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Overview of Grading and Staging

Identification of the process

Tumor is a word of Latin derivation meaning a swelling or protruberance-a "mass." In its broadest sense it includes masses formed by cellular inflammatory infiltrates, controlled proliferations of hyperplastic cells, and uncontrolled proliferations of neoplastic cells (cancer). Controlled proliferations of cells have a recognizable structure, may perform their usual physiologic function, do not invade local tissues, and suffer senescence and programmed cell death (apoptosis). Uncontrolled proliferations may contain cells of variable structure, may be functional or nonfunctional, may invade local tissues or cause local tissue necrosis by their increasing bulk, replicate in a disorderly manner, and do not suffer programmed cell death.

The path to successful treatment of a tumor begins with recognition of the lesion on a gross level, usually by the caretaker of a dog or cat, sometimes by a groomer, or often during a physical exam by a veterinarian. The next step is assignment of the pathological process into a category of inflammation, hyperplasia, or neoplasia, or some combination of these categories. This can be accomplished at the point of care by aspirating the lesion with a needle and examining the individual cells. In the following chapters this will be called fine needle aspiration (FNA). With some tumors, especially papillomas, impression or scraping of the lesion can yield diagnostic cells, but generally this is not the ideal method of collection, as surface contamination can make evaluation difficult. All cytologic samples are stained with Wright-Giemsa (W-G) stain unless otherwise indicated.

Figure 1.1 shows an apocrine gland adenoma FNA. This cluster of small epithelial cells is suggestive of a proliferation of basaloid epithelial cells or the ductular epithelium of an apocrine gland. The cell nuclei are small and regular, and there is scant inflammation, as shown by the neutrophil in this field.

Figure 1.1 Apocrine gland adenoma FNA. 50x.

When FNA of a mass reveals a population of proliferating cells, indicating the lesion is not merely an influx of inflammatory cells that can be relieved by medical means, biopsy allows histopathological evaluation of the affected tissue, showing the architectural arrangement of the cells and allowing for a more definitive diagnosis. This is the point where a hyperplastic growth is distinguished from a neoplastic growth based on how the cells are structurally arranged. FNA cannot evaluate architectural arrangement accurately, because the cells are usually stripped of their association by the process of aspiration. The decision to take an incisional biopsy that removes a portion of the mass, or an excisional biopsy that removes all of the mass, should be based on factors such as the tumor type suggested by the FNA, the size of the lesion, the location of the lesion, the stage of the disease, and other parameters such as the overall health of the patient and wishes of the owner. Ultimately the decision rests on the clinical judgment of the surgeon. All biopsies shown in the following pages are stained with hematoxalin and eosin (H&E), unless otherwise indicated.

Figure 1.2 is a biopsy showing the architecture of the gland aspirated in Figure 1.1. There are double rows of small epithelial cells proliferating in a manner that does not invade into the adjacent stroma, indicating that this is a benign apocrine gland tumor referred to as an apocrine ductular adenoma.

Figure 1.2 Apocrine gland ductular adenoma biopsy. 40x.

FNA can sometimes identify cells that are so clearly abnormal, either by morphology or cell density, that neoplasia can be diagnosed on a presumptive basis.

Figure 1.3 shows a transitional cell carcinoma FNA. An adult female mixed breed dog was presented for hematuria and dysuria. A tentative diagnosis of cystitis was made based on clinical signs, and cystocentesis was performed to collect urine for routine urinalysis and sedimentation. Cytologic exam revealed many clusters of large epithelioid cells with marked anisokaryosis (variation in nuclear size) and basophilic cytoplasm. There were scattered neutrophils, erythrocytes, and cellular debris. No infectious agents were seen. A preliminary diagnosis of neoplasia, probable transitional cell carcinoma, was made. Treatment for infectious cystitis, based just on clinical signs, would prove useless and would delay the true diagnosis. If neoplasia is suspected on presentation, catheterization would be the preferable method of collection.

Figure 1.3 Transitional cell carcinoma FNA. 50x.

If biopsy identifies the process as hyperplastic, and the margins are free of abnormal cells, it can be assumed that the lesion is cured. This does not preclude additional lesions arising adjacent to the removed mass.

If biopsy identifies the process as neoplastic, the tumor can be categorized into type and grade based on published guidelines derived from scores of biopsies and the statistical analysis of their behavior. The purpose of this atlas is to enable visual recognition of lesions and thus the reader will be spared a detailed description of the original research that forms the basis for statistical analysis. Inquiring minds, however, are encouraged to review the documents in the additional journals and books listed in the reference section.

Identification of tumor types

The broadest categories of tumor types are derived from tissue of origin. Epithelial origin tumors are designated as epithelioma or adenoma (benign) and carcinoma (malignant). Mesenchymal origin tumors are typically designated as an -oma prefixed by the tissue of origin (benign) or -sarcoma prefixed by the tissue of origin (malignant). Discrete cells lacking cell to cell adhesion and originating from the specialized tissue and circulating cells of the immune system, such as lymphocytes, plasma cells, histiocytes, mast cells, and a transplantable chymeric neoplasm called transmissible venereal tumor, are designated as round cell tumors, often -omas, prefixed by the tissue of origin (and indicated as benign or malignant). There is a separate category for melanoma, which can have epithelioid, spindloid, and round cell characteristics within the same tumor (both benign and malignant).

Grading

Grading is performed by the pathologist using parameters that can only be assessed by biopsy, including mitotic activity per high power (40x) field, the presence of a recognizable pattern of growth, and invasion into adjacent normal tissue. Mitotic activity is an important part of most grading systems. Mitotic rate or mitotic count is the number of mitotic figures per high-power field (mitotic figures/HPF).1 Mitotic index (MI) is generally accepted as the number of mitotic figures in 10 fields (mitotic figures/10 HPF), but if a different number of fields have been used, it must be stated in the numerical figure.2 Both mitotic rate and mitotic index can vary widely depending on which areas of the tumor are examined. The presence of necrosis and dense inflammatory infiltrates can make identification of mitotic figures difficult, and small biopsies less than 10 fields in size can make enumeration of the mitotic index impossible. Thus, grade is not based just on mitotic activity but also on other aspects of the proliferating population such as the amount of necrosis (also subjective and based on the section examined) and pattern of growth in the tissue. This heterogeneity introduces some variation into the assessment of tumor grade and has contributed to the proliferation of several grading systems for some tumors as pathologists attempt to find the best system (Table 1.1).

Table 1.1 Multiple grading systems for lymphoma.

Grading systems can use a quantifiable descriptive term such as low, medium, and high grade or can assign a numerical label (Table 1.2), and grading systems can use an equation to score several critical features that add up to a sum assigned to a grade (Table 1.3). All of the systems used are designed to succinctly convey the probability that a tumor will be aggressive and likely to invade local or distant tissues. Grading also allows a pathologist to give an oncologist a specified set of details designed to help choose and monitor appropriate therapy. The general practitioner and the oncologist or internist may have different preferences for grading protocols or treatment plans, and may desire different sets of information, resulting in a report listing several grading protocols applicable to the tumor described. These compilations of data can be useful even in the face of periodic modification as the database grows and our diagnostic tools become more refined to include molecular diagnostic parameters such as tumor growth fraction, genetic analysis for c-KIT gene mutation which activates the KIT tyrosine kinase receptor, and polymerase chain reaction (PCR) of antigen...