PART 8: Scoring with KGS Parameters
The KGS Scoring is the calculation of the parametric KGS scores. It is based on the calculation of the tumors’ cellular and metastatic counts. Directly based on the overall summation of the KGS’s scores of the individual cellular and metastatic parameters, the scoring determines the KGS Index.
The parametric KGS scores come from the quantitative parametric KGS data which are collected in five groups of KGS Parameters: “Prime Tumor Cells” (PTCs), “Mitotic Tumor Cells” (MTCs), “Circulating Tumor Tells” (CTCs), “Necrotic Tumor Cells” (NTCs) and “Metastases”(METs).
Apoptotic tumor cells (ATCs) take place in the list as the sixth parametric data group only when they get detected in a significant number.
Although important in tumor progression, and crucial in tumor staging and treatment, tumor size is not regnant enough to qualify as a primary parameter in tumor grading in general; its parametric value in that regard is relative, and therefore it does not take a primary parametric slot in the KGS scoring while keeping its traditional importance as the first-hand constituent of tumor manifestation.
The KGS parameters are the fundamental part of the KGS grading which the crucial details of the KGS pathology report are directly related to and primarily depended on. They are the KGS’s robustly effective diagnostic and prognostic warners and predictors.
The five parametric scores come from the mean percentage of the tumor cells (PTCs) of 10 LPFs (Low-Power Fields), the median of the numbers of the mitotic tumor cells(MTCs) detected in 10 HPFs (High-Power Fields), the circulating tumor cells (CTCs) counts in peripheral blood, the number of metastases (METs) and the mean percentage of the necrotic tumor cells (NTCs) of 10 LPFs. The total score of these parametric groups generates the KGS Index (KGS Index = PTC + MTC + CTC + NTC + MET) which is the critically important prognostic guiding element in the KGS Grading and the primary constituent of the KGS Prognostic Profile and KGS Prognostic Chart (KGS Chart).
KGS Impact Factor (IF): Used with the KGS parameters, the KGS Impact Factor (IF) is the KGS’s mathematical constant. It is not an invariant. While it is not coequal in all the KGS parameters, it is a constant, an unvarying number, in each of the parameters. The ”Effective KGS Score” is generated by the multiplication of the raw parametric ”KGS Score” by the IF:
Effective KGS Score = KGS Score X IF
1. Prime Tumor Cells (PTC)
The prime tumor cells (PTCs) are the cells of the primary tumor in a neoplastic activity in human body. Their KGS calculation provides the KGS’s solid tumor grading with an essential scoring parameter which is symbolized as PTC.
Giving a sizeable prediction of prognosis in cancer, tumour differentiation gets traditionally checked as part of a routine analysis of potential prognostic factors . In assessing the morphological differentiation of tumor cells, we look at their differentiation/undifferentiation ratio. Along with the cells’ nuclear and cytoplasmic morphological features, the easily calculated undifferentiation is an essential to hold to.
Primary Tumor: By being histopathologically examined with its PTC score added to the parametric KGS data, an existing or removed, metastatic or non-metastatic primary tumor fulfills its contribution to the KGS Grading in either way. Although it is used for malignant tumors in the KGS in its own right, the term “Primary Tumor” is also used for benign tumors for the sake of uniformity in the usage of the PTC parameter in the KGS’s Solid Tumor Grading. The KGS’s PTC Score for a malignant primary tumor is based on the total Grade VI (Grade VIA + Grade VIB) and/or Grade VII (Grade VIIA + Grade VIIB) cells’ mean percentage of the10 HPF-supported LPFs from the periphery of the examined tissue. For a Grade IV or Grade V tumor tissue it is based on the total of the Grade IV and V cells’ percentages in the tumor. To be included in the PTC scoring of an examined tumor tissue, any minority low-grade (Grade IV-V) tumor cells must occupy a minimum space of %5 of the tissue while minority high-grade (Grade VI-VII) tumor cells must occupy at least %0.5 of the tissue.
Total of PTC percentages (%) in 10 LPFs
Mean PTC Count (%) = ----------------------------------------------------------
Mean PTC Count (%)
PTC Score = --------------------------------
KGS Impact Factor (IF): The KGS Impact Factor (IF) for the PTC parameter is based on the KGS nuclear grades defined by nuclear atypia. In the KGS’s Grade III tumors, the KGS nuclear grades have no value, and their manifested value in Grade VI andGrade VII tumors is neither crucial nor critical. They are therefore only applied toGrade IV and Grade V tumors where they contribute to the KGS Impact Factor (IF) importantly.
Nuclear A-grade (low-level): At this level, metaplastic and dysplastic cells keep their polarized shape and show uniform nuclei with fine, diffuse chromatin. Slight nuclear atypia may sometimes be seen. They generally fit in Grade IV.
Nuclear B-grade (mid-level): This is the level between A-grade and C-grade and takes place in between Grade IVB- Grade VA.
Nuclear C-grade (high-level): C-grade dysplastic cells show extereme atypia with significantly enlarged and highly pleomorphic, hyperchromatic nuclei with rough-textured chromatin. They are mainly in Grade V.
KGS Impact Factor (IF):
Grade III: 0.30
Nuclear A-grade (low-level): 0.50
Nuclear B-grade (mid-level): 0.75
Nuclear C-grade (high-level): 1
Grade VI-VII: 1
Metastases are not given the PTC scoring. They are meanwhile taken into account in their own separate parametric data entry (MET)
2. Mitotic Tumor Cells (MTC)
The mitotic count in solid tumors holds the foremost rank in the KGS Index scoring [16,90-94,96,97,133].
The mitotic tumor cells’ KGS score (MTC) is based on the median of the numbers of the mitotic cells (MTCs) in 10 HPFs from the periphery of the examined tissue.
Total of MTC counts in 10 LPFs
Mean MTC Count = -----------------------------------------------
MTC Score = Mean MTC Count
KGS Impact Factor (IF): 2
3. Circulating Tumor Cells (CTC)
While physically separate from their primary tumor, circulating runaway cancer cells (CTCs) are inseparable from the oncogenetic progression , and they are therefore an inherently important parameter in the scoring for the KGS’s solid tumor grades with a high impact factor (IF).
CTCs’ scoring share is based on the CTC counts in peripheral blood. The median of CTC counts from three liquid biopsies gives the KGS score of the CTCs. The CTCs are collected from three 7.5 mL anti-coagulated peripheral blood samples:
Count 1 (Liquid Biopsy 1): On the day of the tissue biopsy
Count 2 (Liquid Biopsy 2): 48 hours after the “Liquid Biopsy 1”
Count 3 (Liquid Biopsy 3): 48 hours after the “Liquid Biopsy 2”
Circulating Apoptotic Tumor Cells: Circulating apoptotic tumor cells (ATCs) detected among CTCs are not included in the CTC counting.
Total CTC counts = Count 1 + Count 2 + Count 3
Total CTC counts
Mean CTC Count = ------------------------------
CTC Score = Mean CTC Count
KGS Impact Factor (IF): 3
4. Necrotic Tumor Cells (NTC)
Necrosis has exclusive importance along the oncogenetic process and high prognostic value in the phases of spontaneous and post-therapy tumor regression [19,99-101]. It scores variably depending on the tumor grade and in relation to the particular stages of prognosis and oncotherapy.
Necrotic cells’ “KGS Score” share in a solid tumor tissue is based on the necrotic cell groups’ mean percentage (Necrotic Cells Percentage - NCP) in 10 HPF-supported LPFs.
Total of NTCs in 10 LPFs
Mean NTC Count = ----------------------------------------
NTC Score = Mean NTC Count
KGS Impact Factor (IF): -2/2
High Necrosis (Anaplastic Tumor Necrosis): 2
Low Necrosis (Regressive Tumor Necrosis): -2
5. Metastases (MET)
To the KGS scoring, the parameter of metastases gives indirect but considerable contribution. With the highest impact factor (IF=5) in the scoring, the metastatic KGS parameter is also an important constituent of the KGS Index.
The metastatic KGS score (MET) is based on the counts of metastatically involved organs rather than individual counts of all the metastates:
- PRIMARY TUMORS and LOCAL METASTASES: Any local metastases or synchronous primary tumors along with the first or main primary tumor in the same organ are included in the counting. Each of them is counted as “1” in the scoring.
- INVOLVED ORGANS: Each organ with one or more distant metastases is counted as “1”: A brain, for instance, with two metastases is counted as “1” and adds 1 point to the MET score. Likewise, a liver with multiple metastases is also counted as “1” and added to the score as 1 point.
- PAIR ORGANS: Pair-organs like the lungs, breasts, testes, kidneys and adrenal glands are counted as “2” when bilaterally involved. Two metastatic lungs, for instance, each with solitary or multiple metastases, are counted as “2” and added to the MET score as 2 points whereas just one involved lung with solitary or multiple metastases is counted as “1” and scores 1 point.
- LYMPH NODES: Each involved lymph node, regardless of its distance to the primary tumor, local or distant, is counted as “1”: Three detected metastatic lymph nodes, for instance, local or distant, are counted as “3” and added to the MET score as 3 points.
- BONES: Regardless of the extent of metastatic involvement and numbers and locations of metastases, each of the involved bones is counted as one with a 1-point contribution to the MET score. The Cranium as well as the Pelvis (excluding sacral bone) is counted as one bone. Metastases in a multiply involved Columna Vertebralis, meanwhile, are counted with a “one point per vertebra” rule; in a multiply metastasized spinal column, for instance, two affected vertebrae, one with two metastases and the other with one, add 2 (not 3) total points to the score. TheSternum and each of the costae are also individually counted; when involved, each contributes to the scoring for itself with a 1-point score.
TUMORS of UNKNOWN ORIGIN: In case of a tumor of unknown primary origin, all of the five groups of parametric KGS data (PTC, MTC, CTC, NTC and MET) related to the detected tumor, which is a metastasis, are calculated. In a tumor of unknown primary origin, a detected tumor, a single metastasis, or the largest of reachable multiple metastases is histopathologically examined and scored like a primary tumor. Such metastases are at the same time taken into account in collecting the parametric data of metastases in their own separate entry (MET). So, the tumor, physically metastatic, is put in the KGS Grading like a primary tumor (PTC) while, at the same time, being also taken into account as a metastasis in the parametric MET scoring.
MET Score = Metastatic organ count
KGS Impact Factor (IF): 5
6. Apoptotic Tumor Cells (ATC)
Apoptosis has an important place in oncogenesis and plays quite an important role in oncotherepy although it occurs too little in cancer [15,17,18]. Scoring variably in the KGS depending on the tumor grade and in relation to the stages of both prognosis and treatment, apoptotic cells are only rarely seen in tumor tissues and among circulating tumor cells (CTCs) and they are therefore usually ommitted in the KGS grading and do not appear as a parameter in the KGS’s parametric scoring list. They get included in the parametric scoring list as the sixth parameter only when they contribute to the grading substantially by appearing in a tumor tissue in significant numbers as in spontaneous or post-therapy regression.
ATC Score = The total number of apoptotic cells in 10 HPFs from the periphery of the examined tissue and among the CTCs.
KGS Impact Factor (IF): Grades I-IV: 0
Grade V: -1
Grades VI-VII: -2