It is 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 happy and 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, and normal 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:
The Second 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 IIIB 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).
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
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”
The “Karindas Grades” 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.
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 (CID); 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. While the apoptotic cells may be seen in all ranges of the KGS Grading, 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 rightfully takes 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). [for details, see end of the page]
In pathology reports, some examples of ordinary necrosis may be described as below:
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, all of 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 with a title 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 would be issued with a title 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:
The Final 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 LH-positive adenohypophyseal Grade III tumor cells are settled throughout the tumor tissue in a sinusoidal pattern varying from Grade IIIA to Grade IIIB with distinct cellular borders and oval to round nuclei. While theGrade IIIA cells dominate, the Grade IIIB cells occupy 30% of the Grade III area. Mitotic (Grade IIIm) cells in 10 HPFs: 16 (16/10PHF: 7 Grade IIIAm, 9 Grade IIIBm). Adjacent to the Grade III area are clearly seen groups of Grade II cells and neat locations of Grade I cells.
KGS Grade: IIIA
Overall KGS Grade: III
KGS Index: 6.48
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, loss of normal differentiation, loss of nuclear polarity and atypical mitosis.
Depending upon the degree of cytologic atypism, dysplasia may be interpreted 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 VA AP, 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. 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:
The 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:
The First KGS Report
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”
Using the KGS grading, KGS Pathology Reports give the details of the examined tumor tissues clearly and comprehensively. The instructive KGS terminology and coding used in the reports makes the details and descriptions in the reports neat, brief, and to-the-point, and easy to view, share and record for the professionals of clinical and research medicine.
KARINDAS GRADES in KGS RANGES
Grade 00-0 Inert Range
00 Necrosis (Ordinary)
Grade I-III Physiologic Range
IIIA Low-grade (Ordinary) Hyperplasia
IIIB High-grade (Atypical) Hyperplasia
Grade IV-V Preneoplastic Range
IVA Low-grade Metaplasia
IVB High-grade Metaplasia
VA Low-grade Dysplasia
VB Moderate Dysplasia
VC High-grade Dysplasia (Carcinoma In Situ)
VR Regressive Dysplasia
Grade VI-VII Neoplastic Range
VIA Well-differentiated / moderately undifferentiated
VIB Moderately-differentiated / considerably undifferentiated
VIIA Poorly-differentiated / highly undifferentiated
VIIB Undifferentiated (Fully undifferentiated)
Copyright © 2010-2014 M. M. Karindas, MD
Table 2: The “Karindas Grades” in the “KGS Solid Tissue Ranges”. 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”.
TUMOR NECROSIS IN THE KGS GRADING
(Copyright © 2010-2014 By M. M. Karindas, MD)
Necrosis has an important place in Grade V, Grade VI and Grade VII solid tumors in which a necrotic tissue may appear in two different forms in two different phases of oncogenesis:
- Anaplastic Tumor Necrosis (High Necrosis): In the tissues of advanced anaplasia in high-grade (VIB, VIIA and VIIB) tumors, necrosis frequently emerges as the ultimate characteristic of anaplastic maturement. In the KGS Grading, I entitle the tissue of anaplastic necrosis ”High Necrotic Tissue” (i.e. Grade VIBnecrotic tissue, Grade VIIA necrotic tissue, etc.), and I call the tumor cells it contains “High Necrotic Tumor Cells” grading them as Grade VIBn, GradeVIIAn and Grade VIIBn cells.
- Regressive Tumor Necrosis (Low Necrosis): In “Grade V”, “Grade VI” and “Grade VII” regressive tumors (Grade VR, Grade VIR and Grade VIIR), necrosis may happen either as a result of a successful oncotherapy, or spontaneously. In the KGS Grading, I entitle the necrotic tissue of a regressing or regressed tumor ”Low Necrotic Tissue” (i.e. Grade VR necrotic tissue, Grade VIR necrotic tissue, Grade VIIR necrotic tissue; in more specifically profiled and recorded/reported cases, as Grade VCR, Grade VIAR, Grade VIBR, Grade VIIAR and Grade VIIBR necrotic tissues) and I call the tumor cells it contains “Low Necrotic Tumor Cells” and I grade them as Grade VRn, Grade VIRnand Grade VIIRn cells and the more specific ones as Grade VCRn, Grade VIARn, Grade VIBRn, Grade VIIARn and Grade VIIBRn cells. With the addition of tumors’ PTR (“post-therapy regression”) grading to the KGS grading (e.g. VIIR1: KGS1, VIR5: KGS5, etc.), KGS pathology reports provide much more comprehensive information.
The KGS’s PTR (Post-Therapy Regression) GRADING
________________________________________________________________ PTR Score: 0 (KGS 0)
KGS Range: VIR0-VIIR0
PTR Criteria: Fully credible neoplastic regression. No trace of residual tumor, no viable tumor cells _________________________________________________________________ PTR Score: 1 (KGS 1)
KGS Range: VIR1-VIIR1
PTR Criteria: Substantial neoplastic regression. Rare (<5%) residual tumor cells
_________________________________________________________________ PTR Score: 2 (KGS 2)
KGS Range: VIR2-VIIR2
PTR Criteria: Significant neoplastic regression. 5-15% residual tumor cells
__________________________________________________________________ PTR Score: 3 (KGS 3)
KGS Range: VIR3-VIIR3
PTR Criteria: Considerable neoplastic regression. 15-35% residual tumor cells
__________________________________________________________________ PTR Score: 4 (KGS 4)
KGS Range: VIR4-VIIR4
PTR Criteria: Limited neoplastic regression. 35-50% residual tumor cells
__________________________________________________________________ PTR Score: 5 (KGS 5)
KGS Range: VIR5-VIIR5
PTR Criteria: Insignificant neoplastic regression. >50% residual tumor cells
Copyright © 2011-2014 M. M. Karindas, MD
Table 4: KGS-PTR Grading. The KGS’s PTR Grading, a five-tier-scale system, is based on the existing tumor cells’ proportional value in relation to the proportions of necrosis and fibrosis in regressing solid tumors. In pathologic examination reports, tumors’ PTR scores, which are designated as KGS 0, KGS 1, KGS 2, KGS 3, KGS 4, and KGS 5, also indicate the five levels of the grading where the corresponding KGS ranges take place synchronously (e.g. KGS 3 : VIR3-VIIR3)
Prognostic KGS Ranges
KGS Index: <0
Prognostic KGS Range: Normal (N)
NORMAL RANGE: This is the range where a totally normal tissue and cells are seen. Examples: 1. A normal tissue with no status or history of neoplastic activity, 2. Fully regressed neoplastic tissue.
KGS Index: 1-7
Prognostic KGS Range: Low (L)
LOW RANGE: The range of tumoral activity with no considerable neoplastic weight. Examples: 1. Grade III-IV tumors, 2. Almost fully regressed neoplastic tissue.
KGS Index: 8-18
Prognostic KGS Range: Medium (M)
MEDIUM RANGE: This is the range of emerging neoplastic activity, with considerable neoplastic potential and significance. Examples: 1. Grade VB-VC tumors, 2. Fairly regressed neoplastic tissue.
KGS Index: 19-29
Prognostic KGS Range: High (H)
HIGH RANGE: The high range is the range of established neoplasia where a qualified malignant tumor tissue takes place with all the features of neoplasia: Fully developed cancer (e.g. Grade VIA-VIB tumors).
KGS Index: 30-40
Prognostic KGS Range: Extreme (E)
EXTREME RANGE: This is the range of neoplasia where tumors with full neoplastic features and complications, including necrosis (high necrosis) and metastasis, take place: Full-blown cancer (e.g. Grade VIB-VIIA tumors).
KGS Index: >40
Prognostic KGS Range: Ultimate (U)
ULTIMATE RANGE: The range of the most advanced malignancy with highly malignant anaplastic cells with maximum mitotic, necrotic and metastatic activity: Full-scale anaplasia (e.g. Grade VIIA-VIIB tumors).
Copyright © 2011-2014 M. M. Karindas, MD
Table 5: The Prognostic KGS Range. The prognostic KGS ranging, highly important and crucial to use in the prognostic follow-up of the oncology patient, is directly based on the overall summation of the KGS scores of the individual cellular and metastatic parameters. While the parameters’ KGS scores make up the “KGS Index” through the rational numbers directly generated from the parametric data, the variable levels of the scores in the index engender the “Prognostic KGS Range”.
Copyright © 2011-2014 M. M. Karindas, MD