Sentinel node biopsy for high-risk cutaneous nonanogenital squamous cell carcinoma: a preliminary result.

BACKGROUND: Certain patients with squamous cell carcinoma (SCC) have much higher rates of regional nodal metastases than is often reported. This study aims to further validate sentinel lymph node biopsy (SNB) for SCC and the outcome of these patients following SNB. METHODS: 20 patients with high-risk nonanogenital SCC who underwent SNB between 1998 and 2007 were retrospectively reviewed. SNB was performed under local or general anesthesia following lymphoscintigraphy and blue dye injection. RESULTS: The median follow-up from SNB was 24 months. Tumor location included the head and neck (n = 11), extremities (n = 9) and trunk (n = 1). One patient had a positive sentinel node. This patient developed parotid metastases 13 months after refusing a complete neck dissection and is alive with progressive disease after 31 months. Two patients developed regional recurrence after negative SNB (1 is alive and disease free, the other died of progressive disease). Of the remaining patients, 15 are alive and disease free, 1 died of another malignancy and 1 was lost to follow-up. CONCLUSION: SNB for high-risk SCC is feasible and allows early detection and treatment of nodal metastases. Currently, SNB for SCC is not a standard treatment and requires further investigation to determine which patients would benefit best from this procedure.

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors.

PURPOSE: The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. RESULTS: The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001). CONCLUSIONS: These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.

Minimal axillary lymph node involvement in breast cancer has different prognostic implications according to the staging procedure.

It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1-11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72-5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).

Long-term oncological results of breast conservative treatment with oncoplastic surgery.

Oncoplastic surgery combining breast conservative treatment (BCT) and plastic surgery techniques may allow more extensive breast resections and improve aesthetic outcomes, but no long-term oncological results have been published. Long-term oncologic results of 148 consecutive BCT with concomitant bilateral plastic surgery have been analysed and were compared to historical data of BCT trials. Median follow-up was 74 months. Complete excision was obtained in 135 patients (91%); focally involved margins in 8 (5%); and close (<2 mm) margins in 5 (3%). Five patients developed ipsilateral recurrence (3%), 19 (13%) developed distant metastasis and 11 patients died (7.53%). Patients with tumours larger than 2 cm were at greater risk of local recurrences and distant metastasis. Long-term oncologic results of BCT with oncoplastic surgery are comparable with the results of BCT randomized trials.

[Conservative approach for breast cancer. The experience of the European Institute of Oncology]. / L'approccio conservativo al carcinoma mammario.L'esperienza dell'Istituto Europeo di Oncologia.

Conservative surgery represents the standard care for patients with early breast cancer. The aim of this review was to discuss the extension of conservative surgery in controversial fields such as after primary chemotherapy for large tumours or the possibility to repeat conservative surgery for a local reappearance. The project of a conservative approach to breast cancers continues with sentinel node biopsy which is worldwide performed more and more frequently. In our institute sentinel node biopsy is the standard procedure in the axillary staging of breast cancer even in those clinical scenarios which were previously considered either controversial or a contraindication such as in multicentric breast cancer, during pregnancy, in intra-ductal neoplasias, after primary chemotherapy, and male breast cancer. This conservative approach is completed by the possibility to deliver a partial breast irradiation and to provide patients with more personalized adjuvant treatments tailored on the biological features of the tumour.

Breast cancer diagnosed during pregnancy and lactation: biological features and treatment options.

AIM OF THE STUDY: Assessment of biological features and treatment of patients with breast cancer presenting during pregnancy or lactation. PATIENTS AND METHODS: Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PgR), Ki-67, HER2/neu, prognostic markers, treatment and follow-up of 21 patients with breast cancer during pregnancy (BCdP) and 17 with breast cancer during lactation (BCdL) are presented. RESULTS: Median age was 36 and 33 years, median tumour size was 2.4 and 2.5 cm, axillary lymph nodes were positive in 10 of 21 pregnant patients and 11 of 17 lactating patients, respectively. Both ER and PgR were not expressed in six of 21 pregnant women and nine of 17 lactating patients. All the six women who had concurrent diagnosis of breast cancer and pregnancy (first trimester) preferred termination of pregnancy although an alternative option was discussed. Five patients received anthracycline containing chemotherapy during the second and third trimester with no complications for patient and child. Conservative surgery was performed in 15 of 21 patients during pregnancy with no local reappearance after a median follow-up of 24 months. Three pregnant women underwent lymphoscintigraphy and sentinel lymph node biopsy. CONCLUSIONS: Patients who had concurrent diagnosis of breast cancer and pregnancy (early first trimester) preferred termination of pregnancy to allow easier completion of treatment. Conservative surgery was safe also in women with BCdP. Sentinel node biopsy might be considered for pregnant patients with a clinically negative axilla.

Sentinel node localisation: A new prospective in the treatment of nodal melanoma metastases.

Sentinel node (SN) mapping and biopsy is a procedure that accurately stages the regional lymph node (LN) basin. Defined patterns of lymphatic drainage allow intraoperative determination of the first (sentinel) lymph node in the regional basin, and the absence of metastatic disease in the SN accurately reflects the absence of melanoma in the remaining regional nodes. The use of radiocolloid and a hand-held gamma detecting probe (GDP) together with a vital blue dye provides optimal results, and allows for the successful identification of the SN in over 99% of the procedures. Close collaboration between surgeons, nuclear radiologists and pathologists is required to ensure optimal results. Examination of serially sectioned SNs by hematoxylin-eosin staining (H&E), immunohistochemical staining and perhaps in the near future RT-PCR should reduce the number of patients with missed microscopic melanoma in the regional lymph nodes. Furthermore, the survival benefit recently reported in patients with melanoma metastatic to regional nodes using high dose of interferon alpha-2b signals that the surgeons should aggressively examine patients for the presence of occult regional melanoma metastases. Intraoperative SN mapping and SN biopsy are cost-effective procedures that allows accurate identification of regional lymph nodes that contain metastatic melanoma.

Monoclonal proliferation of germinal center cells (incipient follicular lymphoma) in an axillary lymph node of a melanoma patient.

A monoclonal proliferation of germinal center cells within a lymph node follicle was incidentally discovered during the staging surgical procedures in a patient with Clark III-level cutaneous melanoma. In one of the 19 axillary lymph nodes examined, we identified a single morphologically atypical lymphoid follicle, predominantly composed of medium-sized cells and immunoreactive for B-cell antigens and for the markers of germinal center origin CD10 and bcl-6. A monoclonal rearrangement of the immunoglobulins heavy chains (IgH) was documented by polymerase chain reaction after laser capture microdissection. The cells of the aberrant follicle expressed the bcl-2 protein at higher levels than the surrounding T lymphocytes in the absence of bcl-2 gene rearrangement. We propose for this lesion the designation of incipient follicular lymphoma. The present findings also confirm the previously reported association between melanoma and lymphoproliferative disorders.

Is there a role for sentinel node biopsy in early N0 tongue tumors?

BACKGROUND: Detecting metastases to the cervical lymph nodes is the main problem in the management of squamous cell carcinoma of the tongue. We investigated the ability of sentinel node (SN) biopsy to predict neck status in 11 patients with lateral T1-T2, N0, and M0 squamous cell carcinoma of the tongue who underwent ipsilateral neck dissection 30 to 40 days after primary surgery. METHODS: In 5 patients, technetium 99m-labeled particles were injected close to the operation scar on the day before neck dissection, and the labeled neck nodes were revealed by lymphoscintigraphy. The next 6 patients underwent lymphoscintigraphy both before surgery and before neck dissection. During neck dissection, the ipsilateral SNs were identified by using a hand-held probe and removed separately. RESULTS: Three patients (27%) had metastatic neck nodes. In all cases, labeled nodes were revealed by scintigraphy. Ipsilateral SNs were removed from 8 patients and correctly predicted the state of the neck (6 negatives and 2 positives). Lymphoscintigraphy before and after surgery revealed that drainage was modified after surgery in 5 of 6 patients; the pre-surgery drainage pattern varied markedly among the 5 pN0 patients. CONCLUSIONS: The technique allows easy and safe identification of SNs and shows promise in guiding selective neck dissection. Surgery on the primary tumor often modifies lymphatic drainage, so that SN biopsy may only be useful if the primary operation and neck dissection are performed at the same time.

Sentinel node localization in primary melanoma: learning curve and results.

Ninety primary melanoma patients were studied to investigate the importance of adopting the simultaneous use of patent blue dye (PBD) and lymphoscintigraphy plus gamma detection probe to locate the sentinel node (SN). In total 135 SNs in 105 basins were visualized preoperatively under a gamma camera after lymphoscintigraphy. When a SN was identified intraoperatively, its radioactivity level and colour were verified and documented. Two of the SNs seen on lymphoscintigraphy were not found. Using PBD 78.52% of the SNs were identified; 95.5% were identified using the gamma detection probe. Using both methods together 98.5% of the SNs were detected. Twenty-two patients (24.4%) had pathologically positive SNs. The surgical learning curve was assessed for the two techniques. The learning curve associated with the methodology was important in finding the SN when using PBD associated with lymphoscintigraphy, but not when the gamma detection probe was used; we found a statistically significant reduction in the percentage of stained SNs found using PBD in the initial 14 SNs biopsied compared with the subsequent 121 nodes. This is important as not all institutions have access to a gamma probe. The time required to identify each SN was documented and analysed. The duration of the procedure was significantly shorter for stained SNs than for non-stained SNs, which support the use of both PBD and the gamma probe. In conclusion, SN biopsy should be performed by surgeons and nuclear medicine doctors in co-operation, both methods being adopted simultaneously to reduce the percentage of procedure failures.

Medical decision making for melanoma of the glans penis.

This case report describes a rare presentation of penile melanoma in which 3 successive primaries arose and were operated from an area of melanosis on the glans penis and prepuce. One of the major factors accounting for the poor prognosis of this patient was the long delay in presentation. This was largely due to the patient's reluctance because of the site of the disease. When diffuse melanotic areas are present in the genital region, in particular given the reluctance of patients with skin lesions in this region to present, the index of suspicion should be high with respect to the risk of transformation and an aggressive follow-up policy should be advocated. Treatment guidelines should not significantly differ from the usual approach of cutaneous melanoma.

Rare presentation of small bowel leiomyosarcoma with liver metastases.

Intraabdominal sarcomas are rare tumours usually diagnosed at an advanced stage. These lesions at presentation are bulky and symptoms are often related to pressure effects on adjacent organs. This case report describes a rare presentation of a small bowel leiomyosarcoma whose initial presentation was free haemorrhage into the abdominal cavity and concomitant liver metastases. This case report also demonstrates that, even with such a rare presentation, an aggressive surgical approach is indicated in this type of tumour and helps a patient with advanced disease to live a few disease-free months with a good quality of life.

Huge malignant localized fibrous tumor of the pleura.

Localized fibrous tumor is an unfrequent mesenchymal neoplasm. The malignant variant of the pleura is exceptional and differential diagnosis with the more frequent benign type or with other neoplasms such as soft tissue sarcoma and mesothelioma is rarely possible in a preoperative setting. The best treatment of this disease is radical surgical resection. No definitive data exist about the role of chemotherapy. We report a case of a giant right intrathoracic mass whose preoperative diagnosis, from an open biopsy, was consistent with sarcoma and, in a second review, with fibrous tumor of the pleura without any indication about malignancy. A right pleuropneumonectomy and pericardial resection was performed through a right hemiclam-shell approach. Histology demonstrated an aggressive behaviour: high mitosis rate, Ki 67 of 34% and diffuse necrosis were present. In consideration of the apparent local radicality we did not perform any adjuvant treatment. Six months after the operation a wide local recurrence was evident and a systemic treatment with Ifosfamide and Adriamicina is still in progress. So far a good response has been documented. Preoperative diagnosis of malignancy has an important role as a therapeutic strategy in management of fibrous tumours of the pleura. When there is suspicion of a malignant form neoadjuvant chemotherapy can represent a further tool to control poorly differentiated and large tumors, and a wide surgical resection of the lesion must be performed.

Life-threatening giant mediastinal goiter: a surgical challenge.

Mediastinal goiter is a well known benign disease, usually resectable through a cervical approach with minimal morbidity and mortality. Only occasionally a median sternotomy or a lateral thoracotomy may be required. The present case is worthy of presentation because of the exceptional dimension of the disease and the surgical challenge that it presented. In a 72-year-old woman a large intrathoracic goiter of the right thorax caused a severe dyspnoea due to an important contralateral mediastinal shift with compression of the lung, superior vena cava system and trachea. At surgical exploration, through a cervico-sternotomic approach, the mediastinal structures dislocation and the strong adherences between the anomalous neovascularized capsula of the mass and the surrounding structures, complicated the surgical dissection. An accidental lesion of the innominate artery required its reimplantation on the ascending aorta. An immense mass, was finally removed and pathological examination revealed a rare case of neovascularized, pseudosarcomatoid capsula among a benign hyperplastic proliferation. In spite of its benign nature, a giant goiter caused a life-threatening compression of the respiratory tract and lung parenchyma in this patient. The dimension of the lesions, the mediastinal anatomy alterations and the severe intraoperative haemorrhage represented major technical difficulties during surgical resection.

Dual regulation of Myc by Abl.

The tyrosine kinase c-Abl (or Abl) and the prolyl-isomerase Pin1 cooperatively activate the transcription factor p73 by enhancing recruitment of the acetyltransferase p300. As the transcription factor c-Myc (or Myc) is a known target of Pin1 and p300, we hypothesized that it might be regulated in a similar manner. Consistent with this hypothesis, overexpression of Pin1 augmented the interaction of Myc with p300 and transcriptional activity. The action of Abl, however, was more complex than predicted. On one hand, Abl indirectly enhanced phosphorylation of Myc on Ser 62 and Thr 58, its association with Pin1 and p300 and its acetylation by p300. These effects of Abl were exerted through phosphorylation of substrate(s) other than Myc itself. On the other hand, Abl interacted with the C-terminal domain of Myc and phosphorylated up to five tyrosine residues in its N-terminus, the principal of which was Y74. Indirect immunofluorescence or immunohistochemical staining suggested that the Y74-phosphorylated form of Myc (Myc-pY74) localized to the cytoplasm and coexisted either with active Abl in a subset of mammary carcinomas or with Bcr-Abl in chronic myeloid leukemia. In all instances, Myc-pY74 constituted a minor fraction of the cellular Myc protein. Thus, our data unravel two potential effects of Abl on Myc: first, Abl signaling can indirectly augment acetylation of Myc by p300, and most likely also its transcriptional activity in the nucleus; second, Abl can directly phosphorylate Myc on tyrosine: the resulting form of Myc appears to be cytoplasmic, and its presence correlates with Abl activation in cancer.

Extensive frozen section examination of axillary sentinel nodes to determine selective axillary dissection.

As experience accumulates on the use of sentinel node biopsy in breast cancer, it is becoming clear that the method can reliably predict the state of the axilla and thus be used to decide whether to perform complete axillary dissection. Ongoing controlled trials will soon provide definitive evidence on the latter point. The key issue regarding sentinel node biopsy is pathologic evaluation of the biopsied node, which should be done intraoperatively whenever possible. In our initial experience with a conventional intraoperative frozen section method, the false-negative rate was 19% compared to examination of permanent sections of the biopsied node. We therefore devised a new intraoperative method in which pairs of sections are obtained every 50 mm for the first 15 sections and every 100 mm for any remaining node, which essentially samples the entire node; the method takes about 40 minutes. Sentinel node metastases were found in 119 of 295 (40%) of T1N0 breast cancer patients examined by this new method. This high rate of positivity indicates that the new method is reliable. In all cases, metastases were identified on hematoxylin-eosin (HE)-stained sections, although in 4% of positive cases the HE sections were doubtful, and cytokeratin immunostaining on the adjacent section was useful for confirming malignancy. Of 295 patients, 8 (2.7%) had a negative sentinel node but another axillary node metastasis. In conclusion, we found that extensive intraoperative frozen section examination of sentinel nodes correctly predicts a metastasis-free sentinel node in 95.4% of cases (negative predictive value), it is therefore suitable for identifying patients in whom axillary dissection might be avoided. Immunocytochemical staining for cytokeratins or other epithelial markers may be helpful for reducing the risk of missing micrometastatic foci.

p21WAF1/CIP1 expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations.

Defects in the mechanisms controlling the cell cycle are crucial in cell transformation and/or tumour progression. p21WAF1/CIP1 is an inhibitor of cyclin-dependent kinases, induced by p53-dependent and p53-independent pathways, which can block progression through the cell cycle. p21WAF1/CIP1 expression has been investigated immunohistochemically in a series of 191 patients with colorectal cancer of known p53 status. The purpose of the study was two-fold: to assess the relationship between p21WAF1/CIP1 immunoreactivity and p53 alterations, and to evaluate the prognostic significance of p21WAF1/CIP1 expression. In 96 carcinomas (51 per cent), p21WAF1/CIP1 was expressed in over 10 per cent of tumour cells, whereas in 26, p21WAF1/CIP1 was detected in under 10 per cent of neoplastic cells; 69 tumours lacked p21WAF1/CIP1 expression. Immunoreactivity was more frequent in tumours of the right colon (p < 0.003) and was inversely correlated with tumour stage (p < 0.03), p53 gene mutations (p < 0.0007), p53 protein accumulation (p < 0.019), and Bcl-2 expression (p < 0.0005). In univariate analysis, down-regulation of p21WAF1/CIP1 expression was associated with poor overall (p = 0.0022) and disease-free survival (p = 0.0009). Multivariate analysis, however, did not confirm any independent prognostic significance of p21WAF1/CIP1 expression. The results indicate that p21WAF1/CIP1 is associated with abnormal accumulation of p53 protein and the occurrence of p53 gene mutations in colorectal cancer and that lack of p21WAF1/CIP1 expression is correlated with reduced patient survival in univariate analysis. These data underline the crucial pathogenetic role of the p53-p21WAF1/CIP1 pathway in carcinomas of the large bowel.

Reverse transcription-polymerase chain reaction assay for multiple mRNA markers in the detection of breast cancer metastases in sentinel lymph nodes.

The identification of specific tumor mRNA markers by reverse transcription-polymerase chain reaction might be a valuable diagnostic adjunct for the detection of breast cancer metastases in axillary sentinel lymph nodes (SLNs). In this study we have compared the diagnostic accuracy of an extensive histopathologic examination of 146 SLNs from 123 breast carcinoma patients with that of the evaluation of 5 mRNA markers. When analyzed individually, none of the different markers attained a sensitivity higher than 77.8%, and the general concordance with the histopathologic findings ranged from 78.8 to 83.6%. In a multiple-marker assay, taking into account the expression of at least 1 of the 5 tumor markers, the sensitivity of the test rose to 95.6%, with a specificity of 66.3% and a general concordance with the histopathologic status of 75.3%. Finally, when at least 2 of 3 markers (maspin, cytokeratin 19 and mammaglobin 1) were expressed, the concordance with either SLN or axillary lymph node status was highest (88.4% and 84.6%, respectively). The high prevalence of positive reverse transcription-polymerase chain reaction assays in histologically uninvolved SLNs, however, may hamper extensive application of these techniques in the clinical setting.

Mandible reconstruction and autogenous frozen bone graft: experimental study on rats.

The aim of this study was to evaluate the biological behaviour of a frozen bone graft in orthotopic and heterotopic sites in the rat. The previous experimental study on this subject was published 25 years ago without sufficient detail about the histology and comparison between the orthotopic and ectopic sites. Therefore, being very important for future clinical application, we decided to evaluate the frozen bone graft using rats. The procedure was performed on two groups of five rats each (Charles River). After wide dissection of the inferior border of the mandible from the surrounding muscle, an inferior segmental resection 4 mm in length was performed, taking care not to fracture the superior part and to maintain mucosal integrity. This segment was placed in liquid nitrogen for two periods of 10 minutes each with a third period to allow it to reach room temperature. In the first group (A), the frozen segment was placed ectopically in a gluteal muscle pocket, and in the second group (B), the frozen bone was fixed in the same position in the same mandible. After 1 month of follow-up, the animals were killed, the bone graft was removed, and histology was performed. Results were consistent in both groups. In group A, the segment was surrounded by strong inflammatory reaction, with no vital cells or bone cells, but some vascular penetration. We concluded that there was no bone deposition and no bone rehabitation. In group B, the initial segment was strongly fixed to the remaining mandible, there was an increase of the macroscopic dimension that paralleled the increase in the dimension of the remaining mandible and the growth of the animal. The cortical part had thinned down, the medullary part presented signs of bone deposition as well as bone resorption and vascular penetration. The periosteum from the adjacent normal mandible was growing and covering the frozen bone graft, offering additional stimulus to the bone deposition. In conclusion, the frozen bone graft acts as a normal bone graft. It needs to be placed in contact with vascularised bone and surrounded by well vascularised soft tissue to allow deposition of new bone. If the frozen graft is placed ectopically, it will be surrounded by chronic inflammatory reaction with no bone deposition.