lagios and others studied: “The Influence of Margin Width on Local Control of Ductal Carcinoma in Situ of the Breast.” They concluded that: “our data suggest that excellent local control can be achieved without radiation therapy when margin widths of at least 10 mm are obtained, regardless of nuclear grade, the presence or absence of comedonecrosis, or tumor size.” As I noted below, in the abstract section of the paper they actually use the following measurement: “There was also no statisticallysignificant benefit from postoperative radiation therapy among patients with margin widths of 1 to <10 mm. “ NEJM, Volume 340:1455-1461, May 13, 1999, Number 19). In a related article by Lagios and Silverstein: Sentinel Node Biopsy for Patients With DCIS: A Dangerous and Unwarranted Direction (Annals of surgical Oncology, Volume 8, Number 4 / May, 2001) they define DCIS as: “... a disease with a breast cancer-specific mortality rate of only 1% after mastectomy, suggests that DCIS is exactly what we think it is: a non-obligate precursor of invasive breast cancer with little or no metastatic potential while it is in the in situ phase. (Which should be its ONLY phase, by definition.)
It is instructive to describe the methods used by Silversteain, Lagios etal in their 1999 study: “Tissue sections were arranged and prepared for evaluation in sequence. Pathological evaluation included determination of the histologic subtype, the nuclear grade, the presence or absence of comedonecrosis, the maximal diameter of the lesion, and the margin width. The size of small lesions was determined by direct measurement or by ocular micrometry of specimens stained on slides. The size of large lesions was determined by a combination of direct measurement and estimation according to three-dimensional reconstruction with a sequential series of slides. For example, a lesion that measured 5 mm on a single slide but that extended across 10 sequential sections was estimated to be 25 mm in size, since the average size of each block was 2.5 mm. Tumors were divided into two groups according to size: small (diameter, <=10 mm) and large (>10 mm). Size was also analyzed as a continuous variable.
Margin width was determined by direct measurement or ocular micrometry. The smallest single distance between the edge of the tumor and an inked line delineating the margin of normal tissue was reported. Tumors were divided into three groups according to margin width: close or involved (width, <1 mm), intermediate (1 to <10 mm), and wide (>=10 mm). Margins in patients who underwent repeated excision and in whom no additional ductal carcinoma in situ was found were reported as being at least 10 mm in width.
Tumors were divided into three groups according to nuclear grade, as follows: grade 1, low; 2, intermediate; and 3, high. Our grading method has been described previously.11
Comedonecrosis was considered present if there was any architectural pattern of ductal carcinoma in situ in which a central zone of necrotic debris with karyorrhexis was identified, no matter how limited. Tumors were divided into two groups according to the presence or absence of comedonecrosis.”
Based upon my experience (and that of my associates) during the years when this problem of defining a “surgical margin,” arose, that is to say, the problem of “determining a distance between a lesion and an “inked line,” as Silverstein and Lagios describe, I would have to say that such a determination is doubtful. While the authors have unquestionably done their best, there is a definite elephant in the room when it comes to the validity (accuracy, reproducibility,etc.) of such measured determinations as they have described them.
There is a transformation that occurs between the dissection table and the pristine printed page that results from any medical study. The transformation may be a metaphysical defense against the flux and ambiguities of reality, but however it takes place, matters on paper become orderly and pure. The painter, George Braque offered this: “The senses deform, the mind forms. Work to perfect the mind. There is no certaintude but in what the mind conceives.” I would add, however, better not believe without reservation the products of that conception.
However doubtful may be the question of reproducibility of true surgical margin determination, the study’s conclusion is important: the additional burden of radiation therapy for a patient shown to have “margins” around the abnormal tissue lesion offers opportunity for needless potential morbidity but no improvement of outcome.
Albert North Whitehead suggested a descriptive phrase for specialties that depend upon each other for data. He called it “The Cross Sterilization of Disciplines,” "The bolstering up of arguments in one field with doubtful and imperfectly understood inferences made from another."
And, Samuel Butler suggests to us, we all take our opinions from others, simply because there is neither time nor interest in investigating the questions personally. He said: "The public buys its opinions as it buys its meat or takes-in its milk, on the principle that it is cheaper to do this than to keep a cow. So it is, but the milk is more likely to be watered."
I hope that the observations contained within this essay can be of service to those concerned with the welfare of their patients.
Jack Leissring Santa Rosa, CA January 12, 2010 www.jclfa.com
Jack Leissring.
Santa Rosa, CA,
www.jclfa.com
