Karindas Grading System (KGS) - The First Single Universal Tumor Grading System - WAMS

by M. M. Karindas, MD
President
WAMS, The World Academy of Medical Sciences

ABSTRACT

In oncohistopathology and oncobiopathology today, medical professionals use various systems of measurement, appraisal, assessment and evaluation of tumor cells’ phenotypic character and identity in vivo to provide clinicians and researchers with complementing data in their work, and for case reports, pathology reports and patient files, etc. Often incorporated into tumor staging, the currently available grading systems we clinicians and researchers use, for the prognostic and therapeutic guidance they provide, are designed for certain tumors. Mostly being three-tier-scale systems based on the main histologic characteristics of cells, often including the parameters of mitotic activity and tumor necrosis, they are practically useful. They, however, have limited boundaries of usage in terms of interpretation and application in both clinical and research medicine, and they lack the levels of provision and contentment we critically need in research studies, case discussions, patient files, pathology reports and medical communications and transactions, and for preparing and conducting suitable and efficient oncotherapy. Researchers and clinicians often tend to compare a few grading systems when they grade tumors, and then they either decide on one to follow, or follow two or three of them together; that in either way is not much serviceable for ideal paradigmatic uniformity and does not work best for effective clinical case management. As we continue to use these grading systems in clinical practice and research today, we feel the vital need of a thorough, large-in-scope and all-embracing single universal grading system that we can more comprehensively use in clinical and research oncology and other medical fields. I have currently been working on such a new, wide-ranging, all-encompassing informative grading system which brings a new paradigm for observing and evaluating the phenotypic and genotypic identities of tissue cells, in vivo, as well as the identities of the tissues they belong to. Entitled “The Karindas Grading System” (KGS), this well-rounded and plain grading system has been created to replace the current limited-scale grading systems. It will be used and referred to as a vitally necessary single universal grading system, a well-guiding paradigm, that allows us to grade cells by examining their maturation, differentiation, alteration and activities making their phenotypic and genotypic description in vivo based on how normal or abnormal they look and act and how they organize, and to see their straight profiles in direct views of the progression of any ongoing cellular abnormalities, and also as an indicator of how a tumor is likely to sustain existence, and in what manners to behave, grow and spread, and how fast. While squarely guiding us in the assessment of tumor malignancy, this infallible and dependable new paradigm of cellular and tissue grading also makes us understand oncogenesis better bringing some of its obscure corners to light and improving our understanding of cancer, and thereby helps us employ our knowledge there more with more ability to remark, comment, assess, evaluate and interpret, and to manage and control medical cases, predict and follow prognosis easefully, and determine, develop and conduct the most appropriate oncotherapy for our patients.

INTRODUCTION

To long-term chemotherapy patients’ routine questions like “How is my condition, and how is my chemotherapy doing?”, doctors’ answers ought to be clearer and more reassuring than in-between ones like “We don’t really see the whole picture yet, so we’ll have to wait and see.”, or “We’re not sure, but you seem to be doing well and we hope to get success in this treatment.”, or “Right now, we don’t really know what to tell you.”, or “We’ve got nothing to tell you at this point in time.”

The “Karindas Grading System” (KGS) unprecedentedly gives the physician the capability and ease to inform the patient of the prognostic contour more manifestly and satisfactorily. It provides the clinician with able guidance and tools for the perceptibility of diagnostics and the command of the visibility and judgement of the prognostic progression, and enables the researcher to have a better view, perspective and reckoning and wider qualified space of methodology in oncologic research.

In the histological grading systems we use in oncology today, the grading is done by examining tumor cells in regard to their differentiation and calculating their volume in bulk with the proportions of their differentiation/undifferentiation. Some add to that tumor necrosis and mitotic activity findings, and some further add nuclear pleomorphism. Solely determining the degree of the differentiation of the cells, however, and reckoning them without the rest of the elements and determinants of the oncogenic progression leaves the grading limited and incomplete. This makes the grading weak and ineffective depriving the clinician and researcher of a dependable base of exposure to lean on in their work. Such a grading of low prognostic value is scientifically not full-length serviceable, and it is not practically sufficient to contribute to a standardized phenotypic cellular evaluation of a tumor tissue and its microenvironment while it is fundamentally looked to as an important tool to provide the clinician with a clear path to a successful clinical case management. Together with the overt limitations, this frailness of calibration and under-reckoning in the current grading systems is rather unfortunate as it affects the gradation of the clinical handling of cancer patients in terms of prognostic follow-up and investigative and therapeutic management whose consequential inefficacy ultimately contributes to unimpressive survival rates in clinical oncology.

Having its parameters based on cell–specific features and cell-dedicated conditions, the new informative and instructive “Karindas Grading System” (KGS) provides a universal across-the-board paradigm for examining, observing and evaluating the phenotypic and genotypic identities of the cells of a tissue in question, and also for grading the tissue itself within a wide spectrum of possibilities of conditions and situations ranging from normality to anaplasia.

As a single reference system of grading, with its wide and overall parametric range, the KGS gives an ID to each cell (cell type) by histologic typing; it classifies the cell morphology, how normal or abnormal a tissue’s cells look, what identity changes they may show, how they present their changes, how they arrange themselves in relation to each other, how they behave or misbehave, and how fast they grow when misbehaving, and how quickly they disseminate. Also taking account of additional information related to the changes and happenings around the cells within the microenvironment, it provides the examiner with full guiding data.

Keeping the KGS’s parametric range wide and overall proves essential and necessary since it aims at providing complete guidance with comprehensive pathobiologic data of tissue processes, development, and consequences between inertness, normality and the outermost levels of pathology, the “oncogenesis” itself, the most infamous abnormal tissue event in the human body, a highly-organized cellular disorder which we can not afford to deal with without including all of its players for consideration.

The “Karindas Grading System”

The first and only single tumor grading system, a unique collective universal paradigm, the KGS grades cells, normal or pathological, and classifies them with individual grade IDs within the widest range of cellular morphological, phenotypical and genotypical features while also grading the tissues they belong to. Beginning from the inert and normal forms of morphology of cells and tissues extending to the ultimate level of neoplasia, it covers the full range of cell and tissue conditions and situations in vivo. Providing a new referential guidance platform, not only as a tumor grading system, but also as a cell identification and description paradigm, the KGS opens new avenues for cancer management and diagnostics in clinical medicine and brings wider understanding, reasoning and knowledge as well as more efficiency and practicality in patient management and statistics and epidemiology in clinical and research oncology.

The Importance and Necessity

Today’s tumor grading systems, which are individually designed for certain tumors fall short of the key necessities of prognostic-therapeutic follow-up in cancer management at large. In histopathological tumor grading, which is crucial in oncology as an important guide in cancer management, medical professionals must be guided and led within larger brackets in predicting and following the clinical and biological behavior of tumor cells and their tissues. This is where comes the importance and necessity of a single, full-scale and collective universal grading system that should be used on a conventional homogenous base in clinical and research medicine.

In the wake of the practical incapacity of the tumor grading systems we currently use in clinical and research oncology, the necessity of a single full-scale grading system has been being apparent.

The “Karindas Grading System” (KGS) has been created to provide this ineluctably vital need. Providing in-depth guidance for examining, observing and evaluating cells and their tissues’ identities on the basis of phenotypic and genotypic parameters and data within a wide spectrum of possibilities of conditions and situations ranging from normality to anaplasia, the KGS serves as a universal paradigm we critically need in research studies, case discussions, patient files, pathology reports and medical communications and transactions, and for planning and managing suitable and efficient oncotherapy.

The Universal Range

The paradigm of the “Karindas Grading System” (KGS) covers a cell-tissue range that extends between normality and neoplasia. The KGS grading will be used and referred to as a vitally necessary single universal grading system, a well-guiding paradigm that allows us to grade tissue cells by examining their identity, status, maturation, differentiation and alteration and making their phenotypic and genotypic description in vivo based on how normal or abnormal they are and how they organize, and to see their straight profiles in the progression of any ongoing cellular abnormalities, but also as an indicator of how a tumor is likely to sustain existence, and in what manners to behave, grow and spread, and how fast.

Cell-specific and cell-dedicated, the new, unique universal range of the KGS begins with normal and pathologic ordinary cells and goes as far as the level of anaplastic cells, the highest-level cells of oncogenesis which are ranked as “Grade VII” in the KGS. The grading also, correspondingly, incorporates and applies to the tissues of the cells as well as the tumors they present. Keeping the range this wide gives the examiner a comfortable space to assess, evaluate and interpret more comperatively and enables clinicians and researchers alike to easily apply any cellular state and tissue condition to the KGS ranging from normality to anaplasia within an integrally efficient medium.

Unlike other grading systems, which stage high-grade tumors only, the universal KGS Grading ranges include also normal cells and abnormal non-neoplastic cells. One of the KGS’s unique features, this inclusion is important and necessary since normal cells and abnormal non-neoplastic cells are often a part of the account and record in pathology reports, research materials, case reports, patient files, case discussions, and medical communications and transactions, and also, importantly, in the stage of prognostic follow-up during oncotherapy. At least, to begin with, out of a tumor microenvironment or a tumor tissue, where we see ranges of normal and abnormal cells of various types and morphology in various levels of gradation, we, in grading or staging, can not single out the neoplastic cells and leave out the others which belong to the same microenvironment and tissue. Such a universal paradigm of unarguably needed universal cellular and tissue grading must therefore be a pattern for all normal and abnormal human cells and tissues, and be used as such. In a KGS Pathology Report, a normal lung tissue can neatly be described as “Grade I Lung Tissue”, and a diagnosis like “Grade III Thyroid Tissue” says a lot, and a diagnosis like “Grade VIIBnGlioblastoma Multiforme” tells everything.

The Significance and Practicality

It is always more orderly and effective, and more important to describe a Prostate cancer cell by saying “This is a Grade VII Prostate Cancer cell” than saying “This is a Prostate Cancer cell”, and to fine-tune its significance by further saying “It is rather a Grade VIIB Prostate Cancer cell”.

At an international oncology conference some time ago, I astoundedly witnessed a discussion about a displayed histopathologic image of a prostate tumor whose case was actually presented at the conference as a BPH (Benign Prostate Hyperplasia). Four of the people in the discussion turned the case into a big argument which centered on the histopathological status of the displayed tissue and its cells. The specimen was from a surgically removed part of a BPH prostate. The four participants, who had the knowledge of the case in detail, had various opinions which they insisted on. One of them, the presenter of the case, said that it was a typical BPH tissue which turned out to be a prostate cancer. One of the other three opposed and said that it was nothing more than a BPH and a few cancer-resembling cells would not qualify it as cancer. The third one called it a low-grade PIN (Prostatic Intraepithelial Neoplasia) and the fourth one diagnosed it as a high-grade PIN. As the argument reached a point of impasse, I stood up and told them that all four of them were right. After a moment of absolute silence across the huge hall, I gave a brief and brisk explanation why all of them were right, and then everybody, all of the four and the rest of the hall, was content.

So, the tissue of that transforming tumor was composed of those cells of various morphology, basically the high-grade hyperplastic cells which, in the “KGS Grading”, I put them in Grade IIIB, along with low-grade hyperplastic (Grade IIIA) cells, andnormal cells (Grade I) as well as hypertrophic (Grade II) cells; the emerging cells of low-level (Grade IVA) and high-level (Grade IVB) low-grade (metaplastic) prostatic intraepithelial neoplasia (PIN); low-level (Grade VA), mid-level (moderate) (Grade VB), and high-level (Grade VC)(=Carcinoma In Situ) cells of high-grade intraepithelial neoplasia (dysplasia), and finally the newest kids on the block, the newly emerging Grade VIA cells, the brand new cancer cells. They may be recorded in a KGS Pathology Report as below:

KGS Pathology Report and Diagnostic Profile

Biopsy: Prostate Tumor
Date of Collection: 22.07.2014
Date of Report: 30.07.2014
Diagnosis: Prostatic carcinoma
KGS Grade: VIA

Microscopic Description: The Grade VC tumor’s obvious fresh transformation toGrade VIA. Although not dominant, the Grade VIA cells straightly qualify the tumor as a new “Grade VIA Prostatic Carcinoma”. Among the dominating Grade V(C>B>A) cells, sporadic groups of Grade III cells and equally frequent clusters ofGrade IVA-B (B>A) and Grade VA-B (B>A) cells take place; 21 mitotic cells in 10 HPFs (Grade VC: 18/10PHF, Grade VIA: 3/10PHF).

Original KGS Grade: IIIB
Overall KGS Grade: VC
Diagnostic KGS Grade: VIA
KGS Index: 21.25
First KGS Index: 6.53 [Report Date: 11.03.2014]
KGS Prognostic Range: H
Pathologic Diagnosis: “Grade VIA Prostatic Carcinoma”

Cellular KGS Profile:
(Based on the mean proportional cellular percentages in 10 HPFs)

Current (30/07/14) Previous (11/03/14)

Grade IIIB: 0.5%…………………….Grade IIIB: 91%
Grade IVA-B: 3% (B>A)………….Grade IVA-B: 7% (B>A)
Grade VA: 4.5%…………………….Grade VA: 1.5%
Grade VB: 19%……………………..Grade VB: 0.5%
Grade VC: 67%……………………..Grade VC: 0%
Grade VIA: 6%………………………Grade VIA: 0%
KGS Index: 21.25………………..KGS Index: 6.53

A microscobic tumor image presentation and discussion, at an oncopathology meeting, showing the tumor’s microenvironment explaining how bad the tumor looks, what details the microenvironment shows, how differentiated or undifferentiated the tumor cells are and what other details are on hand, and discussing the tumor with the audience in order to generate opinions for evaluating the case and handling it takes time and effort. With the KGS Grading is in effect, just a brief description in an expression like “We see here a Grade VI microenvironment of a hepatoblastoma” or “This is the microenvironment of a Grade VI Hepatoblastoma” saves a lot of discussion and deliberation. Such a compact identity description saves time also in the management and diagnostics of the case. This is not only just saving time and discussion, but also provision of a very important and vital paradigm that minimizes the time in protocol formalities and makes the practice of the art and science of medicine more substantive, expressive and worthwhile.

The significant weight of the parameters specified and grouped in the wide spectrum of the KGS Grading helps examiners and clinicians prepare their pathology reports and clinical case files and records with a broader view and punctilious praxis, while, with it, common or special communications of information exchange, transfer or transaction can be made more comprehensibly and straightforwardly. Moreover, since the challenging nature of medicine very often puts medical professional across non-textbook cases differing from the norm in clinical and research medicine, and therefore sharing knowledge and conveying medical experience with the help of flawlessly practical and comprehensive guiding tools and materials becomes crucial, our success in patient management and research studies in oncology considerably depends on how, how wisely and in what extent we use such tools and materials. And there, in the same regard, the KGS Grading serves as an invaluable tool with high practical instrumentality.

The Karindas Grades

The “Karindas Grades” in the “KGS Solid Tissue Ranges” are a hierarchical grading range of cell typing and identifying morphologically where the cells’ structures and specialized functions are the most important elements to look at and evaluate for grading. In that regard, the cells’ status and degree of differentiation carries most of the weight in grading both the cell and the tissue.

Karindas Grades in KGS Solid Tissue Ranges

Grade 00-0 Inert Range

00 Necrosis (Ordinary)
0 Atrophy

Grade I-III Physiologic Range

I Normality
II Hypertrophy
III Hyperplasia
IIIA Low-grade (Ordinary) Hyperplasia
IIIB High-grade (Atypical) Hyperplasia

Grade IV-V Preneoplastic Range

IV Metaplasia
IVA Low-grade Metaplasia
IVB High-grade Metaplasia
V Dysplasia
VA Low-grade Dysplasia
VB Moderate Dysplasia
VC High-grade Dysplasia (Carcinoma In Situ)
VR Regressive Dysplasia

Grade VI-VII Neoplastic Range

VI Neoplasia
VIA Well-differentiated / moderately undifferentiated
VIB Moderately-differentiated / considerably undifferentiated
VIR Regressive
VII Anaplasia
VIIA Poorly-differentiated / highly undifferentiated
VIIB Undifferentiated (Fully undifferentiated)
VIIR Regressive

Table 1: The KGS Solid Tissue Grades. This table displays the KGS’s seven-tier solid tissue gradation. It starts from “Grade 00”, which represents ordinary necrosis, includes normal (I) and non-neoplastic abnormal ( 0, II and III) solid tissue grades, and goes as far as the anaplastic grade of VII, the highest KGS grade of neoplasia. The capital letters A, B and C symbolize the sub-grades. The “R” symbolizes the “Regressive” state of a tumor which is either “regressing” or “regressed”.

Karindas Grades in KGS Solid Tissue Cellular Ranges

Grade 000-0 Inert Range
000 Apoptotic Cell
00 Necrotic Cell (Ordinary)
0 Atrophic Cell

Grade I-III Physiologic Range

I Normal Cell
II Hypertrophic Cell
III Hyperplastic Cell
IIIA Low-Grade Hyperplastic Cell: Cell of Ordinary Hyperplasia
IIIB High-Grade Hyperplastic Cell: Cell of Atypical Hyperplasia

Grade IV-V Preneoplastic Range

IV Metaplastic Cell
IVA Low-Grade Metaplastic Cell: Cell of Low-Grade Metaplasia
IVB Low-Grade Metaplastic Cell: Cell of High-Grade Metaplasia

V Dysplastic Cell
VA Low-Grade Dysplastic Cell: Cell of Low-Grade Dysplasia
VB Medium-Grade Dysplastic Cell: Cell of Moderate Dysplasia
VC High-Grade Dysplastic Cell: Cell of High-Grade Dysplasia

Grade VI-VII Neoplastic Range

VI Neoplastic Cell
VIA Well-differentiated / Moderately-undifferentiated Cell
VIB Moderately-differentiated / Considerably Undifferentiated Cell
VIR Regressive Tumor Cell: Regressed or regressing Grade VI Cell
VIm Grade VI Mitotic Tumor Cell
VIc Grade VI Circulating Tumor Cell
VIn High Necrotic Tumor Cell: Grade VI Cell in High (Aggressive Tumor) Necrosis
VIAn High Necrotic Tumor Cell: Grade VIA Cell in High (Aggressive Tumor) Necrosis
VIBn High Necrotic Tumor Cell: Grade VIB Cell in High (Aggressive Tumor) Necrosis
VIRn Low Necrotic Tumor Cell: Grade VIR Cell in Low (Regressive Tumor) Necrosis
VIo Apoptotic Cell of Grade VI Tissue

VII Anaplastic Cell
VIIA Poorly-differentiated / Highly Undifferentiated Cell
VIIB Undifferentiated (Fully undifferentiated) Cell
VIIR Regressive Tumor Cell: Regressed or regressing Grade VII Cell
VIIm Grade VII Mitotic Tumor Cell
VIIc Grade VII Circulating Tumor Cell
VIIn High Necrotic Tumor Cell: Grade VII Cell in High (Aggressive Tumor) Necrosis
VIIAn High Necrotic Tumor Cell: Grade VIIA Cell in High (Aggressive Tumor) Necrosis
VIIBn High Necrotic Tumor Cell: Grade VIIB Cell in High (Aggressive Tumor) Necrosis
VIIRn Low Necrotic Tumor Cell: Grade VIIR Cell in Low (Regressive Tumor) Necrosis
VIIo Apoptotic Cell of Grade VII Tissue

Table 2: The KGS Cell Ranges. Including normal (Grade I) and non-neoplastic abnormal (Grades 000, 00, 0, II and III) cell grades, this table of the KGS cell ranges embraces all the probabilities of cellular changes in human body. The capital letters A, B and C symbolize the sub-grades. The “R” symbolizes the “Regressive” state of a tumor. The lower-case letters c, m, n and o denote circulating, mitotic, necrotic andapoptotic cells respectively.

Grade 000: Apoptosis

Unlike necrotic cells, apoptotic cells are usually single isolated cells or small clusters of cells and they die without causing any damage around them where there is therefore no inflammatory response or secondary tissue damage. In the process of their “Programmed Cell Death”, neatly dying apoptotic cells lose their original structure and morphologic appearance as well as their phenotypic or genotypic cell identity; they have no more functional biologic power or gravity and no physical existence of a viable cell.

An apoptotic cell and its organelles show condensation, but organelles remain functional. The nucleus breaks apart. We typically see pyknosis, formation of condensed cell bodies (apoptotic bodies), plasma membrane blebbing and orderly chromatin condensation and DNA degredation as well as dilation of the endoplasmatic reticulum. The cytoplasm shrinks and condenses, the cytoskeleton collapses and the nuclear envelope disassembles. The plasma membrane integrity is maintained while the membrane asymmetry is lost.

While apoptosis is a part of the maintenance of normal multicellular life, we see it also in cancer tissues where the concern for “Programmed Cell Death” in uncontrolled cell proliferation keeps researchers busy. Apoptotic cells may be seen in all ranges of the KGS Grading, and they bear exclusive importance at the KGS’s VI and VII grade levels where they are graded as VIo and VIIo respectively, and more specifically in the subgrades as VIAo, VIBo, VIIAo and VIIBo.

Grade 00: Ordinary Necrosis

In necrosis, a cell shows a total change in its morphology which is followed by cell death. A leakage of cellular contents followed by loss of membrane integrity culminates in dissolution of the cell which results from the degradative action of enzymes. The leaked cellular contents elicit an inflammatory process whose aim is to eliminate the dead necrotic cells and start a repair process.

In a glassy appearance, necrotic cells and their nuclei shrink and condense, and their cytoskeletons collapse. Their nuclear envelopes disassemble. Their organelles are no longer functional. They lose their membrane asymmetry and plasma membrane integrity. They show granular or vacuolated cytoplasm, swelling and swelling of their organelles, increased eosinophilia, mottled chromatin condensation, random DNA degradation and diffuse fragmentation and karyolysis, pyknosis and karyorrhexis. They may ultimately be replaced by whorled phospholipid masses (myelin figures) which may later lead to calcification.

Unlike apoptotic cells, necrotic cells affects the surrounding normal tissue whose eventual damage leads to inflammatory response and tissue repair.

Necrotic cells, in their own right, take a place in the KGS Grading since they are often seen in tissues in trouble. They can be seen in many types of tissue damages including viral and bacterial infections, inflammation and toxic, chemical and physical injuries, and, of course, quite frequently in cancer.

While being graded as “Grade 00” in ordinary necrosis, necrotic cells appear in two different stages of neoplastic progression: In Grade VIB, Grade VIIA and Grade VIIB tissues, they emerge as the ultimate characteristic of anaplastic maturement and I grade them as High Necrotic Tumor Cells (VIBn, VIIAn and VIIBn); they also appear as an important component in tumor regression where I grade them as Low Necrotic Tumor Cells (VIIRn).

In pathology reports, some examples of ordinary necrosis may be described in the KGS grading as:

Skin Biopsy (of a 3rd degree burn): “Grade 00” Epithelial Tissue (3rd degree burn).
Renal Papillary Biopsy (Renal Papilla necrosis): “Grade 00” Renal (Papilla) Tissue (RPN-Coagulative)
Cerebral Biopsy (Enterobacterial Meningitis): “Grade 00” Cerebral Tissue (Hemorrhagic cerebral necrosis.

Grade 0: Atrophy

Atrophic cells are characterized by shrinkage in size, fewer and smaller organelles and loss of subcellular substances. Unlike apoptotic and necrotic cells, they are living cells despite the significant decrease in their structural components and function.

Grade I: Normality

Since a tumor tissue spans a long period of epic journey from a normal state to a pre-neoplastic stage and then to neoplasia and anaplasia, and gets influenced and characterized, in one way or another, by all its players that take role anywhere between normalcy and the ultimate pathology, the cellular elements of all the stages with their features and identities must be taken into account. So that, normal cells are included in the range of the KGS Grading as “Grade I” cells.

As an example, the pathology report of a normal liver biopsy would be issued in the KGS grading as:

Liver Biopsy: “Grade I” liver tissue.

Grade II: Hypertrophy

Physiologic or pathologic, hypertrophy is an increase in cell size resulting in increase in the size of the tissue and organ. In hypertrophy, there are no new cells. The enlargement is due not to cellular swelling but to the synthesis of more structural components. Hypertrophy is best defined by the increase in cell size per nucleus. In comparison with normal cells, hypertrophic cells have larger DNA content and more structural proteins and organelles. It usually occurs together with hyperplasia.

As an example, the pathology report of a hypertrophic myocardial tissue may be issued in the KGS grading as:

Myocardial Tissue: “Grade II”

Grade III: Hyperplasia

Increased in number, hyperplastic cells are proliferated cells. Their multiplication, usually results in increased volume of the tissue they are in. A continuing proliferation eventually leads to an enlargement of the organ or a benign tumor in it. Usually occuring together with hypertrophy, hyperplastic growth is the hyperactivity of cells that maintain normal regulatory control mechanisms.

Depending on the extent of the cellular proliferation it shows, a hyperplastic tissue may be graded as “Low-grade”(Grade IIIA) or “High-grade”(Grade IIIB).

An example of Grade III pathology report:

KGS Pathology Report and Diagnostic Profile

Biopsy: Pituitary Tumor
Date of Collection: 11.10.2013
Date of Report: 19.10.2013
Diagnosis: Corticotroph Pituitary Adenoma
KGS Grade: IIIA

Microscopic Description: Clustered ACTH-positive adenohypophyseal Grade IIItumor cells are settled throughout the tumor tissue in a sinusoidal pattern varying fromGrade IIIA to Grade IIIB with distinct cellular borders and oval to round nuclei. While the Grade IIIA cells dominate, the Grade IIIB cells occupy 30% of the Grade III area. 16 mitotic (Grade IIIm) cells in 10 HPFs (16/10PHF: 7 Grade IIIAm, 9Grade IIIBm). Adjacent to the Grade III area are clearly seen sporadic groups ofGrade II cells and neat locations of Grade I cells.

KGS Grade: IIIA
Overall KGS Grade: III
KGS Index: 2.48
KGS Prognostic Range: L
Pathologic Diagnosis: “ Grade IIIA Corticitroph Pituitary Adenoma”

Grade IV: Metaplasia

An adaptive response to stress, irritation, chronic inflammation, or other abnormal stimuli, “metaplasia” is a substitution of cells, that are sensitive to such adverse circumstances, by cell types that are better able to survive and withstand the adverse environment. It is a reversible replacement of one differentiated cell type, epithelial or mesenchymal, with another differentiated one.

The metastatic process is the result of a reprogramming of stem cells whose metaplastic act results from changes in their “gene expression” patterns. Squamous metaplasia, where columnar epithelial cells are often replaced by stratified squamous epithelial cells, is the most common epithelial metaplasia. An opposite type of transformation, from squamous to columnar, may also occur as in, for instance, Barrett Esophagus where we see the stratified squamous nonkeratinized epithelium with a transformation into an intestinal-like simple columnar epithelium containing goblet cells.

Metaplasia, unlike dysplasia, is not considered as directly carcinogenetic, but it may switch to dysplasia and be led to a malignant transformation by the persistence of the causative adverse circumstances.

Depending on the extent of the metaplasia it shows, a metaplastic tissue may be graded as “Low-grade”(Grade IVA) or “High-grade”(Grade IVB).

Grade V: Dysplasia

Dysplasia is abnormal cell growth or formation with an expanding number of immature cells of varying size and irregular shape with a corresponding decrease in the number and location of mature cells. Dysplastic cells are “Grade V“ cells which are characterized by irregular cells with large, hyperchromatic nuclei, atypical mitosis, loss of normal differentiation, loss of nuclear polarity.

Depending upon the degree of cytologic atypism, dysplasia may be interpreted in the KGS grading as low-grade (Grade VA), moderate (Grade VB) or high-grade (Grade VC). A high-grade dysplasia (Grade VC) is often considered as “Carcinoma in situ”. Adenomatous (Colonic) Polyp (AP), an adenomatous proliferation, is a typical example of a Grade V tissue where we see different degrees of cell dysplasia; in a Grade VAAP, undifferentiation is around 45% or less with around 55% or more (up to 75%) differentiated cells; the opposite (around 45% or less differentiated cells, and around 55% or more [up to 75%] undifferentiated cells) entitles the tissue the “Grade VB”; and a tissue with 75% or more undifferentiated cells is ranked as “Grade VC”.

Grade VI: Neoplasia

Showing moderate to considerable undifferentiation, and as much abnormally looking and behaving as they can, neoplastic Grade VI cells present themselves as uncoordinated and uncontrollably growing groups of cells that make up a new but abnormal mass of tissue.

In cell cycle acceleration, rapidly getting away from the normal phenotypic and genotypic ID of the cell of origin they come from, Grade VI cells come on the scene with their first marked feature of misbehavior, ever-increasing high-rate multiplication with an increased number of atypical mitoses. They are also characterized by pleomorphism, obvious lack of differentiation and small-volume cytoplasm, which is either deeply-colored or pale, and often filled with vacuoles. Their other typical features include a poorly developed Golgi apparatus and a plain granular endoplasmic reticulum which is reduced to a simplified structure with increased numbers of free ribosomes and polysomes around. Their mitochondria are decreased in volume. They have large nuclei of irregular size and shape with a high nucleo-stoplasmic (N/C) ratio, increased nuclear DNA content, increasing nuclear membrane pores, formation of intranuclear canalicular systems between the nuclear membrane and the nucleolus, nuclear segmentation and invaginations, irregular chomatin distribution, heterochromatin reduction, increase of interchromatin and perichromatin granules and formation of intranuclear inclusion bodies. The nucleoli are prominent and characterized by their movement towards the nuclear membrane, numerical increase, hypertrophy, macrosegregation and microsegregation. The preponderating nuclear changes are the reason for and the basis of various new Grade VI cell clones.

An example of Grade VI pathology report:

KGS Pathology Report and Diagnostic Profile

Biopsy: Pancreatic Tumor
Date of Collection: 07.02.2013
Date of Report: 16.02.2013
Diagnosis: Pancreatic Ductal Adenocarcinoma
KGS Grade: VIB

Microscopic Description: With a sizeably, but not extensively, infiltrative growth pattern, the moderately differentiated Grade VIB cells within dominating poorly-differentiated neoplastic glandular mucoepidermoid and pleomorphic structures; slightGrade VIIA tendency with a few sporadically seen clusters of Grade VIIA cells which quantitatively are not enough to qualify the tissue as Grade VIIA; in 10 HPFs, 14Grade VIBm (mitotic) cells (14/10PHF) and 5 Grade VIBn (necrotic) cells (5/10HPF); sporadic small Grade VC and Grade VIA areas.

KGS Grade: VIB / VIIA
Overall KGS Grade: VIB
KGS Index: 38.72
KGS Prognostic Range: E
Pathologic Diagnosis: “Grade VIB Pancreatic Ductal Adenocarcinoma”

Final KGS Pathology Report and Diagnostic Profile

Biopsy: Post-therapy Pancreatic Tumor
Date of Collection: 07.08.2014
Date of Report: 15.08.2014
Diagnosis: Regressed Pancreatic Ductal Adenocarcinoma
KGS Grade: VIR (Regressed Grade VI Tumor)

Microscopic Description: The Grade VIB tumor’s substantial regression to Grade VIR0 with a zero PTR (Post-Therapy Regression) score (KGS 0); dominating necrosis and fibrosis; no visible/viable tumor cells; rare dying Grade VIB cells among overwhelming groups of Grade VIRn (necrotic) cells; no mitotic (Grade VIBm) cells in 10 HPFs (0/10PHF); 7 Grade VIBo (apoptotic) cells in 10 HPFs (7/10PHF).

Original KGS Grade: VIB
Overall KGS Grade: VIR (VIR0)
KGS Index: 0.50
First KGS Index: 38.72 [Report Date: 16.02.2013]
PTR (Post-Therapy Regression) Score: 0 (KGS 0)
KGS Prognostic Range: N
Pathologic Diagnosis: “Regressed Grade VIB Pancreatic Ductal Adenocarcinoma”

Grade VII: Anaplasia

With a carried-away rate of atypical mitosis, anaplastic Grade VII cells are the most advanced tumor cells seen in the final and ultimate stage of oncogenesis where cellular growth displays its most extreme disturbance with total loss of normal cellular functions, immensely deteriorated cell structures, totally unnatural morphology with extreme to ultimate undifferentiation, and a roaring metastatic escapade.

With occasional giant tumor cells, Grade VII cells typically have a high number of multinucleated cells among them. They have gigantic and abnormally shaped nuclei,a very high N/C ratio, considerably increased nuclear DNA content, increased nuclear membrane pores, formation of intranuclear canalicular systems between the nuclear membrane and the nucleolus, high nuclear segmentation and invaginations, highly irregular chomatin distribution and heterochromatin reduction, increase of interchromatin and perichromatin granules and substantial formation of intranuclear inclusion bodies. The nucleoli are more prominent than that of Grade VI cells and more typically characterized by their movement towards the nuclear membrane with higher numerical increase, hypertrophy, macrosegregation and microsegregation with loss of polarity and loss of specialized functions (e.g. keratin and mucus production). They also typically have poor Golgi apparatus and an impoverished and defective granular endoplasmic reticulums.

Grade VII cells are the holders of the ultimate neoplastic cellular changes in the oncogenetic progression and the leading players of the intensely metamorphosed tumor microenvironment.

An example of Grade VII pathology report:

KGS Pathology Report and Diagnostic Profile

Biopsy: Breast Tumor
Date of Collection: 14.03.2014
Date of Report: 20.03.2014
Diagnosis: Invasive Lobular Carcinoma of the Breast
KGS Grade: VIIA

Microscopic Description: In a deeply infiltrative growth pattern, across abortive tubular structures, dominating clusters of Grade VIIA cells along with sporadic groups of Grade VIIAn (necrotic) cells; 22 Grade VIIAm (mitotic) cells in 10 HPFs (High-power fields) (22/10PHF); sporadic areas of ductal carcinoma in situ (Grade VC) next to the Grade VII area.

KGS Grade: VIIA
Overall KGS Grade: VII
KGS Index: 40.02
KGS Prognostic Range: E
Pathologic Diagnosis: “Grade VIIA Invasive Lobular Carcinoma of the Breast

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