Prognosis and predictive factors

Morphology. Macroscopic and microscopic features reportedly related to prognosis are summarized in Table 6.01 {2348}.

Poor prognosis has been associated with both large and small tumour size, with sessile and ulcerated configuration as contrasted with polypoid cancer, with extensive involvement of the bowel circumference, with the presence of complete bowel obstruction, with perforation, and with serosal deposits.

Fig. 6.44 Dysplasia associated lesion or mass (DALM). A Polypoid lesion. B Raised lesion simulating an ade-
Fig. 6.45 Rectal carcinoma arising in ulcerative colitis. Surface dysplasia overlies invasive carcinoma in this DALM.

Histopathological features related to poor prognosis include deep infiltration of the layers of the wall, extensive involvement of a particular layer, an infil-trative pattern of the invasive edge of the tumour as contrasted to an expansile pattern, and poor differentiation, including signet-ring cell and mucinous adeno-carcinoma, adenosquamous carcinoma, small cell carcinoma and anaplastic carcinoma {1672, 1946, 220, 916, 266}. Mucinous adenocarcinomas of the rectum often present at a later stage and have the poorest overall prognosis {1928}, but the MSI status influences the aggressiveness of this histopathological subtype {1221}. Other studies have shown no significant difference in prognosis between mucinous and non-muci-nous varieties of adenocarcinoma {1543}.

Lymph node metastasis. Metastasis to numerous nodes, those close to the mesenteric margin, at great distance from the primary tumour, or in retrograde lymph nodes, have been associated with poor prognosis while the prognostic value of identification of micrometastasis in lymph nodes by immunohistochemical or molecular techniques is still controversial {1564, 1387, 221}.

Fig. 6.46 Immunoexpression of p53 in intraepithelial neoplasia in ulcerative collitis.

Angiogenesis. Neovascularization of tumour stroma is crucial in supporting tumour growth, and high levels of microvessel density have been interpreted as an adverse prognostic feature {2010}.

Inflammatory response. The presence of an intense inflammatory infiltrate with polymorphonuclear leukocytes (particularly eosinophils), lymphocytes, plasma cells, mast cells and histiocytes, as well as prominent desmoplasia have been associated with improved prognosis {1352}. In the regional lymph nodes, hyperplasia of the paracortical T-lym-phocyte areas and the B-cell germinal centers have also been reported as favourable, as has sinus histiocytosis. Other features of colorectal carcinomas that have been shown to be of prognostic value in some studies include angiolym-phatic invasion, perineural space involvement, extramural venous involvement, peritumoural lymphocytic response, and tumour-infiltrating lymphocytes. Some of these features are evaluated in a classification proposed by Jass {389}. A micro-acinar pattern of growth, defined as discrete, small, relatively regular tubules, is associated with reduced survival {559, 2100}.

Extent of resection. A short longitudinal surgical resection margin (2-5 cm), reflecting the surgical technique employed, has been associated with poor outcome. In rectal cancer, clearance from the circumferential margin is important. The circumferential margin represents the adventitial soft tissue margin closest to the deepest penetration of the tumour. For all segments of the large intestine that are incompletely enveloped by peritoneum or not enveloped, the circumferential margin is created by blunt or sharp dissection at operation. The mesocolic margin in resection specimens of colon cancer is usually well distant from the primary tumour, but the status of the circumferential margin is particularly important in rectal carcinoma due to the anatomic proximity of pelvic structures {15}.

Genetic predictive markers. Some of the genetic alterations identified in colorectal cancers are markers for prognosis {313, 1206}. Allelic loss of chromosome 18q was found to be an adverse prognostic indicator. Other studies reported that loss of chromosomes 17p, 1p, 5q, 8p or 18q, decreased DCC gene expression, p53

Fig. 6.47 Solitary rectal ulcer. A, B Two deep ulcers macroscopically simulating carcinoma.
Fig. 6.48 Solitary rectal ulcer with reactive hyperplastic polyp due to prolapse. This lesion should not be confused with a neoplasm.
Fig. 6.49 Inflammatory cap polyp in a patient with ulcerative collitis.

overexpression, reduced p27KipI expression, high expression of cyclin A, ras gene mutation, expression of enzymes involved in matrix degradation and their inhibitors (cathepsin-L, urokinase, tissue-type plasminogen activator, tissue inhibitors of metalloproteinases), expression of genes involved in apoptosis (bcl2, bax, survivin), expression of cell surface molecules (CD44 and its variants, ICAM1, galectin 3) and metabolic enzymes (GLUT1 glucose transporter, manganese-superoxide dismutase, thymidylate syn-thetase, ornithine decarboxylase, cyclo-oxygenase 2) have prognostic value. In addition, colorectal cancers manifesting MSI-H have been reported to have a lower frequency of metastasis and improved prognosis when compared to microsatellite-stable tumours. Response to therapy. No pathological features have been reported as predictive of therapeutic response, but some molecular alterations have potential as predictive markers. Studies in cell lines of colonic and other carcinomas have shown that in vitro, the status of TP53 is crucial {1382}. The TP53 pathway is closely linked to regulation of the cell cycle and of apoptosis. The presence of wild-type p53 in cell lines is associated with in vitro growth inhibition in response to many chemotherapeutic agents, and with radiation-induced upregulation of p21WAF1/CIP1 and cell cycle arrest. Tumours

Fig. 6.51 Inflammatory cloacogenic polyp with mucous extravasation.

Fig. 6.50 Solitary rectal ulcer. Smooth muscle increased between glands, distorting and displacing them.

manifesting MSI-H may respond to 5-FU-based chemotherapy {1109}, while p53 protein accumulation was associated with lack of response to postoperative adjuvant chemotherapy with 5-FU and levamisole {24}. Chromosome 18q loss was associated with an unfavourable survival rate in this setting.

Fig. 6.51 Inflammatory cloacogenic polyp with mucous extravasation.

Major problems exist in the interpretation of various pathological features as prognostic and predictive markers. Many of these features are interrelated but have been treated for statistical purposes as independent variables in studies. At present, anatomic staging is the mainstay of clinical decision-making.

Table 6.01

Prognostic factors in colorectal carcinoma.

Table 6.01

Prognostic factors in colorectal carcinoma.

Features of the primary tumour

Evidence of vessel invasion

Evidence of host response

Consequences of surgical technique

Anatomic extent of disease (TNM)

Extramural venous involvement

Angiogenesis

Distance between resection margin

Extent of circumferential involvement

Lymphatic vessel or

Local inflammatory and desmo-

and tumour

Bowel obstruction

perineural space involvement

plastic response to infiltrating

Presence of residual tumour

Perforation

tumour

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