Histo-cytological diagnostic accuracy in lung cancer.

OBJECTIVE: The majority of patients with lung cancer are treated on the basis of a diagnosis made from the analysis of a small tumour biopsy or a cytological sample and histotype is becoming a critical variable in clinical workup as it has led to the introduction of newer biologically targeted therapies. Consequently, simply classifying cancers as small cell lung cancers or non-small cell lung cancers is no longer sufficient. METHODS: From 2009 to 2011, a review of the histo-cytological database was conducted to identify all small biopsy and cytology specimens collected for diagnostic purposes in patients with a thoracic lesion. In total, 941 patients were studied by examining exfoliative and/or aspirative cytological samples. To establish the accuracy of these methods, cytological and biopsy diagnoses were compared with each other and with subsequent resection specimens when available. Moreover, during the diagnostic workup, we examined a validated panel of immunohistochemical markers. RESULTS: The diagnostic concordance of pre-operative diagnoses with surgical samples was high in both cytology and biopsy samples [κ = 0.71, confidence interval (CI) = 0.6-0.81; P < 0.0001 and κ = 0.61, CI = 0.41-0.82; P < 0.0001 respectively; good agreement] but concordance between cytology and biopsy was moderate (κ = 0.5, CI = 0.43-0.54; P < 0.0001). Immunohistochemistry-aided diagnoses were definitive for histotype in 92.8% of both cytology (206/222) and biopsy (155/167) specimens. CONCLUSION: We found that lung cancer diagnosis and subtyping of cytology and biopsy samples are highly feasible and concordant; thus, the diagnostic approach to lung cancer does not require more invasive procedures.

Thymomas: clinical-pathological correlations.

AIM: Since World Health Organization (WHO) histologic typing of tumors of the thymus publication in 1999 only a few studies correlated this classification with the clinical features of the patients. We present the results of a retrospective analysis on patients, operated on for a thymoma, whose specimens were available, to compare the WHO thymoma histologic classification to the clinical behavior of the tumors. METHODS: The specimens of 69 patients, who underwent surgical treatment between 1983 and 1998, were analyzed, comparing the clinical features of the patients and the hystological typing of the neoplasm, according to the WHO classification. A survival analysis of clinical and pathological prognostic factors was carried out. RESULTS: The incidence of thymus-related syndrome was related to the histological subtype and increases progressively from A to B3, while in C subtype the incidence was nihl. With a mean follow-up of 108 months (range 54-239 months), we experienced 6 intrathoracic recurrencies, 3 of those were intrapleuric and 3 mediastinal. At the last follow-up, 52 patients were alive; 1 with disease. Five deaths were related to the tumor (2 mediastinal and 3 intrapleuric relapses). Actuarial five-year and ten-year survival was 95% and 88.9%. Because of the absence of deaths related to thymomas in most samples it was not possible to perform a comparison among different histological types and different clinical stages. CONCLUSIONS: The WHO histologic classification seems to correlate with the incidence of thymus related syndromes and the clinical stage of Masaoka. Despite the higher incidence of recurrences in type B3 and C thymoma the WHO classification did not prove to be a prognostic factor.

Immunostaining of cathepsin-d in nonsmall cell lung-cancer - correlations with morphological and biological parameters.

Cathepsin D expression has been assessed by immunohistochemistry in 108 cases of Non-Small Cell Lung Cancer (NSCLC) and its expression has been related to conventional prognostic factors such as tumor size, tumor grade, histotype and nodal involvement. The cancer cells in 41.6% of the tumors showed a granular, cytoplasmic cathepsin D (C-D) positivity. Moreover, some benign macrofage-like stromal cells expressed similar positivity. The C-D immunoreactivity was significantly associated with non-squamous histotype, small size, less advanced and more differentiated cancers. Additionally, in non-squamous tumors we observed a higher significant expression in early-staged (T1-2, NO) than in more advanced neoplasias. No significant associations were found between C-D and Ki-67, PCNA immunoreactivity, DNA ploidy or flow cytometric S-phase data. These findings suggest that NSCLCs also express C-D but, as previously reported for breast cancers, the immunohistochemical C-D expression has a good prognostic significance unlike the results obtained by cytosolic evaluation.

Surgical approaches to membranous tracheal wall lacerations.

BACKGROUND: Smaller postintubation tracheal tears are often misdiagnosed and, when recognized, they are effectively managed in a conservative fashion. Large membranous lacerations, especially if associated with important manifestations, require immediate surgical repair. We report our experience over the past 7 years. METHODS: From 1993 to 1999, 11 patients with a postintubation posterior tracheal wall laceration were treated in our institution. One patient was male and 10 were female, with a mean age of 68 years. Ten patients underwent orotracheal intubation under general anesthesia for elective surgery, 4 of whom were treated with a double-lumen selective tube. One patient underwent emergency intubation because of anaphylactic shock. In 9 cases the tracheal tear was promptly repaired, by way of a thoracotomy in 4 and by way of a cervicotomy and longitudinal tracheotomy in 5. In 2 cases the tear was small and was consequently managed conservatively. RESULTS: All surgical procedures proved effective in repairing the laceration, and there was no mortality or morbidity in the perioperative period. Early and late endoscopic follow-up showed no signs of tracheobronchial stenosis. CONCLUSIONS: When repair of membranous tracheal laceration is required, the surgical approach should be through a thoracotomy if the tear involves the distal trachea, a main stem, or both, and through a cervicotomy when the laceration is located in the proximal two thirds of the trachea. Performing a longitudinal tracheotomy to reach and suture the posterior tracheal wall is a reliable, quick, and safe procedure, and it avoids lateral and posterior dissection of the trachea.

Combined Nd-YAG laser/HDR brachytherapy versus Nd-YAG laser only in malignant central airway involvement: a prospective randomized study.

BACKGROUND: Laser debulking and prosthetic stents are useful modalities in the palliative treatment of initial inoperable or recurrent lung cancer. Recently, endobrochial brachytherapy was introduced to extend the duration of palliation and reduce the number of endoscopic treatments. This trial compares Nd-YAG laser alone and associated to high dose rated (HDR)-brachytherapy. PATIENTS AND METHODS: From 1995 to 1998, 29 consecutive patients, with non-small cell lung cancer (NSCLC) and central airway involvement, were randomized in two groups: group 1 (15 patients) received Nd-YAG laser only; group 2 (14 patients) underwent a combined Nd-YAG laser/ HDR brachytherapy treatment. RESULTS: There was no mortality or morbidity related to the treatment. The period free from symptoms was 2.8 months for group 1 and increased to 8.5 months in group 2 (P<0.05). The disease's progression free period grew from 2.2 months of group 1 to 7.5 months of group 2 (P<0.05) and the number of further endoscopic treatment reduced from 15 to 3 (P<0.05). CONCLUSION: The results confirm the potential of brachytherapy to prolong relief from symptoms, lessen disease progression and reduce costs of treatment. A detailed analysis is presented of both groups.

Pre-operative chemotherapy for stage IIIa (N2) non-small cell lung cancer.

From June 1990 to December 1993, 36 patients were enrolled in a phase II study, aimed at determining the feasibility of surgery, patterns of disease recurrence and survival after neoajuvant chemotherapy in non-small cell lung cancer (NSCLC) stage IIIA-N2. Twenty-seven patients underwent invasive staging procedures (i.e. mediastinoscopy or needle biopsy). Two CHT schedules were used. Cisplatin (P) 90 mg/mq, day 1, mitomycin (M) 6 mg/mq, day 1, and vindesine (V) 5 mg/mq, days 1, 8, 15, were administered every 3 weeks for 3 cycles in the first 20 patients. The last 16 patients were treated with cisplatin (P) 90 mg/mq, day 1, mitomycin (M) 6 mg/mq, day 1, and vinorelbina 20 mg/mq, days 1, 8, 15. Thoracotomy was performed 15-20 days after haematological recovery in the objective-responders. Thirty-two patients were evaluable for response to CHT. The overall objective response (OR) rate was 78.1%. There were three complete (CR) (9.4%) and 22 partial responses (PR) (68.7%). The 25 patients with OR underwent radical surgery (16 pneumonectomies, one bilobectomy, seven lobectomies and one wedge resection). The only morbidity reported was a late broncho-pleural fistula (on post-operative day 37). There were three post-operative deaths in patients who underwent pneumonectomy: two due to an empyema following a broncho-pleural in fistula and one by pulmonary embolism. Histology was negative for the three CRs. Six patients with residual nodal involvement at surgery underwent radiotherapy. Relapse occurred in seven resected patients. Presently 14 patients are alive, all but one being disease-free, with a median follow-up of 30.5 months (15-47). Median survival was 31 months (5-47). Actuarial 3-year survival rate is 49%. Our results confirm the high response rate of CHT, as well as the feasibility and the overall low complication rate of both treatments (CHT and surgery).

Posterior wall laceration of the thoracic trachea: the transcervical-transtracheal approach.

A large membranous wall laceration of the thoracic trachea was surgically treated. The surgical approach consists on a low collar incision followed by a longitudinal tracheotomy. The membranous tear was repaired with a running suture and tracheotomy sutured with interrupted crossed stitches. The procedure was effective and endoscopic follow-up showed a perfect healing process with no signs of tracheal stenosis. This new technique proved to be a reliable, quick and safe procedure, which allows to repair membranous lacerations as far as the carina, avoiding thoracotomy.

Acute major airway injuries: clinical features and management.

OBJECTIVE: Patients with an acute major airway injury are coming at our attention with increasing frequency. Despite of its nature, post-traumatic or iatrogenic, these lesions may be life-threatening. An early diagnosis and a prompt treatment reduce morbidity and mortality. MATERIALS AND METHODS: In the last 10 years, on a total of 55 patients treated in our institution for benign lesions of the major airway, 20 were with an acute injury; eleven females and nine males with a mean age of 58 years (range of 24--92). Twelve lesions were iatrogenic (orotracheal intubation) and eight were post-traumatic (three blunt traumas, five penetrating traumas). The cervical trachea was involved in 13 cases (one associated to an incomplete esophageal transection and two associated to laryngeal injuries), the thoracic trachea in six cases (four extended to the right mainstem one and to the left). Sixteen patients underwent immediate surgical repair (13 direct sutures of the tear and three complex restorations of the airway): 11 by cervicotomy and five by thoracotomy. In six cases the suture of a posterior tracheal wall tear was achieved through a new approach which provides for a small collar incision and a longitudinal tracheotomy. RESULTS: All the patients were discharged healed with a normal patency of the airway. At a mean follow up of 49 months (range of 9--122) endoscopy showed a perfect healing process of the lesions. One patient, treated in a conservative fashion, required endoscopic laser Nd-YAG removal of a granuloma. CONCLUSION: Early diagnosis and surgical repair are the goals to persecute to achieve the best outcomes in this potentially lethal lesions. The surgical approach should be the thoracotomy if the trauma involves the 1/3 inferior trachea and/or a mainstem, the cervicotomy in the case it was injured the 2/3 superior trachea and the larynx. Posterior tracheal wall tears may be repaired via the new transcervical/transtracheal technique. The conservative treatment should be reserved to those patients with minimal signs and symptoms, and with an adequate patency of the airways.

Surgery in the management of small cell lung cancer.

OBJECTIVE: We analyzed our experience in the period January 1975-December 1995 aiming to confirm the role of surgery in the multimodality treatment of small cell lung cancer (SCLC). METHODS: 127 patients (5.28% of the overall lung resections for carcinoma) underwent surgery for SCLC. The median age was 60 years (range 34-73). In 87 patients (68.5%) a pre-operative tissue diagnosis was effected and those patients underwent a complete staging procedure. Fifteen patients received up to six complete courses of neoadjuvant and adjuvant chemotherapy. The surgical procedures included: 50 pneumonectomies, 71 lobectomies and six wedge resections. Two patients experienced a local recurrence and a completion pneumonectomy was performed. RESULTS: The median follow-up is 66 months (range 6-214). The 5-year actuarial survival rate is 22.6% (median 18 months). Twenty-three patients are still alive, 21 of them being disease-free. Considering the most conspicuous group of patients (n = 92) treated by surgery and adjuvant chemotherapy, the survival data were 47.2, 14.8 and 14.4% for Stage I, II and III, respectively (P = 0.001). NO patients had a significantly better survival than N1 and N2 patients (P = 0.035). CONCLUSIONS: Surgery and adjuvant chemotherapy might represent an effective form of treatment of limited SCLC without lymph-node involvement. The role of surgery is yet to be verified as regards N1 and N2 status, where even neoadjuvant chemotherapy has not achieved the hoped-for results (no patient reaching a 2-year survival).

Second primary lung cancer and relapse: treatment and follow-up.

During a 14-year period (1980-1993) second primary lung cancer or relapse was treated in 44 consecutive patients. Thirty-seven patients had synchronous (n = 18) or metachronous (n = 19) second primary lung cancer. Ten synchronous tumors were ipsilateral and treated contemporarily with five pneumonectomies, three lobectomies and two double wedge resections. The bilateral synchronous lesions (8 patients) were treated by staged bilateral thoracotomy (mean interval; 2 months). The first resection consisted of a lobectomy in six patients and wedge resection in two. The second one was a wedge resection in six patients and a lobectomy in two. In the metachronous presentation 15 patients (79%) were asymptomatic and detected by follow-up chest X-ray. In this group the first operation was a lobectomy in 12 patients, a wedge resection or segmentectomy in 6 and a pneumonectomy in 1. The second one was a wedge resection in nine patients, a lobectomy in six and completion pneumonectomy in four. Seven patients, all of them asymptomatic, had local recurrence from their primary lung cancer. The first lung resection was a lobectomy in five patients and a wedge resection in two. The second one was completion pneumonectomy in five patients and completion lobectomy in two. We had no operative death. The actuarial over-all 5-year survival rate after the second pulmonary resection for second primary lung cancer was 38.3% with a median survival time of 13.5 months. The synchronous presentation had a better survival than the metachronous one (46.2% and 25.9%), respectively). The actuarial overall 5-year survival rate for patients with relapse was 38.1% with a median survival time of 37 months. We may conclude that an aggressive surgical approach is safe, effective and warranted in patients with either a second primary lung cancer or relapse from their primary lung cancer. Moreover, for early detection of the second lesions, follow-up at a maximum of 6-monthly intervals should be continued for more than 5 years after the first resection.

Tumor angiogenesis and biologic markers in resected stage I NSCLC.

OBJECTIVE: Microvessel count (MC), as a measure of tumor angiogenesis, has been shown to be significantly correlated with metastatic disease in cutaneous, mammary, prostatic, head and neck cancer. We have previously assessed the role of intensity of angiogenesis as predictor of metastasis in surgically resected T1N0M0 NSCLC. We needed to confirm its value, in a prospective larger study on Stage I NSCLC, before its utilization as a prognostic tool for further clinical investigations. METHODS: In the present report we prospectively investigated 227 patients (206 males, 21 females; median age 65 years) with Stage I NSCLC treated only by radical surgery between March 1991 and December 1994 with utmost care for some biological characteristics (proliferative activity, the blood vessel invasion, angiogenesis and the p53 protein expression). RESULTS: The operative procedures consisted of 62 pneumonectomies, 148 lobectomies and 17 segmentectomies or wedge resections. With a median follow-up of 36 months (range 15-60), eighty patients have already experienced a local (n = 22) or systemic (n = 58) relapse. Univariate analysis revealed that T factor (T1 versus T2)(P = 0.008) and angiogenesis count (< or = versus > median, 17) (P = 0.0006) were significant predictors of survival. The same variables were also significant predictors of long Disease Free Survival (P = 0.006 and P = 0.004, respectively). On multivariate analysis, however, only the microvessel count retained its level of prognostic significance as regards both overall (P < 0.01) and disease-free survival (P < 0.01). CONCLUSIONS: The present study corroborates the role of angiogenesis in the metastatic spread of NSCLC and emphasizes its value in the identification of patients in whom surgery should be supplemented by systemic treatment.

[The diagnosis of primary lesions of the anterior mediastinum]. / Diagnostica delle lesioni primitive del mediastino anteriore.

The treatment of anterior mediastinal tumours is often subordinated to histological diagnosis. Sometimes topographic, radiographic and clinical criteria are sufficient to indicate surgical therapy. From January 1988 to June 1992, 31 patients (40.7%) underwent immediate surgery, while 47 patients (59.3%) underwent fine needle aspiration and Trucut biopsy under ultrasonographic or computed tomographic guidance. Thirteen of these patients had also an anterior mediastinotomy according to McNeill-Chamberlain technique. In 36 patients it was possible to verify accuracy of diagnostic procedures comparing these specimens with surgical histological reports. Only 3 patients had minimal complications. No patients undergone anterior mediastinotomy had morbidity or mortality. Our reports show that transthoracic fine needle aspiration and Trucut biopsy have a diagnostic accuracy of 72% and 83% respectively in identifying malignant from benign lesions. These procedures are not adequate to detail diagnosis for tumours with pleomorphic pathologic characteristics (diagnostic accuracy of 39% and 75% respectively). This disagreement is due to false-positive results (one for fine needle aspiration and four for tru-cut biopsies), this discordance occurred in lymphomas and thymomas groups. Such correct diagnosis is very important either for frequency of these tumours either for different therapeutic approach: chemo-radiotherapy in lymphomas and surgery in thymomas.

[Treatment of malignant pleural effusion by percutaneous catheter drainage and chemical pleurodesis]. / Trattamento dell'effusione pleurica maligna mediante drenaggio con catetere percutaneo e pleurodesi chimica.

From June 1989 to December 1991, 93 patients affected by malignant pleural effusion (MPE) were treated as out patients using a ultrasound (US) guided catheter drainage (10F Percuflex pig-tail catheter-Medi-tech@(PTC) and chemical pleurodesis. The PTC was positioned when the MPE had been diagnosed by X-ray and all the patients had undergone some thoracentesis (mean 3.2, range 2-6). We started a chemical pleurodesis when the MPE was inferior to 100cc/day injecting Epidoxorubicin (EDX 30 mg/mq) in the pleural space on alternate day for three administrations, and then, a lyophilized Corynebacterium Parvum (Wellcome strain CN 6134) (CBP 14 mg) on alternate day for two administrations. The complete response rate of this treatment was 90% (86 pt) with a mean treatment period of 32.9 days (range 12-62). Complete response was assessed as total resolution of pleural effusion. Side effects were short-term hyperpyrexia in 65 cases (69.8%) and pleurodynia in 15 cases (15.7%). Three patients (3.1%) were complicated by a pleural infection which was resolved in 1 case and became chronic in 2. These findings indicate that this technique is an adequate treatment for the control of MPE inducing a clinical and quality-life improvement.

[The role of adjuvant therapy in the management of pN2 non-small-cell carcinoma of the lung]. / Ruolo delle terapie adiuvanti nel trattamento del carcinoma polmonare non a piccole cellule pN2.

Over a period of eleven years (1983-1993), the role of adjuvant chemo and/or radiotherapy was evaluated on 222 resected patients (pts) with NSCLC at atage IIIA(N2). All the patients underwent an attentive mediastinal limphoadenectomy. Fifty-five patients had a clinical mediastinal node involvement. 174 pts had a single mediastinal node station involved while 48 had two or more stations involved. One hundred and seventy-one pts (77%) underwent adjuvant therapies, consisting of citotoxic chemotherapy in 40 pts, radioterhapy in 97 pts and chemoradioterhapy in 34 pts. Follow-up lasted until September 1994. Overall 5-yr survival was 17.5%, the median being 17 months. Forty-two pts were, at that moment, still living (median 43.5 months, min 11-max 120) with 37 disease free. We verified a significant difference concerning survival among the three histologic types (p = 0.03), with the squamous achieving the best result (21.3% at 5-yrs). Surgical N2 had a better survival (20/5% at 5-yrs) than the clinical one (9%), (p = 0.01). In particular, if only one nodal station was involved, survival was 21.3% compared to 4.5% when metastases were present at two or more nodal station (p = 0.0001). Considering the level of mediastinal node involvement, the worst prognosis was linked to the carina node metastases (p = 0.02). Survival benefits were obtained by means of adjuvant therapies (20/2% vs 8.1%), (p = 0.0002). Analyzing all the pts, the best survival was achieved in those treated by surgery plus chemo-radiotherapy (32.4%), (p = 0.0001). As regards the squamous cell tumors, pts who underwent surgery plus radiotherapy had the best prognosis (24.2%), (p = 0.0026). Further, in non-squamous cell tumor, chemo-radiotherapy increased survival (45%), (p = 0.0001). At multivariate analysis, only the level of nodal involvement and the adjuvant therapy maintained their statistical significance. Our results prompt us to conclude that: 1) Squamous cell tumors and single nodal station involvement are linked to the best prognosis; 2) Squamous cell carcinoma should be treated by adjuvant radiotherapy; 3) Non-squamous tumors should undergo to chemo-radiotherapy; 4) Clinical N2 (according to our recent experience) may benefit from neoadjuvant chemotherapy.

Interventional bronchoscopy in the treatment of tracheal obstruction secondary to advanced thyroid cancer.

BACKGROUND: Surgery is the choice treatment for symptomatic tracheal obstruction due to malignant thyroid disease. Few additional therapeutic alternatives are available: radiotherapy (RT), chemotherapy (CT) or radioiodine therapy (1311). Only few studies on interventional bronchoscopy (IB) as well as alternative or palliative procedures have been reported so far. This study is a retrospective report of results of IB performed in patients with severe tracheal obstruction due to advanced thyroid cancer. SETTING: Pulmonary and Endocrinology Units of a University Hospital. PATIENTS AND INTERVENTIONS: From January 2, 2000 to March 1, 2004 14 consecutive patients [5 males, mean age: 62.2+/-10.7 (SD) yr] underwent IB due to tracheal obstruction for anaplastic (ATC: 7 patients), differentiated (DTC: 5), medullary (MTC: 1) and non-epithelial malignant (NEMN: 1) thyroid cancer. Eight out of 14 patients had local advanced inoperable disease, 6 had local relapse after surgery, 1311 or RT. Ten out of 14 patients suffered from severe dyspnea. In 4 patients airway patency was maintained by insertion of a stent; in 3 the tracheal lesion was removed by Nd-YAG laser; in 7 both procedures were performed. RESULTS: All 10 patients with dyspnea showed an improvement in symptoms. Early and late complications were observed in 4 and in 3 patients, respectively. All but 4 DTC patients died 11.9+/-14.2 months after the diagnosis (4.20+/-5.1 after IB). In 4 DTC patients still alive 90.7+/-59.2 since diagnosis and 16.7+/-9.2 months since IB, the airway dilatations allowed further treatments like 131-I and/or RT. CONCLUSIONS: Interventional bronchoscopy, including Nd-YAG laser and airways stenting are alternatives to surgery in inoperable thyroid-induced tracheal obstruction. Moreover, airway dilatation improves dyspnea and may allow further treatment.

Prognostic significance of tumoral angiogenesis in completely resected late stage lung carcinoma (stage IIIA-N2). Impact of adjuvant therapies in a subset of patients at high risk of recurrence.

BACKGROUND: Angiogenesis plays a critical role in human tumor growth and metastasis. Microvessel count (MC), as a measure of tumor angiogenesis, has been significantly correlated with metastatic disease in cutaneous, mammary, prostatic, head and neck, and early stage lung carcinoma. METHODS: Ninety-six consecutive patients affected by T1-3N2MO nonsmall cell lung carcinoma (NSCLC), who underwent radical surgery between March 1991 and March 1995 (in many cases followed by adjuvant therapies) were prospectively investigated to assess the prognostic significance of both traditional and new biologic parameters like proliferative activity, blood vessel invasion by tumoral cells, and neovascularization (estimated by the MC). RESULTS: With a median follow-up of 24 months, the projected 3-year survival was 42.1%. Forty-eight of the patients (50%) had already experienced a local (n=14) or systemic (n=34) relapse. The extent of resection (lobectomy vs. pneumonectomy; P=0.0045), the number of mediastinal lymph node levels (single vs. multiple; P=0.014), and the MC (on a X200 field; P=0.015) correlated significantly with metastatic disease. By univariate analysis, significant predictors of survival were: the extent of surgery (P=0.03), adjuvant therapy (P=0.05), and MC (< or = vs. > cut-off; P=0.00076). On multivariate analysis, however, only the MC (P=0.02) retained its level of prognostic significance. CONCLUSIONS: Our results provide evidence that neovascularization, estimated by the MC, can predict metastatic disease and survival in patients with completely resected T1-3N2M0 NSCLC, and may also be useful in patient selection for effective adjuvant treatment.