Prognostic impact of 18F-FDG PET/CT staging and of pathological response to neoadjuvant chemotherapy in triple-negative breast cancer.

PURPOSE: Mortality is high in patients with locally advanced triple-negative breast cancer (TNBC), especially in those with residual tumour after neoadjuvant chemotherapy (NAC). The aim of this study was to determine if pretreatment (18)F-FDG PET/CT staging and pathological findings after NAC could together allow stratification of patients into prognostic groups. METHODS: Initial staging with (18)F-FDG PET/CT was performed prospectively in 85 consecutive patients with stage II/III TNBC. Correlations between PET findings and disease-specific survival (DSS) were examined. In patients without distant metastases on PET staging, the impact of pathological response to NAC on DSS was examined. Patterns of recurrence were also analysed. RESULTS: (18)F-DG PET/CT revealed distant metastases in 11 of 85 patients (12.9 %). Among 74 M0 patients, 23 (31.1 %) showed a pathological complete response (pCR) at surgery, while 51 had residual invasive disease (no pCR). DSS differed considerably among the three groups of patients (log-rank P < .001): among patients with occult metastases on baseline PET/CT, 2-year DSS was 18.2 %, and among patients without initial metastases on PET/CT, 5-year DSS was 61.3 % in patients without pCR after NAC and 95.2 % in those with pCR. Of the 51 patients who did not achieve pCR, 21 relapsed (17 developed distant metastases). The sites of distant recurrence were: lung/pleura (nine patients), brain (eight patients), liver (six patients), distant lymph nodes (six patients) and bone (five patients). CONCLUSION: In patients with clinical stage II/III TNBC, (18)F-FDG PET/CT findings at initial staging and pathological response at the end of NAC allow three groups of patients with quite different prognoses to be defined. Extraskeletal recurrences predominated. Specific follow-up strategies in patients with TNBC who do not achieve pCR deserve investigation.

Long-term survival of advanced triple-negative breast cancers with a dose-intense cyclophosphamide/anthracycline neoadjuvant regimen.

BACKGROUND: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. METHODS: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide-anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. RESULTS: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07-0.86), P=0.028). CONCLUSIONS: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome of neoadjuvant treatment.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant treatment (NAT) is associated with improved survival of patients with HER2+ breast cancer. We investigated the ability of interim positron emission tomography (PET) regarding early prediction of pathology outcomes. METHODS: During 61 months, consecutive patients with locally advanced or large HER2+ breast cancer patients without distant metastases were included. All patients received NAT with four cycles of epirubicin+cyclophosphamide, followed by four cycles of docetaxel+trastuzumab. ¹8F-fluorodeoxyglucose (¹8F-FDG)-PET/computed tomography (CT) was performed at baseline (PET1) and after two cycles of chemotherapy (PET2). Maximum standardised uptake values were measured in the primary tumour as well as in the axillary lymph nodes. The correlation between pathologic response and SUV parameters (SUVmax at PET1, PET2 and ΔSUVmax) was examined with the t-test. The predictive performance regarding the identification of non-responders was evaluated using receiver operating characteristics (ROC) analysis. RESULTS: Thirty women were prospectively included and 60 PET/CT examination performed. At baseline, 22 patients had PET+ axilla and in nine of them ¹8F-FDG uptake was higher than in the primary tumour. At surgery, 14 patients (47%) showed residual tumour (non-pCR), whereas 16 (53%) reached pCR. Best prediction was obtained when considering the absolute residual SUVmax value at PET2 (AUC=0.91) vs 0.67 for SUVmax at PET1 and 0.86 for ΔSUVmax. The risk of non-pCR was 92.3% in patients with any site of residual uptake >3 at PET2, no matter whether in breast or axilla, vs 11.8% in patients with uptake ≤3 (P=0.0001). The sensitivity, specificity, PPV, NPV and overall accuracy of this cutoff were, respectively: 85.7%, 93.8%, 92.3%, 88.2% and 90%. CONCLUSION: The level of residual ¹8F-FDG uptake after two cycles of chemotherapy predicts residual disease at completion of NAT with chemotherapy+trastuzumab with high accuracy. Because many innovative therapeutic strategies are now available (e.g., addition of a second HER2-directed therapy or an antiangiogenic), early prediction of poor response is critical.

BI-RADS categorisation of 2,708 consecutive nonpalpable breast lesions in patients referred to a dedicated breast care unit.

OBJECTIVES: To determine the malignancy rate of nonpalpable breast lesions, categorised according to the Breast Imaging Reporting and Data System (BI-RADS) classification in the setting of a Breast Care Unit. METHODS: All nonpalpable breast lesions from consecutive patients referred to a dedicated Breast Care Unit were prospectively reviewed and classified into 5 BI-RADS assessment categories (0, 2, 3, 4, and 5). RESULTS: A total of 2708 lesions were diagnosed by mammography (71.6%), ultrasound (8.7%), mammography and ultrasound (19.5%), or MRI (0.2%). The distribution of the lesions by BI-RADS category was: 152 in category 0 (5.6%), 56 in category 2 (2.1%), 742 in category 3 (27.4%), 1523 in category 4 (56.2%) and 235 in category 5 (8.7%). Histology revealed 570 malignant lesions (32.9%), 152 high-risk lesions (8.8%), and 1010 benign lesions (58.3%). Malignancy was detected in 17 (2.3%) category 3 lesions, 364 (23.9%) category 4 lesions and 185 (78.7%) category 5 lesions. Median follow-up was 36.9 months. CONCLUSION: This pragmatic study reflects the assessment and management of breast impalpable abnormalities referred for care to a specialized Breast Unit. Multidisciplinary evaluation with BI-RADS classification accurately predicts malignancy, and reflects the quality of management. This assessment should be encouraged in community practice appraisal.

Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches.

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) are currently the most commonly used methods to assess HER2 status. PCR-based assays allow quantitative determination of HER2 amplification (Q-PCR) or overexpression (Q-RT-PCR), but are not routinely used. We evaluated the relevance of Q-RT-PCR for HER2 status determination. METHODS: We compared IHC and Q-RT-PCR in 466 breast tumours. In discordant or equivocal cases, five additional methods (IHC with two other antibodies, FISH, silver in situ hybridisation (SISH) and Q-PCR) were combined to determine HER2 status. Two cases with HER2 intra-tumour heterogeneity were further explored by allelic profiles analysis and HUMARA clonality determination after microdissection. RESULTS: We observed 97.3% concordance between Q-RT-PCR and non-equivocal IHC. Twelve out of 466 cases (3%) revealed discordances between the two methods. The power of Q-RT-PCR to predict HER2 status (defined by seven methods) was similar to that of IHC. Although rare, some discordances between techniques might be due to HER2 intra-tumour heterogeneity and we report two examples, one tumour containing two distinct clones, another tumour consisting of HER2 amplified and non-amplified subclones. CONCLUSION: Q-RT-PCR and IHC are highly concordant methods for HER2 status assessment, and Q-RT-PCR allows a highly reliable quantitative assessment and could be a useful adjunct to IHC.

[Invasive lobular carcinoma of the breast: specific diagnosis and evolution]. / Cancer lobulaire infiltrant du sein: particularités diagnostiques et évolutives.

Invasive lobular carcinoma accounts for 4 to 10% of breast cancers. The clinical and radiological diagnosis is difficult to make. Its progression is slower than that of ductal cancer, and the prognostic factors are more favourable. Its metastases are more frequently located in the digestive tract and the ovaries. It is more frequently bilateral. Its prognosis is not different from that of infiltrating ductal carcinomas. The choice of therapies depends on the individual characteristics of each patient and of the biological features of each tumour. However, lobular carcinomas seem to be less responsive to chemotherapy.

Stress-induced aberrant splicing of TSG101: association to high tumor grade and p53 status in breast cancers.

The TSG101 gene, identified through insertional mutagenesis, is localized in a region that exhibits LOH in human cancers, suggesting that TSG101 might be a tumor suppressor gene. Numerous studies have then shown the presence of abnormal transcripts in various tumors which appear to result from aberrant splicing of the gene, rather than from intragenic deletions. Moreover, many studies demonstrated that these aberrantly spliced transcripts were not found in matched normal tissues. We have analysed TSG101 transcripts in 85 breast cancer samples and found that abnormal splicing of the gene is tightly correlated with tumor grade and p53 mutation. In addition, stress induced the appearance of these abnormal transcripts in primary lymphocytes. Hence, TSG101 splicing defects, while unrelated to the oncogenic process per se, could reflect the cellular environment of the tumor cells. The proposed role of stress and hypoxia to select p53 mutant cells could account for the tight association with p53 status.

Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery.

Patients with recurrent or metastatic medullary thyroid carcinoma (MTC) were referred for pretargeted immunoscintigraphy (Affinity Enhancement System; AES) and radioimmunoguided surgery (RIGS). Data collected from 13 patients establish that whole-body AES immunoscintigraphy revealed metastases < 360 mg and RIGS detected micrometastases (5-15 mg). All tissue samples removed by the surgeon were diagnosed by histology and immunohistochemistry of calcitonin to check the accuracy of IS and RIGS results. AES immunoscintigraphy is very sensitive. Of 34 metastases or recurrences detected, 22 had escaped physical examination or conventional imaging. The accuracy of RIGS was 86%, its sensitivity 75%, and its specificity was 90% (n = 208). IS and RIGS detected occult tumors that would have escaped surgery, clearly demonstrating clinical benefit. Serum calcitonin (normal, 10 pg/ml) and carcinoembryonic antigen (normal, 5 ng/ml) of two patients were restored to normal. In patients whose tumors were discovered, progression of their disease was slowed, as evidenced by the large decrease in serum calcitonin and carcinoembryonic antigen, an important prognostic factor. Surgery was canceled in one case where IS detected distant metastases out of surgical reach. Thus, AES immunoscintigraphy and RIGS might be of valuable help for the surgical management of medullary thyroid carcinoma.

[Breast lobular carcinoma in situ: diagnosis and evolution]. / Cancer lobulaire in situ du sein. Particularités diagnostiques et évolutives.

The incidence of lobular cancers in situ is increasing, especially in post-menopausal women. Whereas this form of disease was regarded for a long time as nothing but a risk factor of the occurrence of later infiltrating carcinoma, it now tends to represent a precancerous state whose progression to subsequent infiltrating carcinoma does not inevitably occur. The clinical and radiological diagnosis remains difficult and the choice of therapies varies according to teams, ranging from mere surveillance to mastectomy.

Variability of immunohistochemical reactivity on stored paraffin slides.

AIMS: To investigate the effects of slide storage on immunohistochemical staining, since recent reports have indicated that storage of unstained paraffin slides for up to 12 weeks may lead to false negative immunostaining of tumour markers. METHODS: 11 antibodies (anti-cytokeratin, epithelial membrane antigen (EMA), vimentin, smooth muscle actin, PS100, chromogranin, CD45, CD20, CD3, CD30, and oestrogen receptor (OR) were tested on unstained paraffin slides of breast carcinomas, lymphomas, and neuroendocrine tumours that had been stored for three to 10 years. All the paraffin blocks were recut less than one week before immunostaining. Immunostainings of years old slides were compared with those of recent slides in at least five cases for each antibody. For three antibodies (antichromogranin, anti-CD3, and anti-OR) we also tested one year old and three months old slides. RESULTS: Intensity of staining on years old slides was strikingly reduced for chromogranin and CD3 in several cases and was slightly stronger for vimentin. In some cases a significant decrease of OR positivity was observed after three months storage, and a complete loss of OR immunostaining after 12 months. No significant difference was noted with the other antibodies. CONCLUSIONS: Immunohistochemical detection of some antigens located either in the nucleus, in the cytoplasm, or on the cytoplasmic membrane could be impaired by storage of paraffin slides as short a time as three months. One should be cautious of doing retrospective immunohistochemical studies on stored unstained slides.

Gastric metastases from breast cancer: a retrospective series of 12 patients.

Although well described in the literature, gastric metastases are often misdiagnosed in patients with breast cancer. The accuracy of diagnosis is critical because systemic therapy is beneficial, affording symptom palliation and an opportunity to avoid an unnecessary gastrectomy.

[Role of invasive candidiasis in hospital pathology]. / Place des candidoses invasives en pathologie hospitalière.

The frequency, mode of occurrence, diagnostic criteria and main features of systemic and visceral candidiasis have been evaluated in a retrospective study of all cases managed in St Louis Hospital, Paris, during the [June 1, 1985-May 31, 1986] period. During this one year period 23 patients suffered from systemic or visceral candidiasis and Candida spp. accounted for 9.6% of all positive blood cultures, fourth in number after Enterobacteriaceae, Staphylococcus and Pseudomonas. Abnormal underlying condition was present in all patients, mainly haematologic malignancies, serious abdominal surgery and AIDS. In patients with haematologic malignancies C. tropicalis was the main species involved in contrast with surgical patients in whom the dominant responsible species was C. albicans. No Candida oesophagus was common. Therapeutic regimens included amphotericin B in all patients with systemic disease. We conclude that in an institution mainly oriented toward management of cancer and surgical patients, systemic and visceral candidiasis are common and represent a serious problem.

[Retrospective multivariate analysis of radio-pathological correlations of nonpalpable breast lesions. Experience of the Hospital Saint-Louis]. / Analyse rétrospective multivariée de la corrélation radio-anatomopathologique de lésions infracliniques du sein. Expérience de l'hôpital Saint-Louis.

PURPOSE: Several studies have demonstrated that systematic breast cancer screening increases overall survival. We report our experience regarding diagnosis of breast lesions detected using mammography. METHODS: Case reports of patients operated on in either 1992 or 1993 were retrospectively reviewed. A multivariate analysis of the clinico-pathological correlation was performed. RESULTS: Four hundred fifty seven patients representing on total 544 procedures, were included in the study. Mean age was 50.5 years (range 19-80 years). Most of the patients had no previous history of mammary lesion. Mammography was performed with prophylactic intent in more than 60% of the cases. Four hundred twelve (75.7%) benign lesions were diagnosed. Main lesions were: adenofibroma (15.7%), fibrocystic mastopathy (66.3%), adenosis (26.2%), ductal hyperplasia (23.9%), lobular hyperplasia (10.7%), and combined ductal and lobular hyperplasia (8.5%). Hyperplasia accompanied by cytonuclear atypia was observed in 49 (11%) cases. One hundred thirty two (24.3%) malignant lesions were reported, including 69 (52.3%) invasive carcinomas and 63 (47.7%) in situ carcinomas. Only nine axillary lymph node dissections were positive and 75 minimal breast cancers were diagnosed. The multivariate analysis showed that only radiological signs are a risk factor for cancer. The relative risk for cancer when focus of irregular and vermicular microcalcifications are diagnosed is 4.2 (2.0-8.5). It is 5.6 (2.5-12.5) in case of spiculated opacity. CONCLUSION: Exeresis following radiological prophylactic screening allows diagnosis of high-risk benign lesions and low-stage breast cancer. Radiological parameters are the most powerful predictive factors for malignancy.

[Craniofacial granulomatous lesions]. / Processus granulomateux cranio-faciaux.

Granulomatous lesions of the cranio-facial area are frequent and various in their nature: lymphohistiocytic with or without eosinophils, tuberculoid-like with epithelioid and giant cells, or sometimes made essentially of giant cells. Their etiology can be known or easy to find: foreign body granuloma, sarcoidosis, leprosy, rhinoscleroma, fungal diseases especially zygomycosis and rhinosporidiosis, parasitic diseases. The lethal midline granuloma is a clinical entity characterized by its necrotic and relentlessly progressive destructive presentation. After elimination of a malignant process, especially lymphoid, and of a Wegener's granulomatosis the diagnosis will be "idiopathic midline non-healing granuloma". Some of them will stay located at the facial area; others will disseminate as a malignant disease. Central giant cell granuloma and histiocytosis X, especially eosinophilic granuloma, are two other varieties of granuloma, different of the former granulomatous infiltrates by their clinical presentation and their evolution.

[Epithelial-myoepithelial carcinoma of the salivary glands. Study of 15 cases and review of the literature]. / Carcinome épithélial-myoépithélial des glandes salivaries. Etude de 15 observations et revue de la littérature.

Epithelial-myoepithelial carcinoma initially described by Donath in 1972 represents about 0.5% of salivary gland tumors. Total number of reported cases brings to at least 56 cases; we add 15 personal cases. These 71 cases included 46 women and 25 men. The ages range from 23 to 91 years with peak incidence from the 6th to the 8th decades. The majority of tumors (58) arose in the parotid gland. Of the 71 patients local recurrences occurred in 20, cervical lymph node metastasis in 6 and 2 patients died of their disease. Epithelial-myoepithelial carcinoma typically have a multinodular growth pattern with islands of tumors separated by dense fibrous connective tissue. These tumor masses were composed of well-defined tubules lined by two layers of cells: outer cells are large clear with variable amount of glycogen, inner cells are small, cuboidal and eosinophilic. Perineural invasion and necrosis were occasionally seen. In some cases, this biphasic pattern was less apparent with solid masses of clear cells. Electron microscopic and immunohistochemical studies confirmed the epithelial and myoepithelial differentiation. The differential diagnosis included all clear cells tumors of salivary glands (mucoepidermoid carcinoma, acinic cell carcinoma, sebaceous carcinoma) and also metastatic renal carcinoma. Epithelial-myoepithelial carcinoma is a tumor of low-grade malignancy of duct origin which should be differentiated from salivary duct carcinoma.

[Leiomyosarcoma of the larynx. Histological, immunohistochemical and ultrastructural study of a case with review of the literature]. / Léiomyosarcome du larynx. Etude histologique, immunohistochimique et ultrastructurale d'une observation avec revue de la littérature.

Laryngeal leiomyosarcoma: histological, immunohistochemical and ultrastructural study of one case with review of the literature. Leiomyosarcoma of the larynx have rarely been reported and a review of the literature has yielded only 8 cases. Authors report a case in a 45-year-old patient. Histological exam of the surgical specimen showed a malignant spindle cell tumor. Ultrastructurally, neoplastic cells presented some features of smooth-muscle cells. Immunohistochemical studies revealed that most tumor cells coexpressed vimentin and smooth-muscle actin.

[Clear cell carcinoma of the thyroid; diagnostic difficulties]. / Carcinome à cellules claires de la thyroïde, difficultés diagnostiques.

Thyroid carcinomas with clear cell change are rare neoplasms, and always bring up the possibility of a metastasis from another primary clear cell carcinoma. We report the case of a 33-year-old woman operated on for a solitary cold thyroid nodule. Histologic and ultrastructural studies showed a clear cell carcinoma with a trabecular and follicular pattern. Neoplastic cells included lipid droplets, glycogen granules and intranuclear cytoplasmic inclusions, and were stained with one of the two antithyroglobulin polyclonal antibodies used. Radiologic investigations then showed a tumor mass of the right kidney. Surgical management proved it to be a benign cyst, and assessed the absence of kidney neoplasm. Thus, this case exemplifies the pitfalls in the diagnosis of clear cell thyroid neoplasms, and points out the fact that immunohistochemical staining for thyroglobulin should be systematically performed.

[Carcinoma arising within mammary fibroadenomas. A study of six patients]. / Carcinomes développés sur adénofibromes mammaires. A propos de six observations.

We report six cases of carcinomas arising within fibroadenomas. Fibroadenoma is a benign neoplasm occurring in young women. Its association with carcinomas is unfrequent and particularly reported in older women. Few data are available on the histologic features of fibroadenomas harboring malignant lesions. In this study, most cases of fibroadenomas showed cysts, sclerosing adenosis, epithelial calcifications or papillary apocrine changes. These fibroadenomas are classified as complex and are a long-term risk factor for breast cancer. The complex fibroadenoma may be specific of fibroadenoma associated with carcinoma.

[Mycotic infection in immunosuppressed patients. An anatomopathologic study]. / Les infections mycosiques chez les immunodéprimés. Etude anatomo-pathologique.

Mycotic infections are a frequent and often severe complication in the immunosuppressed patient. A review of autopsy findings in 54 cases with gross, histologic and mycologic studies was undertaken among immunocompromised patients after chemotherapy or allogenic bone marrow transplantation: fungal infections were either localized especially in lungs and gastrointestinal tract, or disseminated. Fungi were various: principally Candida and Aspergillus, but also Fusarium, Torulopsis and Trichosporon. In acquired immunodeficiency syndrome (11 autopsy cases), mycotic infections appeared different. Oral and esophageal candidiasis could be found, but cryptococcosis and histoplasmosis were the major generalized mycosis. This study suggests that fungal infections are not the same in patients treated by chemotherapy or bone marrow transplantation, and in acquired immunodeficiency syndrome.

[Rare diseases of the ear: fibrous dysplasia of the tympanic bone, extensive papillomatosis, ceruminoma, aspergilloma, spontaneous évidement of the tympanic bone]. / Quelques affections rares de l'oreille: dysplasie fibreuse du tympanal, papillomatose extensive, céruminome, aspergillome, évidement spontané du tympanal.

The authors report six cases of rare ear diseases: fibrous dysplasia of the tympanum mimicking an partially obstructive osteoma of the external auditory canal. The authors draw a parallel between the rarity of these monostotic forms of the temporal bone which are strictly localised to a single region (tympanum-mastoid-atrium) and the diffuse forms which involve several regions at the same time; extensive papillomatosis of the external and middle ear, a rare condition with serious repercussions; two ceruminomas with very different clinical presentations and outcomes; an atrial pseudo-tumoral aspergilloma which was easily excised ans repaired with a myringoplasty with a good long term result; hypoplasia of the tympanum, which constituted a spontaneous évidement, discovered at operation for an attic cholesteatoma. This finding was sufficiently unusual to warrant reporting.