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Overview of Diagnosis, Categorization, Grading, and Staging

Identification of the process

The practicing veterinarian is sometimes presented with a patient who has a focal swelling. Good communication with the client, using mutually understood terminology, is important to avoid misunderstandings as a patient plan is developed. Tumor is a word of Latin derivation, meaning a swelling or protuberance-a "mass." This word is often misunderstood by the client as "cancer," but technically it includes masses formed by inflammatory infiltrates, controlled proliferations of hyperplastic cells, and uncontrolled proliferations of neoplastic cells (cancer). An astute clinician understands that the word tumor encompasses all of these processes. Failure to consider this wider definition can result in bias that causes an inaccurate or incomplete diagnosis.

Inflammation can be a result of tissue necrosis due to traumatic, chemical, thermal, or ischemic injury, or it can be due to primary or secondary infectious agents. The presence of neutrophils is a signal to be on the lookout for infectious organisms.

Hyperplastic proliferations of cells have a recognizable structure, may perform their usual physiological function, do not invade other tissues, and eventually undergo senescence and programmed cell death (apoptosis).

Neoplastic proliferations may contain cells of varied structure, may be functional or nonfunctional, may invade local tissues, may cause local tissue necrosis by their increasing bulk, tend to replicate in a disorderly manner, and have the ability to escape typical programmed cell death.

Within the realm of neoplasia or "cancer," there are the categories of benign and malignant. At a simplistic level, benign means good and malignant means bad. From a clinician's point of view, a benign cancer is one that stays in place and does not invade beyond the boundaries of the basement membranes or capsule, and a malignant cancer causes harm by invading locally and spreading to distant sites. It can be difficult to categorize a tumor based solely on a few cells collected by fine needle aspiration (FNA) or a small section of tissue collected by punch or needle biopsy. Hyperplastic lesions may become focally neoplastic,1, 2 benign tumors can undergo transformation to malignant neoplasia,3 aggressive tumors can have large areas of necrosis and dense inflammation containing few tumor cells, and occasionally benign and malignant proliferations of multiple cell lines can arise simultaneously and in proximity.4, 5 So how is a tumor identified as malignant? The following list is an indication of the challenge of defining a malignant tumor:

When a mass is judged to be neoplastic, the following criteria can help determine if the tumor is malignant:

1. Has the normal architecture been lost in any area?
2. Is there nuclear and cellular pleomorphism such as nuclear hyperchromia, anisokaryosis, or multiple nuclei?
3. Is the mitotic count (MC) increased beyond what could be expected with a hyperplastic response or benign neoplasm?
4. Is there cellular necrosis that is not related to trauma?
5. Are tumor cells infiltrating into adjacent normal tissue?
6. Have tumor cells lost their normal orientation with the basement membrane (in epithelial tumors) and started to form irregular and disorganized clumps of cells?
7. Is there lymphatic invasion?
8. Is there lymph node invasion?

If points 7 or 8 are present, the tumor is considered malignant. If 1-6 are present, the likelihood of malignancy increases proportionately with an increased number of criteria (adapted from Zappulli et al.6)

Some tumors (anal sac apocrine carcinoma, pheochromocytoma, parathyroid tumor) can cause clinical illness and death without ever leaving the site of origin by releasing substances that disrupt normal metabolic functions. These tumor types are usually labeled malignant only when found at sites distant from the point of origin. The term "malignant" can be subjective in certain circumstances and should be used judiciously.

The path to successful treatment of the patient with a tumor begins with recognition of the lesion on a gross level, usually by the caretaker, sometimes by a groomer, or often during a physical exam by a veterinarian. A persistent and enlarging mass is the most commonly recognized lesion but a waxing and waning mass can also be a sign of a tumor such as a mast cell tumor (MCT). Some tumors, such as cutaneous lymphoma, can present initially as ulcerated sites, crusts, or multiple plaques. The next step is the 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, usually with minimal fuss and expense, by aspirating the lesion with a needle and examining the individual cells. In the following chapters, this will be called 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 cytological samples presented here are stained with Wright-Giemsa (W-G) stain unless otherwise indicated. Figure 1.1 is a flow chart showing that the first step is to decide if the lesion is inflammatory, hyperplastic or neoplastic. If the lesion is neoplastic, the next step is to decide if it is benign or malignant. For example, the process can be named (e.g. a pyogranuloma versus lymphoid follicular hyperplasia versus follicular lymphoma), and if it is a neoplastic lymphoma, mitotic activity can be used to determine a likely behavior pattern (benign versus malignant).

Figure 1.2 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 but present in numbers greater than expected from a normal or hyperplastic structure. There is scant inflammation, as shown by the neutrophil in this field, suggesting a benign tumor rather than a hyperplastic response to chronic inflammation.

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 with histopathological evaluation can show the architectural arrangement of the cells, allowing a more definitive diagnosis. This is the critical test that allows hyperplastic growth to be distinguished from 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 this chapter are stained with hematoxylin and eosin (H&E), unless otherwise indicated.

Figure 1.1 Terminology used to categorize a swelling, mass or tumor.

Figure 1.2 Apocrine gland adenoma fine needle aspiration. 50×.

In Figure 1.3, the biopsy shows the architecture of the gland aspirated (see Figure 1.2). There are double rows of small epithelial cells proliferating in a manner that does not invade the adjacent stroma, indicating that this is a benign apocrine gland tumor referred to as an apocrine ductular adenoma.

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. A cytological diagnosis of a potential tumor type is important to help the surgeon make appropriate margin decisions. The surgeon will want wider margins for a potentially aggressive spindle cell tumor than for a probably benign histiocytoma, and tumors that tend to be poorly circumscribed, such as MCTs, will also require wider margins.

Figure 1.4 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. Current practice is to catheterize or collect a free catch if there is any radiographic or ultrasound suggestion of neoplasia, so that there is no seeding of any potential tumor during cystocentesis. Cytological exam, in this case, 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. This cytological diagnosis can be supported by evaluating the urine sample for genetic mutation of the BRAF gene, providing a significant benefit to the patient, as a treatment for infectious cystitis, based just on clinical signs, would not be curative and could delay the true...