Androgen-independent prostate cancer progression in the TRAMP model.

We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecular mechanisms involved in the initiation and progression of prostate cancer. TRAMP mice display high grade prostatic intraepithelial neoplasia or well-differentiated prostate cancer by 10-12 weeks of age. To test the hypothesis that molecular events leading to androgen independence and metastasis can occur early in the natural history of prostate cancer yet remain silent until selective pressures such as androgen deprivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRAMP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 18 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T24) controls. Median T12/18 and T12/24 genitourinary (GU) weight was significantly less than T18 and T24, respectively. In addition, T12/24 GU weight was significantly greater than T12/18. Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice. All tumors that developed in castrated mice were poorly differentiated in contrast to 27% in noncastrated controls. Although castration significantly decreased GU tumor burden, overall progression to poorly differentiated and metastatic disease was not ultimately delayed. These results demonstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore, early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model to identify specific molecular mechanisms that determine androgen sensitivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.

Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast.

PURPOSE: To determine the 15-year outcome for women with ductal carcinoma in situ (DCIS, intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. PATIENTS AND METHODS: An analysis was performed of 270 intraductal breast carcinomas in 268 women from 10 institutions in Europe and the United States. In all patients, breast-conserving surgery included complete gross excision of the primary tumor followed by definitive breast irradiation. When performed, pathologic axillary lymph node staging was node-negative (n=86). The median follow-up time was 10.3 years (range, 0.9 to 26.8). RESULTS: The 15-year actuarial overall survival rate was 87%, and the 15-year actuarial cause-specific survival rate was 96%. The 15-year actuarial rate of freedom from distant metastases was 96%. There were 45 local recurrences in the treated breast, and the 15-year actuarial rate of local failure was 19%. The median time to local failure was 5.2 years (range, 1.4 to 16.8). A number of clinical and pathologic parameters were evaluated for correlation with local failure, and none were predictive for local failure (all P > or = .15). CONCLUSION: The results from the present study demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of DCIS of the breast using breast-conserving surgery and definitive breast irradiation. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of DCIS of the breast.

Vascularity of proliferative breast disease and carcinoma in situ correlates with histological features.

The level of vascularity within an invasive breast carcinoma is a predictor of metastatic potential and survival. However, little is known about the vascular potential and prognostic value of angiogenesis in preinvasive breast pathology. Women with proliferative breast disease or carcinoma in situ are at increased risk of developing invasive breast cancer. This relative risk increases in correlation with defined histopathological features. We asked whether these early proliferative lesions and carcinoma in situ were capable of inducing a vascular supply. Vascularity in preinvasive archival paraffin-embedded breast tissue from 90 patients was quantified by immunohistochemical identification of vessels using anti-von Willebrand factor. Vascular scores were analyzed with respect to histopathological diagnosis, age at diagnosis, and presence of coincident invasive disease. These data indicate that: (a) the vascularity of histopathologically normal epithelium is greater in breasts containing invasive disease than in breasts lacking invasive disease; (b) simple proliferative breast disease induces a vascular supply greater than that of normal breast epithelium; and (c) vascularity increases in proportion to epithelial lesion progression and relative risk of invasion. These studies indicate that the vascularity of preinvasive breast pathology may be a clinically useful predictor of invasive breast cancer.

Intravesical and intravenous therapy of human bladder cancer by the herpes vector G207.

G207, a conditionally replicating herpes vector, efficiently kills human bladder cancer cells in vitro. To evaluate the therapeutic potential of G207, we have established three in vivo models similar to the clinical situation. In vivo, G207 was intraneoplastically, intravesically, or intravenously inoculated in nude mice. Intraneoplastic inoculation into subcutaneous tumor caused significant tumor growth inhibition. Intravesical inoculation of G207 also caused decreased tumor growth in an orthotopic human bladder cancer model. Furthermore, multiple intravenous inoculation markedly inhibited subcutaneous tumor growth. These results suggest that intravesical therapy with G207 is effective for localized bladder tumor, especially for carcinoma in situ (CIS), and intravenous therapy with G207 is promising for invasive or metastasized bladder tumor.

Results of conservative surgery and radiation for mammographically detected ductal carcinoma in situ (DCIS).

PURPOSE: The role of conservative surgery and radiation for mammographically detected ductal carcinoma in situ (DCIS) is controversial. In particular, there is little data for outcome with radiation in a group of patients comparable to those treated with local excision and surveillance (mammographic calcifications < or = 2.5 cm, negative resection margins, negative postbiopsy mammogram). This study reports outcome of conservative surgery and radiation for mammographically detected DCIS with an emphasis on results in patients considered candidates for excision alone. METHODS AND MATERIALS: From 1983 to 1992, 110 women with mammographically detected DCIS (77% calcifications +/- mass) and no prior history of breast cancer underwent needle localization and biopsy with (55%) or without a reexcision and radiation. Final margins of resection were negative in 62%, positive 7%, close 11%, and unknown 20%. The median patient age was 56 years. The most common histologic subtype was comedo (54%), followed by cribriform (22%). The median pathologic tumor size was 8 mm (range 2 mm to 5 cm). Forty-seven percent of patients with calcifications only had a negative postbiopsy mammogram prior to radiation. Radiation consisted of treatment to the entire breast (median 50.00 Gy) and a boost to the primary site (97%) for a median total dose of 60.40 Gy. RESULTS: With a median follow-up of 5.3 years, three patients developed a recurrence in the treated breast. The median interval to recurrence was 8.8 years and all were invasive cancers. Two (67%) occurred outside the initial quadrant. The 5- and 10-year actuarial rates of recurrence were 1 and 15%. Cause-specific survival was 100% at 5 and 10 years. Contralateral breast cancer developed in two patients. There were too few failures for statistical significance to be achieved with any of the following factors: patient age, family history, race, mammographic findings, location primary, pathologic size, histologic subtype, reexcision, or final margin status. However, young age, positive or close margins, and the presence of a mass without calcifications had a trend for an increased risk of recurrence. There were no recurrences in the subset of 16 patients who would be candidates for surveillance by Lagios' criteria. CONCLUSION: For selected patients, conservative surgery and radiation for mammographically detected DCIS results in a low risk of recurrence in the treated breast and 100% 5- and 10-year cause-specific survival. Improved mammographic and pathologic evaluation results in better patient selection and reduces the risk of the subsequent appearance of DCIS in the biopsy site. The identification of risk factors for an ipsilateral invasive breast recurrence is evolving.

Implant metastasis of gallbladder carcinoma in situ in a cholecystectomy scar: a case report.

A subcutaneous mass within the scar left by cholecystectomy with common bile duct exploration and T-tube drainage developed 6 years after surgery. Pathologic examination of this mass showed features of atypical villous hyperplasia, similar to that identified within the previously removed gallbladder, but with additional foci of carcinoma in situ. Since excision of the mass, the patient has had persistent fluid collections requiring frequent aspiration. Cytologic analysis of the fluid has revealed tumor cells. The cause of this spread has been unclear. Few literature reports have identified biliary drainage techniques as a source for metastatic seeding. The malignant or metastatic potential of severe dysplasia or carcinoma in situ of the gallbladder associated with T-tube drainage and implantation in the drainage tract is previously unreported.

The new era in breast cancer. Invasion, size, and nodal involvement dramatically decreasing as a result of mammographic screening.

OBJECTIVE: To describe the magnitude of changes and opportunities that may arise for simplified surgical procedures for women with breast cancer because of the decreasing size and lymph node involvement in invasive breast cancer and earlier presentation of noninvasive and invasive breast cancer. DESIGN AND MAIN OUTCOME ASSESSMENT: Cases (N=1001) of breast cancer from a tertiary and a community hospital between 1989 and 1993 were analyzed for invasion, size, nodal status, and change over time. RESULTS: Ductal carcinoma in situ constituted 14% and 18% of the cancers at the two hospitals. At the tertiary and community hospitals, the mean maximum diameters were 2.1 and 2.0 cm, respectively, and the median maximum diameters were 1.5 and 1.7 cm, respectively, for invasive breast cancer. Twenty-nine percent and 28%, respectively, were 1 cm or less in diameter. Axillary nodal metastases occurred in only 31% of the invasive cancers (tertiary hospital); only 10% had more than three nodal metastases. In the T1a and T1b cases, nodal metastases occurred in only 10% and 43% of the positive nodes were solitary; only 16% had more than three nodal metastases. The proportion of ductal carcinoma in situ, T1a and T1b, and node-negative cases increased significantly over time. CONCLUSIONS: Within the next decade, the proportion of all breast cancers that are ductal carcinoma in situ will approach 33%, and invasive cancers will approach 1 cm in median maximum diameter. Therapy simplification will be logical because of very small size, low risk of recurrence after breast conservation, and excellent prognosis, and might include increased breast conservation, avoidance of axillary nodal dissection, and omission of radiation therapy to conserve breasts. Adjuvant therapy will be based on the prognostic features of the primary cancer and findings from careful histologic examination of the sentinel lymph nodes.

The impact of microinvasion on axillary node metastases and survival in patients with intraductal breast cancer.

A rational approach to the local treatment of intraductal breast cancer continues to generate considerable debate. However, the finding of an invasive component in intraductal breast cancer is widely regarded as an appropriate indication for axillary node dissection as part of the local treatment and staging of this disease. Despite this view, the natural history of patients with intraductal breast cancer with foci of microinvasion is poorly defined. Between 1965 and 1988, 41 patients with this pathologic finding of intraductal carcinoma with foci of microinvasion were seen at the UCLA Medical Center. Twenty-three patients presented with mammographic abnormalities, while 17 patients presented with a palpable mass. One patient presented with Paget's disease of the nipple. Thirty-three patients underwent axillary node dissection as part of their local treatment. No lymph node metastases were identified. The median follow-up in 37 patients was 47 months. There have been no local recurrences and no deaths from recurrent breast cancer. Intraductal breast cancer associated with microinvasion appears to be an extremely favorable lesion with minimal risk of nodal metastases.

Risk factors in carcinoma in situ of the urinary bladder. Dutch South East Cooperative Urological Group.

OBJECTIVES: In this article we describe the long-term follow-up of patients with carcinoma in situ (CIS) of the urinary bladder and examine whether the extent of CIS, the presence of associated papillary tumors, or the response to treatment influence the course of the disease. METHODS: Fifty-two patients with CIS of the bladder, treated in a randomized prospective study, are described. In 23 patients with concomitant papillary tumors all macroscopically visible lesions were completely resected transurethrally (TUR). CIS was histologically confirmed in all patients by biopsy, 29 of whom had primary CIS. The patients were treated with intravesical mitomycin, bacille Calmette-Guérin (BCG)-RIVM or BCG-Tice and followed regularly by urine cytology, cystoscopy, and biopsy. RESULTS: Complete response was achieved in 65% of the patients. Of these responders, 24% later had a recurrence of CIS or a superficial tumor and 18% had progressive disease (PD). In the nonresponding patients, progression occurred in 67%. In the whole group, PD was seen in 35% of the patients, and radical cystectomy was performed in 21%. The disease-related death rate was 13%. The risk for recurrence or PD was not higher in patients with more extensive CIS, defined as three or more positive biopsy results or when CIS was associated with papillary tumors compared to patients with one or two biopsy specimens positive for CIS or CIS alone. Nonresponding patients showed a significantly higher progression rate and cystectomy rate than responding patients (P = 0.0012 and 0.008, respectively). CONCLUSIONS: CIS of the bladder is a malignancy with a poor prognosis, especially in patients not responding after intravesical treatment. Early detection and adjuvant intravesical treatment after TUR of concomitant papillary tumors are required. In patients not responding after intravesical treatment, radical surgery is necessary before progression occurs. The number of biopsies positive for CIS, not the presence of concomitant superficial tumors, was an indicator for progression or recurrence.

High flow malignant priapism with isolated metastasis to the corpora cavernosa.

Malignant priapism is a rare disease with only 88 reported cases. We present a case of a patient with priapism secondary to isolated metastasis to corpora cavernosa from bladder tumor. Metastasis to penis usually represents evidence of a more widespread disease in 80% to 90% of the patients. Rarely, as in this case, the metastasis is solitary.

Management of superficial G2 (pTa and pT1) bladder cancer.

A total of 143 patients with superficial G2 (pTa, pT1) bladder cancer (48 G2pTa; 95 G2pT1) presenting between 1970 through 1987 were reviewed. Of 48 patients with G2pTa followed for up to eighteen years, G3 recurrence developed only in 1 (2.0%), and invasive cancer (greater than pT2) developed only in 2 (4.2%). They both received radiotherapy and have responded completely. There have been no cancer-related deaths. In contrast, in the 95 patients in whom the basement membrane had been breached (pT1), higher grade tumor (G3) developed in 11 (11.5%), and 15 (16%) had recurrences with invasion of muscle (greater than pT2). Among these there were 7 (7.3%) cancer-related deaths.

Upper urinary tract involvement in patients with bladder carcinoma in situ (Tis): its impact on management.

OBJECTIVES: To analyze the biologic behavior and etiologic mechanism of upper-tract involvement in patients with bladder cancer in situ (Tis) and its impact on management of these patients. METHODS: One hundred thirty-eight patients with bladder Tis, 786 with superficial bladder cancer, and 179 patients with invasive bladder cancer treated by cystectomy were studied: 34 (24.6%), 18 (2.3%), and 7 (3.9%) developed upper-tract involvement in each group, respectively. Sixty-three patients with primary urothelial upper-tract tumors were also studied. Taking progression-free survival as an end point, univariate and multivariate analyses were performed. RESULTS: The upper-tract recurrence rate was significantly higher in patients with bladder Tis than in patients with superficial bladder tumors (P <0.001); it was also significantly higher in patients treated with cystectomy because of bladder Tis compared with those treated because of invasive tumors (P <0.01). Patients with bladder Tis and upper-tract involvement showed high rates of upper-tract bilaterality (32.3%) and prostate involvement (67.4%). On pathologic examination, the upper tract showed predominantly superficial (Ta-T1-Tis) tumors (67.4%) and distal ureter location as the only finding (47%). In patients with bladder Tis, upper-tract involvement alone does not have a negative impact on the survival rate according to univariate and multivariate analysis (P = NS). CONCLUSIONS: In patients with bladder Tis, upper-tract involvement represents a diffuse process; therefore, a close evaluation of both the prostate and the upper tract is recommended. Upper-tract involvement has no impact on bladder-preservation strategy. Many of these patients could also be offered a conservative management for the involved upper tract.

Treatment of carcinoma in situ of the bladder with doxorubicin (adriamycin).

Fifty-five patients with carcinoma in situ of the bladder have been treated with intravesical Adriamycin, the longest follow-up being over 2.5 years. Side-effects were negligible. Primary carcinoma in situ shows the highest overall response rate, with over 80%, followed by secondary carcinoma in situ with no tumours, with 67%; in the presence of active tumour only 25% of patients treated showed any real improvement. Adriamycin is recommended for the conservative management of primary carcinoma in situ.

Intravesical chemotherapy in urinary bladder cancer.

Monthly instillation therapy with Adriamycin in a standardized dose of 300 ng/ml/h together with a phosphate buffer at pH 7.4 seems to give satisfactory results in patients with primary bladder carcinoma in situ and in patients with secondary carcinoma in situ of the bladder who have previously received full courses of irradiation. The side-effects are transient and few.

Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder.

BACKGROUND: Early case reports suggest more frequent and rapid recurrences of carcinoma of the gallbladder after laparoscopic cholecystectomy (LC) than after open cholecystectomy. This cancer has a poor prognosis and occurs in 1 percent of patients who undergo cholecystectomies. STUDY DESIGN: A recent community hospital series of gallbladder carcinoma (GBC) was reviewed and the total reported experience of GBC after LC was compiled. Diagnostic findings were compared for patients with GBC and a consecutive series of 24 patients who had LC for benign disease. RESULTS: Nine patients with GBC were found among 928 patients who had undergone cholecystectomy (0.97 percent incidence). Compared to patients without GBC, patients with carcinoma were older, had thicker gallbladder walls, and had more abnormalities detected intraoperatively (all p < or = 0.05). Recurrence of GBC occurred more rapidly after LC, and in diffuse peritoneal and port sites when compared with recurrence patterns after open cholecystectomy. CONCLUSIONS: In patients with GBC, LC may be sufficient when the disease is confined to the gallbladder mucosa and the gallbladder is excised intact without bile spillage. However, patients whose gallbladders are torn during dissection or patients who have invasive tumors should undergo laparotomy and local reexcision. In situ GBC can be implanted if the organ is torn during dissection. When gallbladders with suspicious wall thickening or adhesions are noted at LC, especially in older patients, the procedure should be converted to open cholecystectomy.

Management of ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is an early, localized stage of breast carcinoma that has an excellent prognosis when it is properly treated. The significant increase in the frequency of diagnosis of DCIS in recent years is the result of both better recognition of DCIS among pathologists and widespread use of screening mammography. Multicentricity, bilaterality and histologic subtype are important considerations in the management of this disease. The clinical presentation of DCIS is the presence of either a palpable mass or a mammographic abnormality, most frequently in the form of an area of microcalcifications. For several decades, total mastectomy was considered the appropriate treatment for DCIS, and it should still be considered the standard to which more conservative forms of treatment must be compared. Breast conservation surgery has been used with increasing frequency in the treatment of DCIS but the adequacy of this approach remains subject to controversy. Segmental mastectomy alone may be applied with caution in carefully selected patients, while the rest of the patients undergoing breast conservation surgery should be treated with breast irradiation. Axillary node dissection is generally considered unnecessary in the treatment of DCIS. There is no role for adjuvant chemotherapy in the management of this disease. The role of tamoxifen in the treatment of DCIS is not clearly defined and it should be given only to patients enrolled in clinical trials. Ongoing research should clarify the controversies surrounding DCIS and enable us to define the optimal management for this disease.

Squamous carcinoma of the colon: primary or metastatic?

A patient is reported who developed a tumour of the transverse colon, which at presentation appeared histologically and clinically to be a primary squamous cell keratinizing carcinoma, arising from an area of in situ carcinoma in the colonic epithelium. However, she had had a stage 1 cervical carcinoma treated by Wertheim's hysterectomy 7 years previously and although there were no other signs of recurrence, this raised the possibility that the lesion might be metastatic. Thirty-seven previously reported cases of primary squamous carcinoma of the colon and those of squamous carcinoma metastasizing to the colon and mimicking primary lesions are reviewed.

Recurrence after breast ablation for ductal carcinoma in situ.

Three patients are described having locally recurrent invasive breast cancer after breast ablation for ductal carcinoma in situ (DCIS). All had initially extensive type ductal carcinoma in situ without evidence of invasion in adequately sampled microscopical studies. One patient developed a scar recurrence and lung metastases 2 years after surgery; one patient showed a scar recurrence 3 years after operation and one patient had a recurrence in the chest wall 27 years after surgery. Although generally stated that ablative therapy offers a 100% cure in case of DCIS, these cases illustrate that local recurrence may occur. Possible causes and preventions are discussed.

Tumor size and axillary metastasis, a correlative occurrence in 1244 cases of breast cancer between 1980 and 1995.

A review of 1244 breast cancer cases from the Tumor Registry of Northwest Community Hospital between 1980 and 1995 was carried out to investigate the incidence of axillary metastasis. There were 442 patients (35.45%) with positive nodes. The small lesions were graded to ascertain if size and grade of small tumors can be used to predict axillary metastasis. One hundred and seventy-nine cases of < or = 1.0 cm were retrospectively reviewed by one pathologist. Tumors <0.4 cm had negative nodes. Those with nuclear and histologic grades of 1 had 3% positive nodes, the remainder had positive nodes ranging from 11% to 19%. Infiltrating duct cancers of nuclear grade 3, histologic grade 2, and positive nodes, showed a 40% mortality. Eighteen patients died in the 0.5-1.0 cm tumor size range, mostly of histologic grade 2 and nuclear grade 3. Nuclear and histologic grade 1 tumors with infiltrating duct cancers had negative nodes and showed a good prognosis. Based on this study, node dissection can be omitted in these patients and in those with tumors < or = 0.4 cm. For all other lesions, full axillary node dissection and detailed pathologic examination is still the gold standard for evaluating the axilla.

Pathology and treatment of impalpable breast lesions.

With the increasing use of mammography, more needle-localized breast biopsies (NLBB) are being done. The purpose of this study was to analyze the pathology of impalpable breast lesions and the impact of NLBB on treatment strategies. From 1985 to 1990, 1,605 NLBB were performed, of which 321 (20%) were malignant. Twenty-five percent of malignant biopsies demonstrated in situ disease only. The average size of all lesions detected was 16 mm, and, for invasive cancer, 12 mm. Eighteen percent of invasive cancers had metastasized to the axillary lymph nodes. Surgical management consisted of mastectomy in 74% of patients and breast conservation treatment (BCT) in 26%. No significant difference in surgical management for women 50 years of age or younger compared with those older than 50 years of age was noted. Although the use of BCT for eligible women is recommended by the National Institutes of Health, it is not widely practiced, possibly reflecting less physician acceptance of BCT. These observations suggest that the detection of smaller, impalpable breast cancers has had no impact on treatment strategies.