Mark L. Silverman

The DCC protein and prognosis in colorectal cancer

BACKGROUND Allelic loss of chromosome 18q predicts a poor outcome in patients with stage II colorectal cancer. Although the specific gene inactivated by this allelic loss has not been elucidated, the DCC (deleted in colorectal cancer) gene is a candidate. We investigated whether the expression of the DCC protein in tumor cells is a prognostic marker in colorectal carcinoma. METHODS The expression of DCC was evaluated immunohistochemically in 132 paraffin-embedded samples from patients with curatively resected stage II and III colorectal carcinomas. The Cox proportional-hazards model was used to adjust for covariates including age, sex, tumor site, degree of tumor differentiation, and use of adjuvant therapy. RESULTS The expression of DCC was a strong positive predictive factor for survival in both stage II and stage III colorectal carcinomas. In patients with stage II disease whose tumors expressed DCC, the five-year survival rate was 94.3 percent, whereas in patients with DCC-negative tumors, the survival rate was 61.6 percent (P<0.001). In patients with stage III disease, the respective survival rates were 59.3 percent and 33.2 percent (P=0.03). CONCLUSIONS DCC is a prognostic marker in patients with stage II or stage III colorectal cancer. In stage II colorectal carcinomas, the absence of DCC identifies a subgroup of patients with lesions that behave like stage III cancers. These findings may thus have therapeutic implications in this group of patients.

Incomplete Renal Tumor Destruction Using Radio Frequency Interstitial Ablation

PURPOSE We evaluate the efficacy of temperature based radio frequency ablation as a potential treatment modality for small (less than 3.5 cm.) renal tumors. MATERIALS AND METHODS We treated 15 patients with a total of 20 tumors with radio frequency ablation through an open surgical approach immediately before partial nephrectomy. All tumors were biopsied before radio frequency ablation treatment. Tumors were heated to 90 to 110C for 6 to 16 minutes (mean 9.1). Tumor ablation was monitored by direct vision and ultrasound. Partial nephrectomy was performed in standard fashion. All specimens were stained with hematoxylin and eosin, and 5 specimens were stained for nicotinamide adenine dinucleotide (NADH) diaphorase activity. RESULTS Tumors ranged from 1.5 to 3.5 cm. (mean 2.4) in greatest dimension. All 20 specimens had evidence of morphologically unchanged tumor and normal renal parenchyma on standard hematoxylin and eosin staining. Of the 5 specimens 4 stained positively for NADH in areas confirmed to be tumor in hematoxylin and eosin stained neighboring sections. There was 1 intraoperative renal pelvic thermal injury requiring pyeloplasty and 2 postoperative caliceal leaks requiring stent placement. CONCLUSIONS In our series radio frequency therapy did not result in total tumor destruction when specimens were examined with hematoxylin and eosin or NADH staining. We believe that radio frequency interstitial tumor ablation of renal cell carcinoma without subsequent tissue resection should continue to be an investigational treatment modality for those who would otherwise undergo partial or radical nephrectomy.

Follicular and Hürthle cell carcinoma: Predicting outcome and directing therapy

BACKGROUND Follicular thyroid cancer is a heterogeneous disease including follicular and Hürthle cell and tumors with and without vascular and major capsular invasion. Analyses of prognosis and risk groups have been criticized for not taking these differences into account. METHODS Retrospective analysis was done of 240 patients treated from 1940 to 1997. RESULTS Ninety-two patients without vascular or major capsular invasion followed up for a median of 14 years had no recurrences or deaths. In the remaining 148 patients, 32 had Hürthle cell and 116 had follicular cell carcinoma. Patients with Hürthle cell carcinoma were significantly older (55 vs 47 years; P = .0014). Lymphatic metastases did not influence outcome. Patients who were at high risk by age and sex, metastases, extent, and size had a 20-year survival rate of 36% for follicular and 35% for Hürthle cell carcinoma; patients at low risk had 20-year survival rates of 94% and 89%, respectively, with no significant difference between follicular and Hürthle cell carcinoma. Recurrences were treated successfully in 33% of patients with follicular carcinoma but never cured in patients with Hürthle cell carcinoma. Bilateral versus unilateral operation or radioiodine for ablation did not alter outcome. CONCLUSIONS Follicular and Hürthle cell carcinoma with minimal capsular invasion behaved benignly. Age and sex, metastases, extent, and size risk criteria differentiate strongly between patients with high-risk and low-risk follicular and Hürthle cell carcinoma. Controlling for risk factors, Hürthle cell and follicular cell carcinomas have similar prognoses.

Carcinomas arising in cystic conditions of the bile ducts. A clinical and pathologic study.

Thirty patients with cystic disease of the bile ducts operated on between 1965 and 1985 were reviewed. Three patients (10%) had a synchronous adenocarcinoma, and in three patients (10%) a metachronous carcinoma developed for a total incidence of malignancy of 20%. All patients died within 1 year of the diagnosis of malignancy. Of 19 benign cysts available for pathologic examination, one third had proliferative epithelial changes, and in two of these patients a metachronous carcinoma developed. Goblet cell metaplasia was prominent in four patients. This suggests the possibility that dysplastic changes and metaplasia of the epithelium could give rise to carcinoma. Resection of benign cysts of the bile ducts is favored, when feasible, in an attempt to decrease the incidence of malignancy.

Hürthle cell carcinoma of the thyroid gland: Prognostic factors and results of surgical treatment

BACKGROUND Hürthle cell carcinomas of the thyroid are unusual variants of well-differentiated thyroid cancers. Considered more aggressive tumors, their optimal treatment is controversial. Our institutions half century of experience, the largest series to date, includes 40 patients with Hürthle cell carcinomas of 1000 well-differentiated thyroid cancers. METHODS A retrospective study was carried out on 40 patients. RESULTS Seventy-two percent were female, with a median age of 53 years. Median follow-up was 9 years. With the AMES risk stratification (age, distant metastasis, capsular extent, tumor size), among the 21 high-risk patients, 10 (48%) had a recurrence or died, with median time to recurrence 3 years (range, 0.5 to 14 years). Of these 10, 5 died of disease, one died of unrelated causes with disease, and 4 are alive with disease. Five recurrences presented as distant metastases. Extent at operation was the strongest predictor of recurrence, occurring in 66% of those with gross extraglandular involvement. CONCLUSIONS The AMES criteria are useful in predicting recurrence and death. Although more aggressive surgery is appropriate for high-risk patients, in general their outlook remains grim.

Crohn's disease and carcinoma: Increasing justification for surveillance?

Carcinoma of the colon that arises in patients with Crohns disease is being reported with increasing frequency. To help clarify the nature of this association, records of 25 patients with Crohns disease and colorectal carcinoma seen from 1957 through 1989 were reviewed. One patient had leiomyosarcoma of the rectum, and two patients had the onset of Crohns disease after the diagnosis and treatment of colorectal carcinoma. Therefore, 22 patients were available for complete retrospective analysis. The median age at diagnosis of Crohns disease was 37 years (range, 15–67 years), and the median age at diagnosis of carcinoma was 54.5 years (range, 32–76 years). The median duration of symptoms preceding the discovery of colorectal carcinoma was 18.5 years (range, 0–32 years). Carcinoma arose in colonic segments with known Crohns disease in 77 percent of patients, and six patients (27 percent) had associated colonic mucosal dysplasia. One lesion was classified as Dukes A, nine lesions were Dukes B, five lesions were Dukes C, and seven lesions were Dukes D. Patients with an onset of Crohns disease before the age of 40 years had primarily Dukes C or D lesions and consequently poor survival. Most patients presented with nonspecific signs and symptoms, with nothing to distinguish the activity of the Crohns disease from the presence of colorectal neoplasm. Younger patients with long-standing Crohns disease should be considered for colonic surveillance to permit earlier diagnosis and treatment of potential colorectal carcinoma.

p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations.

Defects in the mechanisms controlling the cell cycle are crucial in cell transformation and/or tumour progression. p21WAF1/CIP1 is an inhibitor of cyclin‐dependent kinases, induced by p53‐dependent and p53‐independent pathways, which can block progression through the cell cycle. p21WAF1/CIP1 expression has been investigated immunohistochemically in a series of 191 patients with colorectal cancer of known p53 status. The purpose of the study was two‐fold: to assess the relationship between p21WAF1/CIP1 immunoreactivity and p53 alterations, and to evaluate the prognostic significance of p21WAF1/CIP1 expression. In 96 carcinomas (51 per cent), p21WAF1/CIP1 was expressed in over 10 per cent of tumour cells, whereas in 26, p21WAF1/CIP1 was detected in under 10 per cent of neoplastic cells; 69 tumours lacked p21WAF1/CIP1 expression. Immunoreactivity was more frequent in tumours of the right colon (p < 0·003) and was inversely correlated with tumour stage (p < 0·03), p53 gene mutations (p < 0·0007), p53 protein accumulation (p < 0·019), and Bcl‐2 expression (p < 0·0005). In univariate analysis, down‐regulation of p21WAF1/CIP1 expression was associated with poor overall (p = 0·0022) and disease‐free survival (p = 0·0009). Multivariate analysis, however, did not confirm any independent prognostic significance of p21WAF1/CIP1 expression. The results indicate that p21WAF1/CIP1 is associated with abnormal accumulation of p53 protein and the occurrence of p53 gene mutations in colorectal cancer and that lack of p21WAF1/CIP1 expression is correlated with reduced patient survival in univariate analysis. These data underline the crucial pathogenetic role of the p53–p21WAF1/CIP1 pathway in carcinomas of the large bowel. Copyright

Gastric smooth muscle tumors: diagnostic dilemmas and factors affecting outcome.

Abstract. We reviewed the 46 gastric stromal tumors that were treated at our institution between 1958 and 1992. The most common presenting symptoms were gastrointestinal bleeding, pain, and fatigue or malaise. The tumors ranged from 4 to 150 mm, with surgery most often being a wedge excision or partial gastrectomy. Abdominal computed tomography was the most specific diagnostic test obtained preoperatively. Factors associated with decreased survival included size ≥ 8 cm (p = 0.02), more than 0–3 mitoses per 10 HPF (p < 0.001), positive margins or unresectability (p = 0.008), and tumor pathologic grade II or more (p = 0.004). These tumors have an unpredictable behavior. Surgical resection with negative margins remains the best therapy, but resection for palliation is sometimes indicated as it can be associated with prolonged survival.

Lymphatic and blood vessel invasion in breast carcinoma: A useful prognostic indicator?

Recent studies have presented compelling evidence to support the prognostic importance of peritumoral lymphatic and blood vessel invasion in breast cancer. This parameter appears to be particularly valuable in the hands of pathologists who are experienced in diseases of the breast and who have developed standardized criteria and expertise in their recognition. However, its application is seriously hampered by various factors, especially interobserver and intraobserver differences in interpretation. A more uniform and objective approach, such as the use of immunohistochemical techniques, may be helpful in overcoming these obstacles. This may render lymphatic and blood vessel invasion a reliably reproducible indicator that a practicing pathologist can utilize to recognize high-risk patients and recommend appropriate therapy. The extension of this approach to evaluate neoplasms of other organs--such as malignant melanomas and thyroid, uterine, and cervical carcinomas--should also be explored.

Brain necrosis after radiotherapy for primary intracerebral tumor.

Radiotherapy is a standard postoperative treatment for cerebral glioma. We have observed the onset of symptoms related to brain necrosis, as opposed to recurrent tumor, in surviving patients. This has been manifest as dementia with a computed tomographic pattern of low density in the frontal lobe uninvolved with tumor, but within the field of radiotherapy. Two patients presented with mass lesions also unrelated to recurrent tumor. We question the necessity of full brain irradiation and suggest that radiotherapy techniques be altered to target the tumor and not encompass the entire brain.