Pathology Associates Of Lexington, P.A.

Ongoing Surgical Pathology Diagnostic Revolution

We have to take some modern terminology which did not originally exist and place it into the context of this revolution. Each individual has a "genetic makeup" which determines "how we look"...our phenotype (phenotypic expression of our personal genetic foundation...genetic makeup). The degree of any types of the following "expressions" depend on the "penetrance" of that genetic makeup...the power of various aspects of the genetic foundation to variously "express themselves".

In the beginning, Pathology was practiced by physicians who made autopsy or surgical specimen diagnoses by clinical history and judgment, palpation, and naked-eye examinations. In essence, they noted whether there were gross morphological expressions of normal or abnormal genes, possibly complicated by tumor masses.

Genes normally express themselves by their basic & fundamentally vital function of programming the formation of normal organs composed of normal cells with normal cell contents. Mutations of genes are alterations (point mutations of a gene & rearrangements of segments of a gene) of that normal genetic "blueprint". And, mutations cause phenotypic expressions that are abnormal, which expressions may or may not be discernable or known. If the altered genes produce neoplastic expressions, those altered genes are known as oncogenes.

The invention of the microscope in the 1600s lead to the revolutionizing of the diagnostic process (pathologists could look at microscopic morphotypic expressions & coexpressions of genes as to the cytology of cells and the architectural...histological...patterns that those cells formed). All diseases express themselves with variations of tissue components or patterns which have been evaluated & re-evaluated over the past century or more, leading to classifications & reclassifications as the significance of various histologic expressions & co-expressions are found to have significance.

And, these classical H&E observations were soon followed by many different histochemical & cytochemical stains which added diagnostic refinement over the years...beginning the study of cellular proteins (proteomics). Those histochemical stains allowed us to microscopically see certain abnormal phenotypic expressions of altered...mutated...genes. Standardization of the process comes through classical means of training, experience, sharing of cases among associates, the utilization of expert consultations, and the working out of clinico-pathologically discordant results.

As research tools, two revolutions began in Surgical Pathology in the 1960s & 1970s with the introduction of: (1) electron microscopy...EM...(incredible degrees of magnification so as to be able to look at tiny structures forming the internal composition of individual cells...I recall Dr. Hector Battifora, then in Chicago) & (2) immunohistochemical (IHC) staining techniques which “marked”...I think of Dr. Sam Spicer @ MUSC) various sub-microscopic cellular constituents (phenotypic cell-component expressions of genes or mutated genes)...extending the study of "proteomics", a term in increasing use by 2003. These research techniques began to be reduced to practical applications. Highly expensive EM faded. We first utilized IHC through reference laboratories in 1985. Then we began performing the stains in our lab in 1989. Flow cytometry uses these immunostains with cell suspensions. By 2006, we began to get ready to "stain" genes and oncogenes by either FISH, CISH, or SISH methods...and to consider getting into nucleic acid amplification methods (PCR having been developed in 1983 by Nobel winner & local Dreher High School classmate of our long-time dermatologist friend, Fred McElveen, Karry Mullis) for surgical pathology, having already begun it here in clinical lab specimens for a few infectious disease agents in about 2000. In 2008, we will also begun to use slide-based "arrays" of short DNA &/or RNA fragments (oligonucleotides) as ancillary diagnostic tests.

Now, especially in breast cancers and malignant lymphomas, IHC staining for various “markers” has become a vital part of (1) precise diagnosis, (2) ancillary prognostic parameters, & (3) targeted treatment (pharmacodiagnostics; pharmDX). FISH (fluorescent in situ hybridization of DNA...one way to look at some "genomics"), CISH (chromogenic in situ hybridization of DNA) and other marker techniques are appearing. There is significant concern, worldwide, about standardization of such determinations (such as HER-2) so that results in one lab would be similar to results in another quality lab. But, I hope that attempts to assure quality don't over-regulate or over-legalize what practitioners must do in order to bring valuable techniques to the "point of service". At least until as late as the 1970s, medical students learned much of the massive amount of 'how to" stuff needed to practice on the basis of "see one, do one, teach one".

As it turns out, as with previous chemical analyses of tumors, it is not actually possible to produce “calibration standards” in order to assure accurate and reproducible quantitation (of such things as estrogen receptor content) between laboratories. Image analyzers have been developed, but these simply dumbly measure what the technical process produces…leaving plenty of room for error. They also allow (in 2007) a higher diagnostic financial charge (we have resisted using such). Marker positivity must be concordant with correct cellular morphology (a human determination)...a grade I breast cancer appearing to be HER-2 positive is discordant.

So, accuracy with standardization is again striven for through classical measures: (1) utilization of professional personnel who are competent, who use correct testing protocols, and who are outstandingly motivated to act in the best interests of the patients, (2) the utilization of known positively and negatively reacting internal and external marker control tissues, and (3) participation in one or more accreditation and survey programs operated by an appropriate professional organization. FDA certification does not assure anything other than methodological reliability of a specific product in the hands of experts...which a given lab may or may not be able to effect. Departments of Pathology and Laboratory Medicine, worldwide, have produced highly reliable results without FDA approval for over 100 years and still do so with 1000s of tests & techniques that the FDA has no position on. Your lab team at LMC uses a wide range of these quality efforts in providing these services to your patients.

(posted 2003; latest update 18 April 2008)