Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study.

INTRODUCTION: Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. MATERIALS AND METHODS: We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). RESULTS: 13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DISCUSSION: This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. CONCLUSION: Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.

Adjuvant bacillus Calmette-Guérin therapy in non-Hodgkin's malignant lymphomas: long-term results of a randomized trial in a single institution.

Between 1973 and 1977, 48 patients less than 65 years old with non-Hodgkin's malignant lymphoma (NHML) of poor prognosis (+/- high grade malignancy, +/- clinical stages III or IV, +/- first or repeated relapse) were included in a prospective clinical trial. After complete remission (CR), obtained with chemotherapy and radiotherapy, patients were randomized to receive bacillus Calmette-Guérin (BCG) or no further therapy. BCG was administered in weekly scarifications up to 3 years. Forty-three patients are assessable. Twenty-four patients have relapsed: nine out of 21 in the BCG group, and 15 out of 22 in the control group. There is a significant difference in favor of the BCG group in disease-free survival (P = .03). Twenty-one patients have died, 18 from NHML: seven in the BCG group, and 11 in the control group. There is a significant difference in favor of the BCG group for overall survival at 10 years (P = .05). A multivariate analysis points out BCG as a significant prognostic factor. Adjuvant BCG may improve particularly disease-free survival and overall survival for patients with clinical stages I and II or intermediate- and high-grade malignancy. These results suggest that in patients less than 65 years old with NHML of poor prognosis, BCG may significantly increase disease-free survival and overall survival.

Low-grade follicular lymphomas: analysis of prognosis in a series of 281 patients.

From 1963 to 1988, 281 patients with newly diagnosed follicular lymphomas were treated and followed at the Foundation Bergonié. Distribution of stages was: 72 I, 61 II, 83 III and 65 IV. Within stage III, two subgroups were retrospectively defined: stages III1 (32 cases) included patients with less than 8 involved sites, only 1 or 2 above diaphragm, and no spleen or mediastinal enlargement. Stage III2 (51 cases) included the remaining stage III cases. Median follow-up was 9 years. Complete remission (CR) rate was 82%. 10-year overall survival (OS) and time to treatment failure (TTF) rates were, respectively 38% and 29.5%. 10-year time to relapse (TTR) rate was 36%. Statistical analyses showed concordant results with two main prognostic factors: age (less than 60/greater than 60) and stage (I to III1/III2 and IV). Age was the most important factor for OS analysis and stage for CR and TTR analysis. This leads to only three prognostic groups with different outcome. The first includes younger patients (less than 60 years) with limited stages (less than or equal to III1); the second, patients either older than 60 or with advanced stages; the last, elderly patients with advanced stages. CR rates of these three groups were, respectively 97%, 75% and 57%. 10-year OS were, respectively 73.5%, 27% and 0%; 10-year TTR were 54%, 22% and 0%. These results have lead to data which are easy to handle and which can help to establish a rationale for further prospective trials.

Obvious peritumoral emboli: an elusive prognostic factor reappraised. Multivariate analysis of 1320 node-negative breast cancers.

This study was conducted to determine the prognostic influence of obvious peritumoral vascular emboli as prospectively determined by a simple routine slide examination in patients with operable node-negative breast cancer. Obvious peritumoral emboli (OPE) were defined by the presence of neoplastic emboli within unequivocal vascular lumina (including both lymphatic spaces and blood capillaries) in areas adjacent to but outside the margins of the carcinoma. OPE were assessed routinely on 5 microns thick haematoxylin and eosin-stained sections for each of 1320 primary operable node-negative breast cancers from 1975 to 1992 at our institution. OPE and other prognostic variables (tumour size, SBR grade, oestrogen and progesterone receptor status) were correlated to overall survival (OS) and metastasis-free interval (MFI) by means of univariate and multivariate analysis with a median follow-up of 103 months. OPE were found in 19.5% of tumours. In univariate analysis, OPE were related to tumour size (P = 6.3 x 10(-5)) and histologic grade (P = 4.9 x 10(-7)). Statistically significant correlations were found with OS (P = 4.6 x 10(-5)) and MFI (P = 6.4 x 10(-9)). Furthermore, in multivariate analysis, OPE was an independent prognostic variable, the most predictive factor for MFI (P = 7.7 x 10(-7)) before tumour size and grade, and was second after tumour grade for OS (P = 0.002). This study on a large unicentric series and with a long follow-up confirms the prognostic significance of vascular emboli in patients with operable node-negative breast carcinoma. Importantly, vascular emboli were found to be accurately detectable by a simple routine and non-time-consuming method. Therefore, such obvious vascular emboli should be considered as an important cost-effective, prognostic variable in patients with node-negative breast carcinoma.

Benign lymphocytic angiitis and granulomatosis: a T-cell lymphoma?

Benign lymphocytic angiitis and granulomatosis is a T-cell lymphoproliferative disorder confined to the lung and corresponding to a low-grade angiocentric immunoproliferative lesion. Controversy remains as to whether these lesions are lymphomas. We report such a case in an 8-year-old patient with Burkitt's lymphoma in remission who presented with persistent bronchopneumopathy and bilateral pulmonary infiltrates on tomodensitometry. Surgical resection revealed the histologic changes of benign lymphocytic angiitis and granulomatosis. Immunohistochemistry showed no aberrant pan T-cell marker loss. Genetic analysis of frozen tissue by Southern blot DNA hybridization with probes to T-cell receptor beta- and gamma-chain genes and to the immunoglobulin heavy chain joining region gene (JH) identified no clonal rearrangement. Search for Epstein-Barr virus-DNA sequences by in situ hybridization and Southern blot analysis provided negative results. Our data imply that lowgrade angiocentric immunoproliferative lesions are not exclusively lymphomas but might represent a borderline lymphoproliferative disease (seen in the course of many diseases), perhaps corresponding to host immune response.

Malignant adenomyoepithelioma of the breast. An immunohistochemical, cytophotometric, and ultrastructural study of a case with lung metastases.

Adenomyoepithelioma of the breast is a rare tumor that, on the basis of histologic, immunohistochemical, and ultrastructural features, has a bicellular pattern of epithelial and myoepithelial cells regularly distributed in tubular structures. Until now, this tumor was thought to be a benign or low-grade malignant lesion because of possible local recurrences (7 recurrent cases of 60 in the literature). Only one of these cases had nodal involvement, thereby suggesting the possible malignancy of this lesion. This paper reports the first documented case of malignant adenomyoepithelioma with lung metastases presenting the same biphasic pattern as the primary tumor.

CD30-positive cutaneous large cell lymphomas. A comparative study of clinicopathologic and molecular features of 16 cases.

The authors have analyzed and compared the clinicopathologic and molecular features of 16 cases of large cell cutaneous lymphomas expressing CD30 antigen. Three main clinical groups were defined: (1) a group of localized skin disease (7 cases); (2) a group of multicentric skin disease (5 cases); and (3) a group of concomitant skin and extracutaneous disease. Good prognosis was associated with localized skin disease and no history of lymphoma. Interestingly, a majority of Reed Sternberg-like cells was only observed in this group (5 of 6 cases). The two other groups did not show distinctive evolutive nor morphologic features. Southern blot and/or polymerase chain reaction (PCR) technique showed clonality and a T-cell genotype in respectively 13 of 14 and 12 of 12 analyzed cases. Viral infection of tumoral cells was investigated by PCR, in situ hybridization (ISH) or electron microscopy. Epstein-Barr virus (EBV) sequences were detected by PCR and ISH in tumoral cells of cutaneous lesions in one case of skin lymphoma with extracutaneous spreading. No EBV sequence was detected by ISH in the localized lymphomas, whereas HIV particles were visible in tumoral cells in one of these cases. No human T-cell lymphotropic virus (HTLV) tax sequence was amplified by PCR in any case of our series. Our results confirm that CD30-positive cutaneous large cell lymphomas are different clinical and molecular entities. However, a combined clinical and morphologic analysis may help to identify a subset of CD30 cutaneous lymphomas with favorable prognosis.

Analysis of 676 cases of ductal carcinoma in situ of the breast from 1971 to 1995: diagnosis and treatment--the experience of one institute.

Six hundred seventy-six patients with ductal carcinoma in situ of the breast (DCIS) from 1971 to 1995 were included in the study. Computerized patient files were retrospectively analyzed. Clinical findings were less frequently reported to reveal DCIS after 1989. Positive mammographic findings were obtained in 87% of patients and were mainly represented by microcalcifications (79.4%). Treatment procedures were breast-conserving surgery (BCS) alone (37.5%), BCS followed by radiation (BCSR) (25.5%), or mastectomy (M) (37%). The actuarial local recurrence was 2.6% in the M group (94 months of follow-up), 14.5% in the BCS group (85,7 months of follow-up), and 7.5% in the BCSR group (78.8 months of follow-up). Predictive factors of recurrence in all patients were invaded margin status and age. In the BCS group, grade was also a predictive factor. The analysis per decade shows that the lesions currently diagnosed are less serious than those of the past. All the recurrence in patients with positive margins was in the same quadrant as the original lesion. This further emphasizes the need for clear margins.

Lhermitte-Duclos type cerebellum hamartoma and Cowden disease.

A Lhermitte-Duclos type cerebellum hamartoma is reported in a woman with a diffuse hamartomatous condition involving the breast, thyroid, colon, skin, and kidney. The family history demonstrated the autosomal dominant transmission of this hamartomatous syndrome, and indicated the diagnosis of Cowden disease. This observation supports the recent hypothesis of Lhermitte-Duclos disease associated with Cowden disease as being a single phakomatosis.

Prognostic value of phenotyping by Ber-H2, Leu-M1, EMA in Hodgkin's disease.

The purpose of this report is to assess whether phenotyping by three monoclonal antibodies routinely used in paraffin sections (Ber-H2-Leu-M1-EMA) and shown to be the most useful for diagnosis may be a predictive factor for recurrences. Among 563 patients diagnosed as having Hodgkin's disease (24% of whom had recurrence), we selected 153 patients with and without recurrence, with matching clinical stage. For all of these cases, histologic material was tested by immunostainings with satisfactory control samples. No phenotype was specific for Hodgkin's disease, although the phenotype Ber-H2-Leu-M1-EMA was predominant. No phenotype was found to be a predictive factor for recurrences, and none was unchanged during the clinical course, except when recurrence occurred as non-Hodgkin's lymphoma.

Adenoid cystic carcinoma of the breast. Value of immunohistochemical study in diagnosis.

An immunohistochemical study of 5 cases of adenoid cystic carcinoma (ACC) of the breast was performed with antibodies against keratin, EMA, vimentin, S-100 protein, alpha-smooth muscle actin and collagen IV. Results show the following: 1) ACC may be diagnosed and differentiated from ductal carcinoma (invasive or in situ). The key to diagnosis is positivity within tumor masses of alpha-smooth muscle actin, a specific marker for myoepithelial cells. Actin-rich cells are not generally observed in ductal carcinomas, except at the periphery of a few invaded ducts, corresponding to a residual myoepithelial cell layer. Other markers may be positive in both ACC and ductal carcinoma; these are not specific and only the percentage and distribution of positive cells are helpful for diagnosis (small clusters of keratin-positive cells in ACC "versus" most positive cells in ductal carcinoma). 2) The functional pleomorphism of the cell population is underlined with cells differentiating towards epithelium and myoepithelium stained by corresponding markers, and undifferentiated cells unstained by any marker. These results confirm the value of an immunohistochemical study in the diagnosis of ACC of the breast.

The incidence of cancer in contralateral reduction mammaplasty after mastectomy and reconstruction of the removed breast.

Fourty-one patients underwent breast reconstruction after mastectomy for cancer and reduction plasty of the second breast, over a 36-month period. These plasties were performed only for reasons of asymmetry, in the absence of any positive preoperative finding. Histologic examination using semiserial sectioning of the whole excised sample detected a high frequency of unsuspected cancer 14/41 (34%). There was a strong predominance of in situ carcinomas 11/41 (27%) over invasive carcinomas 3/41 (7%). These results were compared with those of other bilateral cancer series. When such cancers were detected by random biopsies or mastectomies, the rate of in situ carcinomas was much greater than in cancers detected only by physical and mammographic examination.

The value of immunohistological techniques in undifferentiated cancers.

From 1980 to 1984, we observed 144 undifferentiated cancers, of which 116 (0.9% of all cancers treated during this period) were treated in our center. Immunohistochemical study classified 130 tumors (90%), which comprised 82 non-Hodgkin's lymphomas (57%), 32 carcinomas (22%), 7 melanomas (5%), 7 sarcomas (5%) and 2 others (1%). Sixty-nine patients, with the diagnostic problem of non-Hodgkin's lymphoma versus carcinoma, which was solved by immunohistology, were followed up for 44 +/- 20 months. Lymphomas (57 cases) had a better clinical course than carcinomas (11 cases), and a clinical course similar to high-grade lymphomas identified by conventional histology. For 66 patients with the same problem, the treatment was started before the immunohistochemical diagnosis. This treatment was inappropriate in the light of the correct diagnosis in 16 of 66 cases (24% of all cases).

[Inflammatory breast cancers: correlation between anatomopathology and steroid receptor assay]. / Les cancers du sein inflammatoires: corrélation entre anatomopathologie et dosage des récepteurs stéroïdiens.

From a series of 89 clinically inflammatory breast cancers, the authors settle a subgroup of tumors, the infiltrative ductal carcinomas with a pleomorphic structure. They have better histological and hormonal prognostic criteria than the other carcinomas, especially the infiltrative ductal carcinomas with an atypical structure: lower SBR grading (p = 6.10(-5)), estrogen and progesterone receptors positive rate more frequently (p = 10(-4)). A prospective study will allow to confirm the better response to treatment and especially the better survival rate of this metastatic high risk breast cancer subgroup.

[Analysis of 1125 partial breast resections for diagnostic purposes. Occurrence of cancer and its histology]. / Analyse de 1 225 exérèses mammaires partielles à visée diagnostique. Incidence du cancer et contexte histologique.

One thousand two hundred and twenty-five partial breast resections, examined in serial gross sections have been retrospectively reviewed. The percentage of benign lesions in comparison with malignant lesions is 70 per cent-30 per cent. The percentage of malignant lesions is maximum (43%) in clustered microcalcifications which are so the best criteria of malignancy. A diagnosis of non infiltrating carcinoma has been misdiagnosed at the first examination in 6 per cent of cases. This misdiagnosis is partially explained by very small foci of carcinoma and recent recognition of certain histological types of early carcinoma. It must be noticed the unsuspected frequence of carcinoma (17%) detected by random in ipsilateral breast tissue from plastic surgery, after controlateral reconstruction for carcinoma. The analysis of benign lesions associated with carcinoma shows a significative frequent association with carcinoma in two types of lesion: radial scar and late phase of blunt duct adenosis.

[Lymphoid depletion type 4 Hodgkin disease. Anatomoclinical review of 35 cases]. / Maladie de Hodgkin type 4 à déplétion lymphoïde. Révision anatomoclinique de 35 cas.

The pathological material of 35 patients with Hodgkin's disease lymphocyte-depletion type (type 4) is reviewed with an immunohistochemistry study on paraffin-embedded sections. The new pathologic data are compared with clinical features. These 35 patients are 4.7% of 742 previously untreated patients managed in this institution from 1960 to 1991. The diagnosis of 31 of the 35 patients was rectified, 17 to non-Hodgkin's lymphoma (12 unclassifiable and five anaplastic Ki-1 positive) and 14 to another type of Hodgkin's disease (six nodular sclerosis and eight mixed cellularity). In four cases, the pathologic material was neither sufficient nor satisfactory to allow a clear-cut distinction between Hodgkin's disease and non-Hodgkin's lymphoma. The analysis of clinical data before and after pathological revision did not show any difference in clinical features, either between Hodgkin's disease "type 4" and other types (1, 2 or 3) or between cases with Hodgkin's disease and those with non-Hodgkin's lymphoma. There is, however, a significant male predominance for Hodgkin's disease versus non-Hodgkin's lymphoma (P = 0.029, exact Fisher test), and B symptoms in non-Hodgkin's lymphomas (P = 0.056), whereas B symptoms are commonly seen in advanced stages of Hodgkin's disease. It is emphasized that all Hodgkin's disease of lymphocyte-depletion type should be reviewed and discussed before any treatment, and this diagnosis actually means non-Hodgkin's lymphoma or other types of Hodgkin's disease.

[Contribution of drill-biopsies to pre-treatment investigation of breast adenocarcinomas (author's transl)]. / Apport de la drill-biopsie dans le bilan préthérapeutique des adénocarcinomes mammaires.

The sensitivity of drill-biopsies (Rousseau's technique) was studied before using them routinely in pre-treatment investigation of breast adenocarcinomas. Results of histological examination, and estrogen (ER) and progesterone (PR) receptors levels obtained preoperatively by this technique, were compared with those from the corresponding mastectomy or tumourectomy specimens in 85 cases. Cytological examination of the various specimens, performed on prints, was used to compare their cellular density. Measurement of receptors included the determination of cytosolic and nuclear sites, and was performed by the single point dextran charcoal method. The limits of positivity established for ER and PR were 10 and 15 fM/mg protein respectively. The results showed sensitivity of 91.8 p. cent for pathology examinations; furthermore, the Scarff-Bloom-Richardson histoprognosis grading could be performed satisfactorily on drill-biopsy specimens. No significant difference was observed between the percentage of positivity for ER and PR from surgical and drill-biopsy specimens. Good correlation existed between values obtained from drill-biopsy and from surgery both for ER (r = 0.86, p less than 10(-5)) and PR (r = 0.86, p less than 10(-5)).

[Prognostic significance of isolated local recurrences in breast cancer following mastectomy and axillary node excision. Apropos of 77 recurrences in 2362 patients]. / Signification pronostique des récidives locorégionales isolées dans les cancers du sein après mastectomie et curage axillaire. A propos de 77 récidives chez 2 362 patientes.

During the years 1958-1984, 2 362 patients presenting with breast carcinoma were treated at the Fondation Bergonié by modified radical mastectomy and followed or not by radiotherapy or adjuvant chemotherapy. A retrospective analysis of this series showed that 77 patients (3.3%) presented an isolated locoregional recurrence as the first sign of treatment failure. A chest wall recurrence alone was noted in 47 patients, while 30 presented an involvement of the lymph nodes, sometimes associated with chest wall disease. The prognosis' factors of isolated locoregional recurrence, studied by multidimensional analysis by Cox's model are by decreasing order the disease free interval and the Scarf and Bloom's histologic grade. The median survival is 29 months after isolated locoregional recurrence and the survival curve is very similar to that of patients with isolated bone metastatic recurrences (median survival of 26 months) and slightly better than the median survival of patients with non osseous metastasis (median survival of 16 months).

[Extramammary carcinoid tumor metastatic to the breast. Apropos of a case]. / Les carcinoïdes d'origine extramammaire métastasiant au sein. A propos d'une observation.

We report the case of a 42-year-woman treated for an appendicular carcinoid tumor with bilateral ovary metastases and mesenteric node involvement. After a systematic mammography, an infraclinical lesion of the breast was detected. Mammographic and echographic images revealed nodular mass with possibly malignant features. Fine-needle aspiration biopsy indicated malignancy. The definitive diagnosis of breast metastasis of a carcinoid tumor was made by biopsy. This case is related to 14 previously published cases. The authors emphasize the importance of making a precise histological diagnosis to avoid overtreatment of a metastatic lesion.

[Mediastinal large B-cell lymphoma. A retrospective anatomic-clinical study of 26 cases]. / Lymphomes médiastinaux à grandes cellules B. Etude anatomoclinique rétrospective de 26 cas.

Mediastinal B-cell lymphomas (with or without sclerosis) have been recently recognized as an entity with particular clinical features. We report 26 patients with a mediastinal large B-cell lymphoma. They represent 5% of the patients with aggressive non-Hodgkin's lymphoma and 2% of all non-Hodgkin's lymphoma seen in our centre between 1962 and 1990. They include 19 females (73%) and 7 males (27%). The sex ratio was 2.7 and the median age was 44 years (range: 17-84 years). Compressive symptoms in relation with a bulky mediastinum were present in 21 cases (80%) and with B symptoms in 5 cases. All these patients received 2 to 4 cycles of chemotherapy with a CHOP-like protocol (epirubicin or doxorubicin, cyclophosphamide, vincristine and prednisone) followed in 24 cases by mediastinum irradiation (40 Gy). Two patients progressed during chemotherapy and did not receive radiotherapy. Nineteen patients had a consolidation chemotherapy according to the same protocol. Twenty-one patients achieved a complete remission after chemotherapy or radiotherapy and 5 failed. Two patients relapsed at 10 months and 9 years. Seventeen patients are alive and in first complete remission with a median follow-up of 102 months (range: 60-260 months). Using the Kaplan-Meier method, the overall survival at 5 and 10 years was respectively 77 and 61% and the relapse-free survival was respectively 68 and 57%. These results confirm the previous findings concerning this distinct entity which is characterized by a predilection for young women, compressive symptoms, a slow response to treatment and a rather good prognosis.