Franco Rilke

Radiotherapy after Breast-Preserving Surgery in Women with Localized Cancer of the Breast

BACKGROUND AND METHODS Conservative surgery and radiotherapy have become well-established treatments for breast cancer, and many trials in progress are attempting to define the most acceptable type of procedure. Between 1987 and 1989 we randomly assigned 567 women with small breast cancers (< 2.5 cm in diameter) to quadrantectomy followed by radiotherapy or to quadrantectomy without radiotherapy. All patients underwent total axillary dissection. The median follow-up period was 39 months (range, 28 to 54). RESULTS The incidence of local recurrence was 8.8 percent among the patients treated with quadrantectomy without radiotherapy, as compared with 0.3 percent among those treated with postsurgical radiotherapy (P = 0.001). However, there was a substantial effect of age: patients more than 55 years old who did not receive radiotherapy had a low rate of local recurrence (3.8 percent). The four-year overall survival was similar in the two treatment groups. CONCLUSIONS Administering radiotherapy after quadrantectomy reduces the risk of local recurrence in women with small cancers of the breast, but radiotherapy may not be necessary in elderly women.

Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients

Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

Neuroendocrine (Merkel cell) carcinoma of the skin.

Merkel cell carcinoma was diagnosed in 10 patients (eight females and two males) with a mean age of 66 years and a range of 44–84. The most common sites of the primary tumor were the skin of the limbs, girdles, and head. Sixty percent of the cases had recurrences and 50% regional nodal metastases that appeared within 1 year. Of the patients treated variably with surgery, chemotherapy, and radiotherapy and followed for a mean period of 28 months, two were alive and free of disease, two were alive with disease after 3 and 6 years, and two have died of metastatic disease to the lungs and liver. The primary lesions showed quite distinctive clinical and gross features in terms of size, shape, and color. Histologically, the growth was usually diffuse and occasionally trabecular or pseudoglandular; infiltration was predominantly in the papillary and reticular dermis. The uniform, poorly cohesive cells contained argyrophilic granules in the cytoplasm and round to oval nuclei with frequently indented membranes. The mitotic index was high. Ultrastructurally, in two cases, two cell types were identified that probably represented the neoplastic counterpart of normal Merkel cells in different stages of maturation. Both cell types contained cytoplasmic neurosecretory granules and intermediate filaments, even though their cytoplasms were differently shaped.

Distribution of axillary node metastases by level of invasion. An analysis of 539 cases

Five hundred and thirty‐nine patients with carcinoma of the breast treated with total axillary dissection and with positive axillary nodes were evaluated. The total number of lymph nodes removed was 11,082, with an average of 20.5 nodes per patient. The average number of lymph nodes at the first level was 13.8, at the second level 4.5, at the third level 2.2. The average number of nodes was 20.7 in cases treated with Halsted mastectomy, 20.9 with total mastectomy and axillary dissection, 20.3 with quadrantectomy and axillary dissection. Of 3259 metastatic nodes, 64 were site of micrometastases; 797 were partially involved, 441 were totally involved and 1957 were site of metastases with extracapsular invasion. In 314 (58.2%) the first level only was involved, in 117 cases (21.7%) metastases were present at the first and second level, whereas in 88 cases (16.3%) all the three levels were sites of metastases. Only 20 cases showed skipping distribution. In 1.5% of the cases the first level was skipped by metastases, in 0.4% the first and second levels were both skipped. The predicting value of the first level is considerable: when the nodes of the first level are clear the chances that metastatic nodes are present at the second and third levels are negligible. When the nodes at the first level are positive, the chances that metastases are also present at the higher levels are of the order of 40.0%. Cancer 59:682‐687, 1987.

Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-hodgkin's lymphoma

Abstract In order to improve the prognosis of patients with localized non-Hodgkins lymphomas (NHL) who are treated with radiotherapy (RT), a prospective controlled study utilizing a combined modality approach was carried out in patients with pathologic Stage 1[-II NHL. After treatment with regional RT, patients in complete remission were randomized to receive either no further therapy or 6 cycles of cyclophosphamide, vincristine and prednisolone (CVP). At 5 years from completion of irradiation, the relapse-free survival was 46.3% after RT and 72.1% after RT plus CVP ( P = 0.005). The corresponding findings for the overall survival calculated from the beginning of irradiation were 55.8 and 82.8% respectively ( P = 0.03). The favorable effects of adjuvant chemotherapy on relapse-free survival were statistically significant only in the subgroup with diffuse histology. In patients who relapsed after RT alone, the salvage therapy failed to induce a high incidence of second durable remission. Adjuvant chemotherapy is indicated to improve the cure rate in pathologic stage I-II NHL with diffuse histology when regional RT is utilized.

Second malignancies in Hodgkin's disease: A complication of certain forms of treatment

A total of 764 patients with Hodgkins disease treated with radiotherapy (RT) or chemotherapy or both were reviewed 3-186 months (median 43 months) after initial treatment to assess the incidence of second malignancies. Incidence of solid tumours and acute non-lymphoblastic leukaemia (ANLL) were calculated by a life-table method and percentages of patients affected derived from life-table plots. Within 10 years after initial treatment the overall incidence of second solid tumours was 7.3%, and over a comparable period 2.4% of patients developed ANLL. Solid tumours occurred only in patients given RT with or without adjuvant chemotherapy, and ANLL occurred only after treatment with MOPP (mustine, vincristine, procarbazine, and prednisolone) or modified MOPP regimens. Neither solid tumours nor ANLL occurred in patients given ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The highest incidence of leukaemia (5.4%) occurred after treatment with extensive RT plus (5.4%) occurred after treatment with extensive RT plus MOPP; hence the benefits of this approach in Hodgkins disease must be weighed against its carcinogenic potential.

Primary non-Hodgkin's lymphomas of the female breast

The charts of 35 women with primary malignant non‐Hodgkins lymphomas (NHL) of the breast were retrieved from the files of the Istituto Nazionale Tumori, Milan, over a 30‐year period (1957 to 1986). These cases represented 0.1% of the more than 25,000 primary malignant tumors of the breast treated during the same period. The median age of these patients was 57 years (range, 28 to 81 years). In most cases, the clinical diagnosis was carcinoma. The tumors were either Stage IE (48%) or IIE (52%) at presentation, and only two patients, had B symptoms. The right breast was involved in 17.patients, the left breast in 14, and both breasts in two. According to the updated Kiel classification and the Working Formulation (WF) for Clinical Usage, three cases were lymphoplasmacytoid (immunocytoma) NHL (WF, A); three, centroblastic‐centrocytic, follicular NHL (WF, B); four, centroblastic‐centrocytic, diffuse NHL (WF, F); 17 centroblastic NHL (WF, G); three immunoblastic NHL (WF, H); two B‐lymphoblastic NHL (WF, I); and one, a Burkitt‐like NHL (WF, J). Treatment consisted either of a combination of surgery, radiation therapy, and chemotherapy or radiation therapy and chemotherapy. The follow‐up period for 32 patients ranged from 6 to 161 months (mean, 45 months); 17 patients died of their disease. The prognosis appeared to be related to the histologic type and stage of the disease. Median survival periods were 63, 52, 42, and 47 months for centroblastic‐centrocytic follicular, centroblastic‐centrocytic diffuse, centroblastic, and immunoblastic NHL, respectively. The overall 5‐year survival rate was 43%; the 5‐year survival rate and the probability of freedom from progression at 5 years were, respectively, 61% and 50% for Stage I and 27% and 26% for Stage II disease.

Distinct mdm2/p53 expression patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms.

Recent findings have indicated that TP53 inactivation in sarcomas may result from mutation and/or deletion of the TP53 gene or, alternatively, from binding to the MDM2 gene products. To investigate further a possible role of the two genes in sarcomas, 24 large and deep‐seated lipomas and 74 liposarcomas of various subtypes were analysed for mdm2 and p53 overexpression by immunocytochemistry. Nineteen cases of the same series were also molecularly analysed for both MDM2 gene amplification and TP53 mutations, and a further ten cases for non‐random chromosomal abnormalities. In the retroperitoneal well‐differentiated–dedifferentiated (WD–DD) group, 15/16 WD and 8/8 DD liposarcomas displayed the mdm2+/p53+ phenotype, consistent with MDM2 gene amplification in the absence of TP53 mutations. In the non‐retroperitoneal WD–DD group, 5/11 WD liposarcomas also retained the mdm2+/p53+ phenotype whereas all DD liposarcomas showed an immunophenotype and, when assessed, a genotype consistent with mutant TP53. Null mdm2 immunophenotype, coupled with evidence of a specific chromosome translocation t(12;16), was constantly observed in both the usual and the cellular subtypes of myxoid liposarcoma, three cases of which also showed TP53 alterations at the genetic or protein level. Neither mdm2 nor p53 overexpression was observed in the lipomas. The results show the existence of three main pathogenetically distinct groups of liposarcoma. The first retroperitoneal WD–DD group, which represents a novel class of tumours within a single histological category of sarcoma, where MDM2‐mediated inactivation of p53 could be related to the pathogenetic mechanism. The second is the non‐retroperitoneal WD–DD group, where the TP53 mutations appear to correlate with the dedifferentiation process. The third is the myxoid group, which is characterized by its own unique cytogenetic profile and never shows any involvement of TP53 or MDM2 genes. As for diagnostic significance, the absence of mdm2 and p53 reactivity in lipomas seems to represent a useful marker for differential diagnosis from lipoma‐like WD liposarcomas.

Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma.

A study of 50 consecutive cases (22 men, 28 women; age range, 39 to 84 years; mean age, 65 years) of cutaneous neuroendocrine Merkel cell carcinoma (CNC), 39 of whom had a mean follow-up of 34 months, revealed that the prognostic significance of the histopathologic subtyping in trabecular, solid, and diffuse variants of CNC was not as important as the pathologic postsurgical staging in localized, regional, and extraregional disease. The overall mortality was 23.5%. None of the 19 patients with localized disease died of CNC, while 11% of the 24 patients with regional disease and all seven patients with extraregional disease at presentation died of CNC. A second primary malignancy was found to be associated with the CNC in 15% of the cases. The clinical course in patients with localized disease was favorable in spite of the high number of local recurrences. Also, the presence of regional metastases was not related to an unfavorable prognosis. In 68% of the cases the disease involved the lower limbs or girdle. In ten cases the overt exophytic presentation of primary CNC was replaced by the presence of tumor masses infiltrating the inguinal soft tissues with or without nodal involvement.

Insular carcinoma : a distinct de novo entity among follicular carcinomas of the thyroid gland

We reclassified 720 nonmedullary invasive thyroid carcinomas diagnosed and treated between 1975 and 1993. Twenty-seven cases met the criteria of insular carcinoma and 29 cases those of widely invasive follicular carcinoma. Comparison of these histotypes with respect to pathologic stage and overall, relative, and visceral metastasis-free survival showed a significant association between histotype and pT and pN categories. In particular, pT4 (p < 0.001) and pN1 (p < 0.001) categories were more frequent in the insular carcinoma histotype. By contrast, no significant differences in overall, relative, or visceral metastasis-free survival were observed between insular carcinoma and widely invasive follicular carcinoma. Molecular analysis by polymerase chain reaction-single-strand conformation polymorphism demonstrated RAS gene family point mutations in five of eight cases analyzed in each of the two histotypes, with a high proportion of CAA-->AAA transversion at codon 61 of the N-RAS gene in insular carcinoma. These findings suggest that insular carcinoma represents a de novo entity distinct from widely invasive follicular carcinoma, that widely invasive follicular carcinoma has biologic characteristics more consistent with poorly differentiated than well-differentiated carcinomas, and that both insular carcinoma and widely invasive follicular carcinoma share similar molecular alterations.