PART 4: The KARINDAS GRADES
The KARINDAS GRADES
The “Karindas Grades” in the “KGS Solid Tissue Ranges” are a hierarchical grading series 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 (Tables 1 & 2).
KARINDAS GRADES in KGS SOLID TISSUE 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)
Table 1: The Karindas 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 Hyperplasi
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 Neoplastic Cell
VIB Moderately-differentiated / Considerably Undifferentiated Neoplastic 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 Anaplastic Cell
VIIB Undifferentiated (Fully undifferentiated) Anaplastic 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 Karindas Cellular Grades. 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, necroticand apoptotic cells respectively.
Grade 000: Apoptosis
Unlike necrotic cells, apoptotic cells are usually isolated single cells or small clusters of cells. 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 as ever [15,17,18]. 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 Grade VIo and Grade VIIo respectively. In the KGS subgrades, they are more specifically seen as Grade VIAo, Grade VIBo, Grade VIIAo and Grade 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 the loss of membrane integrity culminates in the cell’s dissolution 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, their cytoskeletons collapse and 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 seriously disturbed tissues. 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 name them as High Necrotic Tumor Cells [19,99] and grade them as VIBn, VIIAn and VIIBn respectively; they also appear as an important component in tumor regression where I name them as Low Necrotic Tumor Cells [100,101] and grade them as 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 functions.
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 are taken into account in the KGS. So that, normal cells are included in the range of the KGS Grading and they are KGS-graded and KGS-ranked as Grade I cells and their tissues are also KGS-graded as Grade I.
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 Biopsy: “Grade II Myocardial Tissue”
Grade III: Hyperplasia
Increased in number, hyperplastic cells are proliferated cells, normal looking but with an abnormal growth pattern. Their multiplication, usually results in increased volume of the tissue they belong to. A continuing proliferation eventually leads to an enlargement of the organ and/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 KGS-graded as “Low-grade” (Grade IIIA) or “High-grade” (Grade IIIB). A typical example is the hyperplasia of the breast whose ordinary type, usual ductal hyperplasia is represented by Grade IIIA and the more abnormally-progressed (atypical) one, atypical ductal hyperplasia is Grade IIIB.
Being at the end point of the KGS’s physiologic range as the key-level Grade III, hyperplasia at the same time bears a pre-neoplastic push, as Grade IIIB, at the border of the pre-neoplastic KGS range (Table 1, Table 2); we see its non-neoplastic disposition as Grade IIIA, typically in BPH, which is not considered to be a precursor of prostate cancer , while we often see its pre-neoplastic IIIB sub-grade as various types of hyperplasia as precursors including atypical adenomatous hyperplasia (AAH) [49-56,69,72] congenital adrenal hyperplasia (CAH) , atypical ductal hyperplasia (ADH) [39,41,134] and endometrial hyperplasia .
A sample “Grade III tumor” Pathology Report:
The KGS Pathology Report
KGS Diagnostic Profile:
Biopsy: Pituitary Tumor
Date of Collection: 11.10.2013
Date of Report: 19.10.2013
Clinical Diagnosis: Corticotroph Pituitary Adenoma
Microscopic Description: Clustered ACTH-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 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, 9 Grade IIIBm). Adjacent to the Grade III area are clearly-seen sporadic groups of Grade 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, which are sensitive to such adverse circumstances, by cell types that are more 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).
Low-grade prostatic intra-epithelial neoplasia (LGPIN)  is a characteristic Grade IV tumor. Intestinal metaplasia of the stomach, the metaplasia of gastric epithelial cells, is another typical example of Grade IV tumor which is associated with a high risk of gastric carcinoma [128-131].
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, increasing nucleo-stoplasmic ratio (N/C), prominent nucleoli, atypical mitosis and loss of normal differentiation and nuclear polarity. While A-grade (low-level) dysplastic cells keep their polarized shape and show uniform nuclei with fine, diffuse chromatin take place in Grade VA, significantly enlarged hyperchromatic nuclei with high pleomorphism and rough-textured chromatin make the dysplastic lesion C-grade (high-level) qualify it for Grade VC. Any cellular grade in between is B-grade (middle level) which is graded as Grade VC.
Having a critical locality in the KGS’s pre-neoplastic range at the border of the neoplastic KGS range (Table 1 & 2), dysplasia holds a well-known facet of sizeable malignant potential (carcinoma in situ-CIS), as Grade VC, which is typically seen in ductal carcinoma in situ (DCIS) of the breast as the best known example of CIS.
High-grade prostatic intra-epithelial neoplasia (HGPIN) [43-56,70,71,73-75], an intraductal dysplasia, is another typical example of Grade V tumor which is a a precursor of prostatic adenocarcinoma [42,43]. I meanwhile prefer holding low-grade prostatic intra-epithelial neoplasia (LGPIN) in Grade IV, to putting it in Grade V together with HGPIN; LGPIN, formerly PIN I, which is not a straight prostatic cancer precursor, can hardly surpass its pre-neoplastic limits while HGPIN, formerly PIN II-III, rightfully qualifies for Grade V and dwells in all the Grade V subgroups, Grade VA, Grade VB, Grade VC fitting in with its low, middle and high level nuclear parameters respectively.
Adenomatous (Colonic) Polyp (AP), an adenomatous proliferation which very often contains CIS, is also 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
Although its literal meaning is new growth and actually embraces a wide range of abnormal new growth patterns including hyperplasia, metaplasia and dysplasia, the term neoplasia today habitually represents malignancy. Here, in the KGS, the term covers the Grade VI range. 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, the 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 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 clone. Well-differentiated (moderately-undifferentiated) Grade VI cells are sub-graded as Grade VIA and moderately-differentiated (considerably undifferentiated) ones as Grade VIB.
A sample “Grade VI tumor” Pathology Report:
The 3rd KGS Pathology Report
(See also Tables 6 & 7 and Figure 2)
KGS Diagnostic Profile:
Biopsy: Pancreatic Tumor
Date of Collection: 13.06.2013
Date of Report: 21.06.2013
Clinical Diagnosis: Pancreatic Ductal Adenocarcinoma
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; slight Grade 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, 29 Grade VIBm (mitotic) cells (29/10PHF) and Grade VIBn (necrotic) cells which occupy around 15% of the tumor tissue; sporadic small Grade VC and Grade VIA areas.
KGS Grade: VIB / VIIA
Overall KGS Grade: VIB
KGS Index: 24.84
KGS Prognostic Range: H (High Range)
Pathologic Diagnosis: “Grade VIB Pancreatic Ductal Adenocarcinoma”
The Final KGS Pathology Report
(See also Tables 6 and 7 and Figure 2)
KGS Diagnostic Profile:
Biopsy: Post-therapy Pancreatic Tumor
Date of Collection: 07.08.2014
Date of Report: 15.08.2014
Clinical Diagnosis: Regressed Pancreatic Ductal Adenocarcinoma
Microscopic Description: The Grade VIB tumor's substantial regression to Grade VIR0 with a zero PTR (Post-Therapy Regression) score (KGS 0) ending up in Grade I with a normal-range profile (N); dominating necrosis and fibrosis; no visible/viable tumor cells; rare dying Grade VIB cells among overwhelming groups of Grade VIRn (necrotic) cells; no Grade VIBm (mitotic) cells in 10 HPFs (0/10PHF); 7 Grade VIBo (apoptotic) cells in 10 HPFs (7/10PHF).
Original KGS Grade: VIB
Overall KGS Grade: VIR0 (Regressed Grade VI Tumor)
KGS Index: 0.20
First KGS Index: 24.84 [Report Date: 21.06.2013]
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 absolute 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.
Poorly differentiated (highly undifferentiated) Grade VII cells are sub-graded as Grade VIIA and undifferentiated (fully undifferentiated) ones as Grade VIIB. With their difficult-to-recognize cell of origin, the Grade VII cells, the cells of extreme undifferentiation, are the holders of the ultimate neoplastic cellular changes in the oncogenetic progression and the leading players of the intensely metamorphosed tumor microenvironment. Some certain tumor cell and tissue conditions and circumstances automatically qualify the cells and tissues they involve to be graded as VII. A circulating tumor cell for instance, is automatically a Grade VIIB cell, and the primary tumor it comes from is a Grade VIIB tumor. Likewise, a metastasis is always graded as a Grade VIIB tumor.
A sample pathology report of Grade VII tumor:
KGS Pathology Report
KGS Diagnostic Profile:
Biopsy: Breast Tumor
Date of Collection: 14.03.2014
Date of Report: 20.03.2014
Clinical Diagnosis: Invasive Lobular Carcinoma of the Breast
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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