Predicting the Stage of Progression-Prognosis

27 May

A patient always wants to know the outcome of his or her disease, whether treated or untreated. This desire is critical in patients suffering from cancer, both before and after treatment. Thus, a variety of biological, cellular, and molecular features of neoplastic development  in the human have been studied, so that the patient may be informed of the most probable outcome of the disease with the greatest degree of accuracy. At the cellular level, malignant neoplasms in the human have been divided according  to histological  grade. The grade of a neoplasm  is deter- mined by its degree of anaplasia, both positional and cytological, although the latter characteris- tic usually predominates  in the final determination  of the grade of a malignant neoplasm. The grading of neoplasms by the pathologist can be done most easily with certain types of carcino- mas, especially epidermoid carcinomas. A grade 1 carcinoma is a highly differentiated, slightly anaplastic carcinoma. At the other extreme, a grade 4 carcinoma is histologically very similar to a carcinosarcoma, a highly malignant, aneuploid, rapidly growing neoplasm. Grades 2 and 3 are intermediate  stages, and their designation  is obviously  somewhat  subjective.  The histological grading of the tumor is always done by grading the most anaplastic  histological  areas of the neoplasm. In general, those neoplasms exhibiting lower grades offer the best prognosis, whereas high-grade malignancies offer a poorer prognosis.

In contrast to the histological grading of neoplasms by the pathologist, many histogenetic types of malignant neoplasms in the human have been subjected to the process of staging for the purposes of prognosis as well as therapy. The staging of neoplasms has been employed to char- acterize the lesion’s invasive and extensive characteristics. For example, in the case of carcinoma of the cervix, a stage zero tumor would be a carcinoma in situ. Carcinoma in situ, of course, would not have invaded deeply into the cervix, although it might have invaded into the surround- ing epithelium.  Such intraepithelial  invasion may also be seen in Paget disease of the nipple, which heralds a malignant neoplasm of the breast. One of the earlier examples of tumor staging was that of invasive cervical carcinoma. This scheme depended on whether the tumor was con- fined to the uterus (stage I), extended into neighboring regions such as the vagina and uterine ligaments (stage II), or showed distant metastases (stage III). The efficacy of therapy of a neo- plasm will vary depending on the stage at which the neoplasm is first treated. However, in order to compare treatment regimens as to their effectiveness, it is important for the physician to make such comparisons at a specific stage.

The International Union Against Cancer in cooperation with the World Health Organiza- tion has recently devised a general method for the clinical staging or description of the extent of neoplastic disease in the human patient. This system has been termed the TNM system (Sobin et al., 1988). In general, it identifies the extent of disease by the use of three symbols:

T = extent of primary neoplasm

N = condition of regional lymph nodes

M = distant metastases

A typical example of such a classification is seen in Table 10.6. This system, unlike attempts to standardize  the histological  classification  of neoplasms,  has enjoyed general acceptance,  with modifications  necessitated  by the histological  type of neoplasm  by most of the international medical community. It is already being used extensively for malignant neoplasms of the breast, oral cavity, urinary bladder, lung, and other organs. Besides the obvious significance of staging in relation to the medical prognosis of the disease itself, staging has found extensive usefulness in the therapy and management of various types of malignant neoplasms. One of the best exam- ples of this is the complicated  staging of Hodgkin disease, a specific type of malignant lym- phoma seen in the human. The method of staging used for this disease is more complicated than

the simple TNM system. Definitive therapy for each stage of the disease has now been designed and has resulted in cure rates for this neoplasm exceeding 90% (Moormeier et al., 1989).

With the refinement of cellular and molecular techniques, a variety of prognostic indica- tors have now been developed and are being employed more frequently, together with grading and staging, in the prognosis of neoplasia. Table 10.7 lists a variety of genetic alterations seen in neoplasms in relation to their predictive effectiveness in the prognosis of specific neoplasms. As noted in the table and as expected, both mutations and amplification or overexpression of proto- oncogenes and tumor suppressor genes result in a poorer prognosis. The fact that mutation in the p53 tumor suppressor gene in patients with colon carcinoma already exhibiting metastases indi- cates a more favorable response might suggest that such cells are more sensitive to some of the

Table 10.7 Molecular Indicators of Prognosis of Neoplasia

chemotherapeutic  regimens utilized. The bcl-6 proto-oncogene  is structurally related to a class of transcription factors involved in the regulation of cell proliferation, differentiation, and organ formation (cf. Offit et al., 1994). The TRK proto-oncogene is one component of the high-affinity nerve growth factor receptor in neuronal cells (cf. Nakagawara et al., 1993). However, it is diffi- cult to explain the favorable prognostic features that result from rearrangement  or overexpres- sion of these two proto-oncogenes.

Not appreciated from the table is the growing evidence that multiple alterations in molecu- lar species such as those depicted in Table 10.7 within the same cell almost always indicate a less favorable prognosis (Zheng et al., 1991; Henry et al., 1993). Again, this is to be expected, as karyotypic instability leads both to the selection of altered genotypes and the further amplifica- tion of a variety of proto-oncogenes.  As yet, however, these molecular prognosticators  (Table 10.7) are only a research tool. Not until many more analyses have been carried out on numerous patients with a variety of different neoplasms will it be possible to add molecular indicators of prognosis to the classical grading and staging methods that are in primary use today.

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