p53 in node-negative breast carcinoma: an immunohistochemical study of epidemiologic risk factors, histologic features, and prognosis

PURPOSE: The present study explores p53 in relation to the following four aspects of node-negative breast carcinoma: epidemiologic risk factors, tumor histopathology, prognosis, and HER2/neu (HER) expression. MATERIALS AND METHODS: Immunohistochemical (IH) staining for p53 was performed on formaldehyde-fixed, paraffin-embedded primary invasive carcinomas from 440 node-negative patients with a median follow-up duration of 119 months. RESULTS: The IH expression, or lack thereof, of p53 separately or in combination with HER did not prove to be prognostically significant and there was no consistent association of p53 with epidemiologic risk factors. p53 was expressed in 68% of medullary carcinomas (MEDs), which is a significantly higher frequency (P < .001) than in lobular (9%) and duct (23%) carcinomas. p53 was not found in some types of low-grade carcinomas (tubular and papillary), and was observed in a minority of mucinous carcinomas. p53 was present significantly more often in carcinomas with high-grade or poorly differentiated nuclear grade than in low- or intermediate-grade tumors. There was an inverse statistically significant relationship between estrogen receptor (ER) positivity and p53 expression. Tumors with the p53(+)/HER(-) immunophenotype tended to be MEDs or duct carcinomas with a marked lymphoplasmacytic reaction. Infiltrating lobular carcinomas (IFLCs) were largely p53(-)/HER(-). p53(+)/HER(+) carcinomas had the best prognosis. The poorest outcome was associated with the p53(-)/HER(+) immunophenotype. This trend was statistically significant for recurrence-free and overall survival in patients with T1NOMO infiltrating duct carcinoma (IFDC). CONCLUSION: The IH demonstration of p53 was not a reliable prognostic indicator in the node-negative breast carcinoma patients studied and it was not associated with major epidemiologic risk factors. The combined immunophenotypic expression of p53 and HER was significantly associated with some histologic types of breast carcinoma and with prognosis in T1NOMO breast carcinoma.     

Intracellular mucin production by lobular breast carcinoma cells

Slides from ten cases of infiltrating lobular and ten of in situ lobular breast cancer were studied with mucicarmine stain to determine the incidence of intracellular mucin in such cases. Nine of the ten infiltrating carcinomas and six of the ten in situ tumors contained such cells. None of the cases contained infiltrating duct or "colloid" carcinoma and none had in situ carcinoma of major ducts.     

Expression of c-erbB3 protein in primary breast carcinomas

Expression of c-erbB3 protein was investigated in 104 primary breast carcinomas comprising nine comedo ductal carcinoma in situ (DCIS), 91 invasive ductal carcinomas and four invasive lobular carcinomas using two monoclonal antibodies, RTJ1 and RTJ2. Of the 91 invasive ductal carcinomas, seven contained the comedo DCIS component adjacent to the invasive component. An immunohistochemical technique was used to evaluate the association between expression of c-erbB3 and clinical parameters and tumour markers such as epidermal growth factor receptor (EGFR), c-erbB2, cathepsin-D and p53 in archival formalin-fixed paraffin-embedded tumour tissues. Our results indicated that RTJ1 and RTJ2 gave identical staining patterns and concordant results. It was found that the overexpression of c-erbB3 protein was observed in 67% (6/9) of comedo DCIS, 52% (44/84) of invasive ductal carcinomas, 71% (5/7) of carcinomas containing both the in situ and invasive lesions and 25% (1/4) of invasive lobular carcinomas. A significant relationship (P < 0.05) was observed between strong immunoreactivity of c-erbB3 protein and histological grade, EGFR and cathepsin-D, but not with expression of c-erbB2, p53, oestrogen receptor status, lymph node metastases or age of patient. However, we noted that a high percentage of oestrogen receptor-negative tumours (59%), lymph node-positive tumours (63%) and c-erbB2 (63%) were strongly positive for c-erbB3 protein. We have also documented that a high percentage of EGFR (67%), c-erbB2 (67%), p53 (75%) and cathepsin-D-positive DCIS (60%) were strongly positive for c-erbB3. These observations suggest that overexpression of c-erbB3 protein could play an important role in tumour progression from non-invasive to invasive and, also, that it may have the potential to be used as a marker for poor prognosis of breast cancer.     

Correlation of alpha 2 beta 1 integrin expression with histological type and hormonal receptor status in breast carcinomas

Interactions between cells and extracellular matrix are mediated in part by a family of alpha beta heterodimeric molecules known as integrins. Immunohistochemical studies have shown that benign hyperplastic/neoplastic mammary epithelium expressed high levels of alpha 2 beta 1 collagen/laminin receptor. In contrast, malignant cells of breast carcinoma exhibited marked diminuition or loss of the alpha 2 beta 1 integrin. A correlation has been suggested between the loss of the alpha 2 beta 1 expression and the increased invasiveness of neoplastic cells. This study investigated the expression of alpha 2 beta 1 integrin and its extracellular ligand collagen TV by using monoclonal antibodies on the cryostat section of 124 invasive mammary carcinomas. Two patterns of alpha 2 beta 1 immunoreactivity, i.e. pericellular and basolateral, were identified in breast carcinomas and correlated with their histological type. In most invasive ductal carcinomas of no special type (NOS), integrin staining tended to decrease in both pericellular and basolateral aspects. Loss of basolateral staining for alpha 2 beta 1 integrin corresponded closely to the loss of immunoreactivity for collagen IV. Mucinous and medullary carcinomas showed strongly alpha 2 beta 1 pericellular staining, but no basolateral reactivity or collagen IV expression. Only two of the infiltrating lobular carcinomas expressed strong pericellular reactivity. In 82 ductal carcinomas NOS, the abnormally low expression/absence of alpha 2 beta 1 integrin correlated with estrogen and progesterone receptor negativity (p < 0.04 and p < 0.002, respectively). No correlation between integrin expression, histological grade, nodal involvement and proliferative activity was found. The results of the present study suggest that changes in alpha 2 beta 1 expression correlate with the histological type and hormonal receptor status in breast carcinomas. The clinical implications of these findings remain to be elucidated.     

Occurrence of asthma and chronic bronchitis among female hairdressers. A questionnaire study

AIMS: We examined the relationship between apoptosis and three different major stages of human breast carcinoma: intraductal carcinoma (DCIS), infiltrating duct carcinoma (IDC) and metastatic carcinoma in lymph nodes. We also determined the correlation between apoptosis and oestrogen receptor (ER), progesterone receptor (PR) and p53. METHODS AND RESULTS: The study investigates the extent of apoptosis in 63 breast carcinomas by in-situ end-labelling, in formalin-fixed, paraffin-processed tissue sections. The 63 breast carcinomas, included 22 DCISs, 26 IDCs, three infiltrating lobular carcinomas (ILC) and 12 metastatic lymph nodes. The apoptotic labelling index was higher in DCIS than IDC and metastatic carcinoma (P < 0.001, P < 0.007, respectively). By immunohistochemistry, we also analysed p53, ER and PR. Apoptosis correlated significantly with p53 (r = 0.748, P = 0.0004) in IDC. Also, ER correlated significantly with PR (r = 0.629, P = 0.00001). No apparent correlation was found between the apoptosis and ER or PR. CONCLUSION: Our data suggest that not only does apoptosis differ between intraductal carcinoma and infiltrating carcinoma but also it might be regulated by altered p53 expression.     

Immunohistochemical distribution pattern of intermediate filament proteins and muscle actin in feline and human mammary carcinomas

Thirty-seven feline and 38 human spontaneous mammary gland carcinomas were studied immunohistochemically. Commercially available antibodies directed against high and low molecular weight keratins (RCK-102 and NCL-5D3), vimentin, desmin, glial fibrillary acidic protein (GFAP), neurofilament (NF) proteins and muscle actin (HHF35) were used in the avidin biotin peroxidase complex (ABC) technique on formalin-fixed paraffin wax-embedded tumour tissue samples. Healthy feline and human mammary gland tissue adjacent to the neoplasms was also examined. The distribution pattern of intermediate filament proteins and muscle actin was comparable in healthy mammary gland tissue of the two species: both RCK-102 and NCL-5D3 antibodies reacted with luminal epithelial cells of ducts and acini, but basal/myoepithelial cells were stained by RCK-102 exclusively. In addition, basal/myoepithelial cells expressed vimentin and muscle actin in both species, and GFAP was found in some feline basal/myoepithelial cells. No immunoreactivity to desmin and NF proteins was observed. Feline mammary gland carcinoma cells reacted with RCK-102 (89%), NCL-5D3 (62%), vimentin (76%) and GFAP (30%) antibodies, while human mammary gland carcinoma cells reacted with RCK-102 (95%), NCL-5D3 (100%) and vimentin (13%) antibodies. HHF35 immunoreactivity was observed in stromal cells only. These results indicate that mammary gland carcinomas of both species share a heterogeneous immunophenotype with respect to intermediate filament proteins, which adds to the list of known similarities between mammary gland carcinomas of both species.     

The intermediate filaments and prognostically oriented morphological classification in ductal breast carcinoma

The expression of cytokeratins 7, 8, 14, 18, 19 and vimentin was examined in 100 cases of ductal invasive breast carcinomas. While the predominantly diffuse immunohistological positivity of simple epithelia cytokeratins 7 (in 93), 8 (in 100), 18 (in 100) and 19 (in 97) cases represents a constant feature of these tumors, cytokeratin 14 was detected in only 36 cases which were mostly of low grade and in a focal pattern. Vimentin positivity was found in 53 intermediate and high grade tumors and, again the pattern was also rarely diffuse. The ductal carcinomas can be grouped into four classes according to vimentin and cytokeratin 14 immunoreactivity. This grouping correlates well with tumor grade and with simple histological classification of ductal breast carcinoma, consisting of the low, intermediate and high malignancy categories, as proposed here. The types ofductal carcinomas can be sorted into prognostically different subgroups, according to ICD-O morphologic terminology and commonly adopted results of morphologic and prognostic studies.     

c-Met expression of thyroid tissue with special reference to papillary carcinoma

It has become clear that papillary carcinomas of the thyroid often express the receptor for c-Met/hepatocyte growth factor (HGF) receptor, but little is known about the role of the HGF and c-Met system in the pathogenesis of thyroid carcinoma. In this study, the expression of c-Met/HGF receptor was evaluated in thyroid tissue by western blot and immunohistochemistry, and compared with the concentration of HGF. Clinicopathological characteristics were also compared. Fifteen of 20 papillary carcinomas (75%) showed c-Met bands of 145 kDa. No or only a low frequency of c-Met expression was detected in healthy thyroid tissue (0/5), thyroiditis or Basedow's disease (0/2), adenomatous goiters (0/8), follicular adenomas (1/9, 11%) and undifferentiated carcinomas (0/2). These results were confirmed by immunohistochemistry, but a relatively higher frequency of c-Met expression was detected in adenomatous goiters (25%), follicular adenoma (44%) and papillary carcinoma (100%) using formalin-fixed and paraffin-embedded materials. A strong immunoreaction for c-Met was observed in the tumor cytoplasm of papillary carcinomas among the fibrous tissues situated at the periphery of the tumor. The densitometrically measured expression of c-Met had no relation to tumor stage in papillary carcinoma, but did correlate to the concentration of HGF in papillary carcinomas. In conclusion, in thyroid lesions, c-Met was highly expressed specifically in the cytoplasm of papillary carcinomas. c-Met expression was not related to the aggressiveness of the tumor but was related to the concentration of HGF, which was probably derived from the stroma. Also, the c-Met system might play a role in the pathogenesis of papillary carcinoma of the thyroid.     

Bilateral medialization laryngoplasty

To investigate the possible role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in the prognostic evaluation of primary breast cancer, we studied 86 patients with T1-3 (TNM classification) breast tumours before surgery and compared the tumour FDG uptake, calculated as a standardized uptake value (SUV), with postoperative histopathological findings, steroid hormone receptor status of the tumour, thymidine labelling index (LI) and tissular expression of p53. SUV was significantly higher in infiltrating ductal carcinomas (n = 68; median SUV = 5.6) than in lobular ones (n = 18; median SUV = 3.8), and in grade 3 carcinomas (n = 26; median SUV = 6.2) than in grade 1-2 ones (n = 60; median SUV = 4.9). Moreover, SUV was significantly higher in carcinomas with high levels of p53 (n = 12; median SUV = 9.5) than in those with low levels (n = 48; median SUV = 4.25). By contrast, there was no significant correlation between SUV and the steroid hormone receptor status or LI of tumours. Our data demonstrate that FDG uptake, expressed as SUV, is associated with certain prognostic factors in breast cancer, such as histopathological grading and p53 expression, which can be assessed only by means of postoperative in vitro examinations. Hence, the information provided by FDG-PET is to some extent related to relevant information on tumour biology. The clinical value of these data will have to be confirmed by analysis of the independence of SUV from other prognostic factors by means of a multivariate analysis performed on a larger series of patients with adequate follow-up. If SUV is confirmed as an independent variable, FDG-PET could assume an important role in the determination of appropriate therapeutic strategies for primary breast cancer.     

Pleomorphic lobular carcinoma of the breast: clinicopathologic features of 12 cases

Pleomorphic lobular carcinoma (PLC) of the breast was recently identified as a histologic variant of infiltrating lobular carcinoma (ILC) with a poor prognosis. Twelve cases identified from a large series of breast carcinomas were studied retrospectively. Of 11 cases with adequate follow up, 9 were fatal. This was significantly worse than either infiltrating ductal carcinoma (IDC) or classical ILC (P < or = .002), even when stratified by axillary lymph node status. Among the fatal cases, the median survival time was 2.1 years, significantly shorter than that for classical lobular, but not ductal, carcinoma A distinctive pattern of in situ carcinoma, which has been described as PLC in situ, was identified in 7 of the 12 patients. This in situ component was composed of tumor cells with nuclear atypia, cytologically similar to the invasive tumor. Most PLCs lacked estrogen and progesterone receptors and stained with BRST-2, an antibody to gross cystic disease fluid protein-15, suggesting the presence of apocrine differentiation. In summary, PLC has many of the histologic features of ILC but has anaplastic nuclei, abundant cytoplasm, and apocrine differentiation. PLC is often aneuploid, usually lacks steroid receptors, and has a significantly poorer prognosis than does classical ILC.     

Expression of CD44 standard and CD44 variant 6 in human lung cancer

We immunohistochemically examined the expression of CD44 standard (CD44 st) and CD44 variant 6 (CD44 v6) in 112 cases of primary lung cancer, and their relationship to the clinical milieu, including the clinical stage. In 46 cases of squamous cell carcinoma, expression of CD44 st was observed in 45.7% of the cases, and expression of CD44 v6 was observed in 60.9%. In 43 cases of adenocarcinoma, positive staining of CD44 st and CD44 v6 was seen in 2.3% and 4.7% of the cases, respectively. None of 21 small cell carcinomas was positive for CD44 st or CD44 v6. In squamous cell carcinomas, the expression of CD44 st and CD44 v6 was observed at a rate significantly higher than in other histologic type. Most specimens positive for CD44 st stained positively for CD44 v6. Therefore, it seems likely that the CD44 expression observed in squamous cell carcinoma of the lung was a variant CD44 containing the domain encoded by variant exon 6. The expression of CD44 v6 was not related to the clinical stage. Significant association between CD44 v6 and differentiation of squamous cell carcinoma was seen; 2/7 (28.6%) for poorly differentiated, 19/31 (61.3%) for moderately differentiated, and 7/8 (87.5%) for well differentiated squamous cell carcinomas (p = 0.02 by trend test). It was previously reported that CD44 st and CD44 v6 were expressed in both normal bronchial epithelium and squamous cell metaplasia. These results suggest that the expression of CD44 v6 in squamous cell carcinoma of the lung may reflect the immunohistochemical characteristics of the tissue from which such carcinoma emerge.     

Expression of CD44 variant exons by primary and metastatic oral squamous carcinomas

Abnormal CD44 expression in many neoplasms correlates with behaviour, but reports on its role in oral squamous carcinoma are contradictory. CD44 expression was characterised in a closely matched series of oral carcinomas with and without metastases in both frozen and formalin-fixed tissue and correlated with behaviour and histological grading parameters. Eleven primary oral squamous carcinomas without metastases and nine primary carcinomas with 19 matched metastases were stained immunocytochemically for CD44H and products of variant exons v3, v4/5, v6 and v9. Patterns of staining in frozen and formalin-fixed tissue were correlated with invasive front grading and behaviour using exact inferential statistics. Most primary carcinomas stained for all exons tested but some showed loss of expression of v4/5. Loss of expression was more marked in metastases, but there was no correlation between expression and behaviour or grade. Stromal surfaces of epithelial cells often expressed variant exon products reflecting loss of polarity. This, together with selective loss of v4 and v5 in primary carcinomas and their more frequent loss in metastases, suggests that CD44 may play a role in metastasis of some oral squamous carcinomas.     

Tubulolobular invasive breast cancer: a variant of lobular invasive cancer

Attention is directed to an apparently unique form of invasive breast cancer designated as tubulolobular invasive cancer. These neoplasms exhibit small tubules as well as cords of neoplastic cells in a lobular configuration reminiscent of lobular invasive carcinoma. The clinical and pathologic characteristics encountered in 24 examples were statistically compared with those of infiltrating ductal carcinomas without special specific features, pure tubular, and pure lobular invasive cancer. The results of these analyses as well as the morphologic characteristics of these lesions prompt the conclusion that this lesion represents a tubular variant of lobular invasive carcinoma. Short term treatment failure rates in patients with tubulolobular invasive carcinoma are intermediate between those of pure tubular cancer and lobular invasive carcinoma.     

Breast cancer screening: first round in the population-based program in Valencia, Spain. Collaborative Group of Readers of the Breast Cancer Screening Program of the Valencia Community

PURPOSE: To analyze the results of round 1 of the population-based Valencia Breast Cancer Screening Program. MATERIALS AND METHODS: In this program, 78,224 (72.98%) of the 107,178 women invited (aged 45-65 years) underwent screening. Complementary views were obtained in 5,771 women (7.38%). Among the total population studied, 3,502 (4.48%) underwent short-term mammographic follow-up studies; 3,898 (4.98%) underwent additional studies and treatment at hospitals. Five hundred eighty-seven women (0.75%) underwent biopsy. RESULTS: Cancer was detected in 334 patients (4.27 cancers per 1,000 women [3.24 per 1,000 women aged 45-49 years, 6.30 per 1,000 women aged 60-65 years]; six patients with lobular carcinoma in situ excluded). The estimated sensitivity was 89%; specificity, 99%. The positive predictive value of mammography was 8.56%; of mammography with additional examinations, 26.82%; and of biopsy, 56.89%. Forty-one patients (12.28%) had ductal carcinoma in situ; 284 (85.03%) had infiltrating carcinoma. In 73 (25.70%) of the 284 patients, infiltrating carcinomas were smaller than 1 cm. Two hundred twenty-five patients (76.27%) had no lymph node involvement. One hundred seventy-nine (61.09%) had stage 0 or 1 cancer. CONCLUSION: Results are consistent with other published results; differences are due to methods and patient population characteristics.     

Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer

PURPOSE: To identify predicting factors for local failure and increased risk of distant metastases by statistical analysis of the data after breast-conserving treatment for early breast cancer. METHODS AND MATERIALS: Between January 1976 and December 1993, 528 patients with nonmetastatic T1 (tumors < or = 1 cm [n = 197], >1 cm [n = 220]) or T2 (tumors < or = 3 cm [n = 111]) carcinoma of the breast underwent wide excision (n = 435) or quadrantectomy (n = 93) with axillary dissection (negative nodal status [n-]: 396; 1-3 involved nodes: 100; >3 involved nodes: 32). Radiotherapy consisted of 45 Gy to the entire breast via tangential fields. Patients with positive axillary lymph nodes received 45 Gy to the axillary and supraclavicular area. Patients with positive axillary nodes and/or inner or central tumor locations received 50 Gy to the internal mammary lymph node area. A boost dose was delivered to the primary site by iridium 192 Implant in 298 patients (mean total dose: 15.2+/-0.07 Gy, range: 15-25 Gy) or by electrons in 225 patients (mean total dose: 14.8+/-0.09 Gy, range: 5-20 Gy). The mean age was 52.5+/-0.5 years (range: 26-86 years) and 267 patient were postmenopausal. Histologic types were as follows: 463 infiltrating ductal carcinomas, 39 infiltrating lobular carcinomas, and 26 other histotypes. Grade distribution according to the Scarff, Bloom, and Richardson (SBR) classification was as follows: 149 grade 1, 271 grade 2, 73 grade 3, and 35 nonclassified. The mean tumor size was 1.6+/-0.3 cm (range: 0.3-3 cm). The intraductal component of the primary tumor was extensive (EIC = IC > or = 25%) in 39 patients. Tumors were microscopically bifocal in 33 cases. Margins were assessed in the majority of cases by inking of the resection margins and were classified as positive in 13 cases, close (< or = 2 mm) in 21, negative (>2 mm tumor-free margin) in 417, and indeterminate in 77. Peritumoral vascular invasion was observed in 40 patients. Tamoxifen was administered for at least 2 years in 176 patients. At least six cycles of adjuvant systemic chemotherapy were administered in 116 patients. The mean follow-up period from the beginning of the treatment was 84.5+/-1.7 months. RESULTS: First events included 44 isolated local recurrences, 8 isolated axillary node recurrences, 44 isolated distant metastases, 1 local recurrence with synchronous axillary node recurrence, 7 local recurrences with synchronous metastases, and 2 local recurrences with synchronous axillary node recurrences and distant metastases. Of 39 pathologically evaluable local recurrences, 33 were classified as true local recurrences and 6 as ipsilateral new primary carcinomas. Seventy patients died (47 of breast carcinoma, 4 of other neoplastic diseases, 10 of other diseases and 9 of unknown causes). The 5- and 10-year rates were, respectively: specific survival 93% and 86%, disease-free survival 85% and 75%, distant metastasis 8.5% and 14%, and local recurrence 7% and 14%. Mean intervals from the beginning of treatment for local recurrence or distant metastases were, respectively, 60+/-6 months (median: 47 months, range: 6-217 months) and 49.5+/-5.4 months (median: 33 months, range: 6-217 months). After local recurrence, salvage mastectomy was performed in 46 patients (85%) and systemic hormonal therapy and/or chemotherapy was administered to 43 patients. The 5-year specific survival rate after treatment for local recurrence was 78+/-8.2%. Multivariate analysis (multivariate generalization of the proportional hazards model) showed that the probability of local control was decreased by the following four independent factors: young age (< or = 40 yr vs. >40 yr; relative risk [RR]: 3.15, 95% confidence interval [CI]: 1.7-5.8, p = 0.0002), premenopausal status (pre vs. post; RR: 2.9, 95% CI: 1.4-6, p = 0.0048), bifocality (uni- vs. bifocal; RR: 2.7, 95% CI: 2.6-2.8,p = 0.018), and extensive intraductal component (IC <25% vs. IC > or = 25%; RR: 2.6, 95% CI: 13-5.2, p = 0     

Lobular carcinoma of the breast: cytological features supporting the diagnosis of lobular cancer

Lobular carcinomas have a distinct natural history with a better response to endocrine therapy and a higher incidence of local recurrence and are more often bilateral. The cytological diagnosis of lobular carcinoma permits a discriminating therapeutic approach with pre-operative Tamoxifen, more generous resection margins, and assessment of the contralateral breast. The cytological features of lobular cancer however are not well defined and the low cell yield from such neoplasms can result in a high false negative rate. To determine whether we could improve the pre-operative diagnosis, we reviewed the cytological features of 112 lobular carcinomas. They had small uniform sized nuclei with irregular outlines and inconspicuous nucleoli. The degree of dissociation was similar to duct carcinomas and the incidence of inadequate aspirates was no higher. We found no features that confidently diagnosed lobular cancer or its sub-types. However, using a combination of features, typing of lobular cancer on aspirated material is possible and should be attempted.     

The pathology of the pulmonary arteries in lung tumors

A study was undertaken to analyse the type and extent of pathological changes in the pulmonary arteries in non-small cell malignant tumours of the lung. Large-section histological preparations were made from 33 squamous cell carcinomas and 30 adenocarcinomas (T1 and T2 tumours) and classified according to tumour margin area (zone 1), intermediate area (zone 2) and tumour centre (zone 3). Transmural tumour growth with intraluminal cell formations in the pulmonary artery branches were found in the centre of all adenocarcinomas and 86% of squamous cell carcinomas, involving subsegment, prelobular and lobular arteries. Obstructive and obliterative changes in the pulmonary arteries as the result of tumour compression and secondary fibrosing changes predominantly occurred in the centre of all tumours. They were less common and less marked in zones 1 and 2. -Pulmonary artery branches in lung tumours of stages T1 and T2 showed marked infiltrating, obliterative and secondary inflammatory changes as far as complete vascular occlusions. These observations indicate that cytotoxic drugs, introduced via the systemic circulation, cannot reach and therefore not exert their effects in extensive areas of tumour.