Quantitative nuclear morphometry by image analysis for prediction of recurrence of ductal carcinoma in situ of the breast.

Clinical management of ductal carcinoma in situ (DCIS) remains a challenge because significant proportions of patients experience recurrence after conservative surgical treatment. Unfortunately, it is difficult to prospectively identify, using objective criteria, patients who are at high risk of recurrence and might benefit from additional treatment. We conducted a multi-institutional, collaborative case-control study to identify nuclear morphometric features that would be useful for identifying women with DCIS at the highest risk of recurrence. Tissue sections of archival breast tissue of 29 women with recurrent and 73 matched women with nonrecurrent DCIS were stained for DNA, and nuclei in the DCIS lesions were evaluated by image analysis. A clear correlation between mean fractal2_area (FA2) and nuclear grade was observed (P < 0.001), allowing an objective determination of nuclear grade. Several nuclear morphometric features, including mean and variance of variation of radius, mean area, mean and variance of frequency of high boundary harmonics (FQH), and variance in sphericity, were found to be useful in discriminating recurrent from nonrecurrent DCIS subjects. However, the nuclear features associated with recurrence differed between high- and low-grade lesions. For lesions with high FA2 (nuclear grade 3), mean variation of radius, mean FQH, and mean area alone yielded recurrence odds ratios of 4.55 [95% confidence interval (CI) 0.45-45.96], 3.86 (95% CI, 0.88-16.98), 2.90 (95% CI, 0.31-27.2), respectively. Using a summed feature model, high-FA2 lesions showing three poor prognostic features had an odds ratio of 15.63 (95% CI, 1.22-200), compared with those with zero or one poor prognostic feature. Lesions with low mean FA2 (nuclear grade 1 or 2) showing high variances in sphericity and FQH had an odds ratio of 7.71 (95% CI, 1.77-33.60). Addition of other features did not enhance the odds ratio or its significance. These results suggest that nuclear image analysis of DCIS lesions may provide an adjunctive tool to conventional pathological analysis, both for the objective assessment of nuclear grade and for the identification of features that predict patient outcome.

The influence of margin width on local control of ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ is a non-invasive carcinoma that is unlikely to recur if completely excised. Margin width, the distance between the boundary of the lesion and the edge of the excised specimen, may be an important determinant of local recurrence. METHODS: Margin widths, determined by direct measurement or ocular micrometry, and standardized evaluation of the tumor for nuclear grade, comedonecrosis, and size were performed on 469 specimens of ductal carcinoma in situ from patients who had been treated with breast-conserving surgery with or without postoperative radiation therapy, according to the choice of the patient or her physician. We analyzed the results in relation to margin width and whether the patient received postoperative radiation therapy. RESULTS: The mean (+/-SE) estimated probability of recurrence at eight years was 0.04+/-0.02 among 133 patients whose excised lesions had margin widths of 10 mm or more in every direction. Among these patients there was no benefit from postoperative radiation therapy. There was also no statistically significant benefit from postoperative radiation therapy among patients with margin widths of 1 to <10 mm. In contrast, there was a statistically significant benefit from radiation among patients in whom margin widths were less than 1 mm. CONCLUSIONS: Postoperative radiation therapy did not lower the recurrence rate among patients with ductal carcinoma in situ that was excised with margins of 10 mm or more. Patients in whom the margin width is less than 1 mm can benefit from postoperative radiation therapy.

A prognostic index for ductal carcinoma in situ of the breast.

BACKGROUND: There is controversy and confusion regarding therapy for patients with ductal carcinoma in situ (DCIS) of the breast. The Van Nuys Prognostic Index (VNPI) was developed to aid in the complex treatment selection process. METHODS: The VNPI combines three significant predictors of local recurrence: tumor size, margin width, and pathologic classification. Scores of 1 (best) to 3 (worst) were assigned for each of the 3 predictors and then totaled to give an overall VNPI score ranging from 3 to 9. Three hundred thirty-three patients with pure DCIS treated with breast preservation (195 by excision only and 138 by excision plus radiation therapy) were studied with detection of local recurrence as the end point. RESULTS: There was no statistical difference in the 8 year local recurrence free survival in patients with VNPI scores of 3 or 4, regardless of whether or not radiation therapy was used (100% vs. 97%; P = not significant). Patients with VNPI scores of 5, 6, or 7 received a statistically significant 17% local recurrence free survival benefit when treated with radiation therapy (85% vs. 68%; P = 0.017). Patients with scores of 8 or 9, although showing the greatest relative benefit from radiation therapy, experienced local recurrence rates in excess of 60% at 8 years. CONCLUSIONS: DCIS patients with VNPI scores of 3 or 4 can be considered for treatment with excision only. Patients with intermediate scores (5, 6, or 7) show a 17% decrease in local recurrence rates with radiation therapy. Patients with VNPI scores of 8 or 9 exhibit extremely high local recurrence rates, regardless of irradiation, and should be considered for mastectomy.

Predicting axillary node positivity in patients with invasive carcinoma of the breast by using a combination of T category and palpability.

BACKGROUND: In spite of the development of numerous new tumor markers, axillary lymph node status continues to be the single most important prognostic variable regarding survival of patients with carcinoma of the breast. This study was undertaken to determine whether or not the combination of T category (TNM staging system) and palpability would be a better predictor of nodal positivity than T category alone. STUDY DESIGN: Clinical and pathologic data were analyzed for 1,554 patients who underwent axillary lymph node dissection as part of their treatment for invasive carcinoma of the breast. Data were analyzed by the primary lesion's T category and whether or not the lesion was palpable. RESULTS: Five hundred fifty-one (35 percent) of 1,554 axillary node dissections contained metastases. The probability of nodal involvement was significantly higher and the average tumor diameter was slightly, but significantly, larger for palpable T1b, T1c, and T2 lesions when compared with nonpalpable lesions within the same T category (all p values less than or equal to 0.003). The probability of lymphatic tumor emboli or vascular invasion was generally higher for palpable lesions compared with nonpalpable lesions and increased as lesions got larger. The percentage of patients with low nuclear grade and favorable histology was generally lower for patients with palpable lesions compared with those having nonpalpable lesions and decreased as lesions got larger. CONCLUSIONS: Nodal positivity was significantly higher for palpable T1b, T1c, and T2 carcinoma of the breast when compared with nonpalpable carcinoma of the breast within the same T category. The combination of T category and palpability was a more accurate predictor of nodal positivity than T category alone.

Prognostic classification of breast ductal carcinoma-in-situ.

We present a new prognostic classification designated the Van Nuys classification for ductal carcinoma-in-situ (DCIS). The classification combines high nuclear grade and comedo-type necrosis to predict clinical recurrence. Three groups of DCIS patients were defined by the presence or absence of high nuclear grade and comedo-type necrosis: 1--non-high-grade DCIS without comedo-type necrosis, 2--non-high-grade DCIS with comedo-type necrosis, 3--high-grade DCIS with or without comedo-type necrosis. There were 31 local recurrences in 238 patients after breast-conservation surgery 3.8% (3/80) in group 1, 11.1% (10/90) in group 2, and 26.5% (18/68) in group 3. The 8-year actuarial disease-free survivals were 93%, 84%, and 61%, respectively (all p < or = 0.05). The Van Nuys classification defines three distinct and easily recognisable groups, each of which has a different likelihood of local recurrence if treated with breast conservation.

Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast.

The 10-year results of 300 patients with ductal carcinoma in situ (DCIS) without microinvasion are reported; 167 treated with mastectomy and 133 treated with excision and radiation therapy. There was a significant difference in disease-free survival at 10 years, in favour of those treated with mastectomy, 98% versus 81% (P = 0.0004). Multivariate analysis confirmed nuclear grade as the only significant predictor of local recurrence (P = 0.02) or invasive local recurrence (P = 0.03) in patients with DCIS treated with excision and radiation therapy. There was no difference in breast cancer-specific survival or overall survival between the two treatment groups.

Can intraductal breast carcinoma be excised completely by local excision? Clinical and pathologic predictors.

BACKGROUND: Microscopic evaluation of excised intraductal breast carcinoma (DCIS) specimens using a serial subgross technique reveals that in many patients the lesion is larger than expected, often making complete excision impossible with less than a true quadrantectomy. Data is presented on 181 patients with DCIS in whom the initial biopsy was performed using a more cosmetic wide local excision rather than a true quadrantectomy. METHODS: Clear margins were defined as no tumor within 1 mm of any inked or dyed margin. All of these patients subsequently underwent mastectomy or reexcision of the initial biopsy site. This allowed pathologic evaluation for residual disease. RESULTS: At mastectomy or reexcision, 76% of patients with initially involved margins had residual DCIS, as did 43% of patients with initially clear margins (P < 0.0001). Larger tumor size was a statistically significant predictor of initial margin involvement and residual DCIS (P < 0.05). Patients with comedo-DCIS had a greater tendency toward positive initial histologic margins and residual DCIS, but this trend was not statistically significant (P < 0.1). CONCLUSION: DCIS presents major problems to both surgeons and pathologists. It is difficult to excise completely using a wide local excision. Histologically negative margins do not guarantee that residual DCIS has not been left behind. Inadequate excision of the primary lesions may be the most important cause of local failure after conservative treatment for intraductal breast carcinoma.

Infiltrating lobular carcinoma. Is it different from infiltrating duct carcinoma?

BACKGROUND: Infiltrating lobular carcinomas (ILC) represent approximately 10% of all breast cancers. The literature is mixed regarding their prognosis when compared with infiltrating duct carcinomas (IDC). There are few data regarding the treatment of ILC with radiation therapy. METHODS: The clinical, pathologic, laboratory, and survival data of 161 patients with ILC were compared with the data of 1138 patients with IDC. RESULTS: ILCs were larger, more difficult to excise completely, and more difficult to diagnose clinically. All prognostic factors measured were more favorable for ILC. Nodal positivity for ILC was 32%, compared with 37% for IDC (P = 0.22). The 7-year disease-free Kaplan-Meier survival (DFS) was 74% for patients with ILC and 63% for patients with IDC (P < 0.03). The 7-year breast cancer specific survival (BCSS) was 83% for patients with ILC and 77% for patients with IDC (P < 0.04). Selected patients with smaller lesions were treated with excision and radiation therapy. Patients with ILC treated with radiation therapy had a better DFS and BCSS than did patients with IDC treated with radiation therapy. CONCLUSIONS: ILCs often are homogeneous, small cell tumors of low nuclear grade. Their desmoplastic reaction may be absent or less marked than that of IDC, making them more difficult to palpate and to visualize mammographically. Despite this, they can be treated successfully with either mastectomy or excision and radiation therapy.

Axillary lymph node dissection for T1a breast carcinoma. Is it indicated?

BACKGROUND: Axillary dissection has been a routine part of breast cancer treatment for more than 100 years. Axillary node involvement is the single most important prognostic variable in patients with breast cancer. Recently, routine node dissection has been eliminated for intraductal carcinoma because so few patients had positive nodes. With the availability of numerous histologic prognosticators and the development of new immunochemical prognostic indicators, it is time to consider eliminating routine node dissection for lesions more advanced than duct carcinoma in situ (DCIS) but with extremely low likelihood of axillary involvement. METHODS: Axillary node positivity, disease-free survival, and breast cancer-specific survival were determined for six breast cancer subgroups by T category: Tis (DCIS), T1a, T1b, T1c, T2, and T3. RESULTS: Nodal positivity for DCIS was 0%; for T1a lesions, 3%. A large increase in nodal positivity was seen in lesions larger than 5 mm. (T1b, 17%; T1c, 32%; T2, 44%; T3, 60%). The rate of nodal positivity was statistically different as each T category was compared with the next more advanced T category. The disease-free survival and breast cancer-specific survival decreased with every increment in T value. CONCLUSIONS: Axillary node positivity increases as the size of the invasive component increases and is an excellent predictor of DSF and breast cancer-specific survival. Consideration should be given to eliminating axillary node dissection for T1a lesions because of the low yield of positive nodes. Axillary node dissection should be performed routinely for T1b lesions and larger.

Duct carcinoma in situ: 227 cases without microinvasion.

From 1979 to 1990, 227 patients with intraductal carcinomas (DCIS) without microinvasion were selectively treated; the least favourable (large lesions with involved biopsy margins) with mastectomy, the most favourable (small lesions with clear margins) with breast preservation. The preservation group was further subdivided into those who received radiation therapy (excision and radiation) and those who did not (excision alone). In the mastectomy group, there were 98 patients (43%) with an average lesional size of 3.3 cm; 41% had multifocal lesions, 15% had multicentric lesions. There has been one local invasive recurrence and no deaths. The 7-year actuarial disease-free survival is 98% with mastectomy. In the excision and radiation group, there were 103 patients (45%) with an average lesional size of 1.4 cm. 10 patients have had local recurrences (5 invasive and 5 noninvasive) one of whom has died. The 7-year actuarial disease-free survival is 84%, a statistically significant difference when excision and radiation is compared with mastectomy (P = 0.038). In the excision alone group, there were 26 patients (11%) with an average lesional size of 1.0 cm. There have been two local recurrences (8%), one of which was invasive and no deaths. The 7-year actuarial disease-free survival is 67%, but only 3 patients have been followed for more than 4 years. A total of 163 axillary node dissections were done; all were negative. Since DCIS without microinvasion rarely metastasizes to axillary lymph nodes, routine dissection should not be performed. Patients in this series with intraductal carcinoma treated with excision and radiation recurred locally at a statistically higher rate than those treated with mastectomy, in spite of the fact that those chosen for excision and radiation had clinically more favourable lesions. 6 of 12 (50%) local recurrences in conservatively treated patients were invasive. There was, however, no significant difference in overall survival in any subgroup regardless of treatment.

Axillary lymphadenectomy for intraductal carcinoma of the breast.

During a ten year period, 175 axillary lymph node dissections were done as part of the treatment for intraductal carcinoma of the breast; 98 patients were treated with modified radical mastectomy and 77 were treated by mammary preservation, consisting of excision of the lesion, axillary dissection and radiation therapy. One of 175 axillary node dissections yielded positive nodes. Axillary dissection for intraductal carcinoma of the breast is unlikely to yield involved nodes and is not indicated for use in most instances. It should be reserved for lesions demonstrating microinvasion.

Intraductal carcinoma of the breast (208 cases). Clinical factors influencing treatment choice.

Two hundred eight cases of intraductal breast carcinoma (DCIS) were selectively treated; 97 with mastectomy, 96 with radiation therapy, and 15 using excisional biopsy only. Mastectomy patients tended to have larger tumors, involved biopsy margins, palpable and often multifocal tumors. Breast preservation patients tended to have smaller, often occult, tumors with clear surgical margins. Before 1983, mastectomy was more common; during and after 1983, breast preservation was more common. Comedocarcinomas were the most frequent tumors. They were the largest, had the highest percentage of microinvasion (20%), and had the highest recurrence rate (8%). Noncomedo DCIS had a recurrence rate of 1%, one of 103 tumors. The recurrence rate for comedocarcinomas treated with radiation therapy was nearly three times higher than for those treated with mastectomy (11% versus 4%). One of 164 (0.6%) axillary lymph node dissections yielded positive nodes. Nine patients have recurred: two in the mastectomy group and seven in the breast conservation group (P less than 0.1). Eight of nine recurrences were the comedo subtype (P less than 0.05). Three patients developed metastatic disease, two of whom have died. Axillary dissection for intraductal carcinoma of the breast is unlikely to yield involved nodes and is not indicated for most cases. It should be reserved for lesions revealing microinvasion. Conservative therapy for comedocarcinoma must be viewed with caution.

Nonpalpable breast lesions: diagnosis with slightly overpenetrated screen-film mammography and hook wire-directed biopsy in 1,014 cases.

Slightly overpenetrated screen-film mammography and hook wire-directed localization were used in 1,014 breast biopsies performed for nonpalpable, mammographically detected breast abnormalities. One lymphoma and 205 breast cancers (20%) were found; 115 breast cancers (56%) were noninvasive, and 90 (44%) were invasive. Mastectomy was performed in 69 breast cancers (34%); 136 (66%) were treated conservatively, 28 with biopsy only and 108 with lumpectomy, node dissection, and radiation therapy. All patients with noninvasive breast cancers treated with axillary dissection had uninvolved lymph nodes. Of the 90 invasive breast cancers, six (7%) had metastases to axillary nodes, which, to the authors' knowledge, is lower than percentages reported in other studies of wire-directed breast biopsies. The authors believe that the slightly overpenetrated technique is a valuable adjunct to screen-film mammography.

Hooked-wire-directed breast biopsy and overpenetrated mammography.

Six hundred fifty-three biopsies were performed for clinically occult, mammographically detected breast abnormalities. One hundred forty-seven cancers (22.5%) were found. Eighty-nine of those cancers (60.5%) were noninvasive. None of the in situ lesions had involved axillary lymph nodes. Of the 58 invasive cancers, only six (10.3%) had metastases to axillary nodes. Fifty-four patients (36.7%) were treated by mastectomy while 93 patients (63.3%) were treated conservatively, 20 by biopsy only, and 73 by lumpectomy, axillary node dissection, and radiation therapy. Only four patients (0.7%) had significant complications.

Intravenous Imferon masquerading as an acute hemolytic transfusion reaction.

The case of a 74-year-old woman with a history of chronic iron deficiency anemia requiring transfusion is reported. Shortly after receiving intravenous iron-dextran, the patient was transfused with two units of crossmatch compatible packed red blood cells and subsequently experienced severe racking chills associated with mild elevation of temperature. In the evaluation of this febrile reaction, her serum exhibited a distinct red-brown discoloration which was interpreted as free hemoglobin. Laboratory studies performed to evaluate the possibility of acute intravascular hemolysis were all within normal limits. Subsequent investigation revealed that the color of the recipients serum was due to iron-dextran. Caution is urged in the evaluation of patients for hemolytic transfusion reactions who have been administered intravenous iron-dextran, since the drug imparts a red-brown tinge to the plasma which may be misinterpreted as free hemoglobin.