Focal Tumor Research Articles

Issues in the assessment of the pathologic effect of primary systemic therapy for breast cancer

Emerging evidence suggests that induction of pathologic complete response (pCR) after primary systemic therapy (PST) is, at least to some extent, predictive of survival. However, standards for processing surgical specimens and for histopathologic evaluation of the pathologic response to therapy appear to be lacking. To perform a systematic review of representative articles on this topic, a computerized (MEDLINE) search was undertaken followed by a manual search based on the reference lists of the publications identified. Several classification systems have been used to assess pathologic response to PST, the term pCR has not been applied in a consistent standardized manner, and only limited information is available about the reliability and validity of these classification systems. However, definitions of pCR can be summarized as follows: near pCR, only focal invasive tumor residues in the removed breast; quasi pCR, total or near total disappearance of invasive tumor in the removed breast; pCRinv, only in situ tumor residual in the removed breast; comprehensive pCR, no evidence of residual invasive tumor in the removed breast; strict pCR, disappearance of all tumor cells in the removed breast; comprehensive pCR (br+n), no evidence of residual invasive tumor in the breast and axillary nodes; strict pCR (br+n), no malignant tumor cells in the removed breast and axillary nodes. Comparison of the use of the term "pCR" in various trials reveals that it is not applied equivalently in these studies. Assessment of pCR needs to be standardized, with verification for reliability and validity. For now, the non-equivalency in the definition of pCR should be taken into account when comparing the results of PST.

Report of an unusual problematic uterine smooth muscle neoplasm, emphasizing the prognostic importance of coagulative tumor cell necrosis

Follow-up data of the clinical behavior of uterine smooth muscle tumors with low malignant potential are scarce. We present a woman suffering from a uterine smooth muscle cell tumor with increased cellularity, absence of significant atypia, and two to three mitotic figures per 10 HPFs but with minimal focal coagulative tumor cell necrosis (CTCN). These microscopic features are currently accepted to label the lesion as a “smooth muscle neoplasm of low malignant potential, limited experience.” After a disease-free survival of 4 years, two retroperitoneal tumors around the iliac vessels were extirpated. Both tumors consisted of smooth muscle cells with mild to moderate atypia and a mitotic index of 5–10 per 10 HPFs but with multifocal and extensive CTCN. These microscopic features were sufficient to establish the diagnosis of leiomyosarcoma. This case adds to the limited experience of the clinical behavior of problematic uterine smooth muscle cell neoplasms and underscores the prognostic importance of CTCN.

Report of an unusual problematic uterine smooth muscle neoplasm, emphasizing the prognostic importance of coagulative tumor cell necrosis

Follow-up data of the clinical behavior of uterine smooth muscle tumors with low malignant potential are scarce. We present a woman suffering from a uterine smooth muscle cell tumor with increased cellularity, absence of significant atypia, and two to three mitotic figures per 10 HPFs but with minimal focal coagulative tumor cell necrosis (CTCN). These microscopic features are currently accepted to label the lesion as a "smooth muscle neoplasm of low malignant potential, limited experience." After a disease-free survival of 4 years, two retroperitoneal tumors around the iliac vessels were extirpated. Both tumors consisted of smooth muscle cells with mild to moderate atypia and a mitotic index of 5-10 per 10 HPFs but with multifocal and extensive CTCN. These microscopic features were sufficient to establish the diagnosis of leiomyosarcoma. This case adds to the limited experience of the clinical behavior of problematic uterine smooth muscle cell neoplasms and underscores the prognostic importance of CTCN.

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria

The field of interventional oncology with use of image-guided tumor ablation requires standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison between treatments that use different technologies, such as chemical (ethanol or acetic acid) ablation, and thermal therapies, such as radiofrequency (RF), laser, microwave, ultrasound, and cryoablation. This document provides a framework that will hopefully facilitate the clearest communication between investigators and will provide the greatest flexibility in comparison between the many new, exciting, and emerging technologies. An appropriate vehicle for reporting the various aspects of image-guided ablation therapy, including classification of therapies and procedure terms, appropriate descriptors of imaging guidance, and terminology to define imaging and pathologic findings, are outlined. Methods for standardizing the reporting of follow-up findings and complications and other important aspects that require attention when reporting clinical results are addressed. It is the group's intention that adherence to the recommendations will facilitate achievement of the group's main objective: improved precision and communication in this field that lead to more accurate comparison of technologies and results and, ultimately, to improved patient outcomes. The intent of this standardization of terminology is to provide an appropriate vehicle for reporting the various aspects of image-guided ablation therapy.

Granular cell tumor of the penis: clinicopathologic evaluation of 9 cases

The occurrence of granular cell tumor (GCT) in penile tissue is very rare, with only 9 examples reported to date in the English-language literature. Herein, we describe the clinicopathologic and immunohistochemical findings in 9 additional cases. The patients ranged in age from 20 to 60 years (mean, 42 years; median, 40 years) at time of diagnosis. All penile tumors were solitary and arose in the dermis of the penile shaft (n=4), prepuce (n=3), and corona (n=2). A patient had a history of multiple cutaneous GCTs. Duration of symptoms before surgery ranged from 5 days to 2 years with the presence of an asymptomatic nodule representing the most common tumor-related complaint (n=8). The lesions ranged in size from 0.6 to 2.5 cm (mean, 1.5 cm; median, 1.5 cm). Microscopically, the tumors were moderate to highly cellular and were composed of oval to polygonal-shaped cells with abundant coarsely granular eosinophilic cytoplasm. Tumor cells grew in infiltrating nests, cords, and trabeculae and showed neural (n=2) and vessel wall (n=1) invasion or formed a relatively well-marginated solid nodule. Bland cytological features with only rare cells showing nucleomegaly (n=7) or spindling (n=3) were exhibited by 8 tumors. A tumor demonstrated diffuse nuclear atypia and was classified as "atypical." Mitotic activity ranged from 0 to 8 mitoses (mean, 1.4 mitoses) per 50 high-powered fields with no atypical division figures identified. All tumors tested showed moderate to strong immunohistochemical expression of S100 protein (n=6) and low-affinity nerve growth factor receptor (n=5), which was useful for detecting small deposits of tumor and helpful in evaluating surgical margins. Focal tumor cell immunoreactivity was observed for calretinin (4/6 cases) and glial fibrillary acidic protein (1/6 cases). All patients underwent simple (local) excision of their tumor. Complete follow-up data (mean, 21 years; interval range, 0.5-28 years) were available for 6 patients. No patient experienced recurrence or metastatic spread of tumor although surgical margins were microscopically involved by tumor in 5 cases. Benign GCT involving superficial soft tissue of the penis can be adequately managed by a simple excision. Patients with microscopically involved surgical margins can be clinically followed without immediate additional surgery.

E-cadherin Suppression Accelerates Squamous Cell Carcinoma Progression in Three-Dimensional, Human Tissue Constructs

We studied the link between loss of E-cadherin-mediated adhesion and acquisition of malignant properties in three-dimensional, human tissue constructs that mimicked the initial stages of squamous cell cancer progression. Suppression of E-cadherin expression in early-stage, skin-derived tumor cells (HaCaT-II-4) was induced by cytoplasmic sequestration of beta-catenin upon stable expression of a dominant-negative E-cadherin fusion protein (H-2Kd-Ecad). In monolayer cultures, expression of H-2Kd-Ecad resulted in decreased levels of E-cadherin, redistribution of beta-catenin to the cytoplasm, and complete loss of intercellular adhesion when compared with control II-4 cells. This was accompanied by a 7-fold decrease in beta-catenin-mediated transcription and a 12-fold increase in cell migration. In three-dimensional constructs, E-cadherin-deficient tissues showed disruption of architecture, loss of adherens junctional proteins from cell contacts, and focal tumor cell invasion. Invasion was linked to activation of matrix metalloproteinase (MMP)-mediated degradation of basement membrane in H-2Kd-Ecad-expressing tissue constructs that was blocked by MMP inhibition (GM6001). Quantitative reverse transcription-PCR showed a 2.5-fold increase in MMP-2 and an 8-fold increase in MMP-9 in cells expressing the H-2Kd-Ecad fusion protein when compared with controls, and gel zymography showed increased MMP protein levels. Following surface transplantation of three-dimensional tissues, suppression of E-cadherin expression greatly accelerated tumorigenesis in vivo by inducing a switch to high-grade carcinomas that resulted in a 5-fold increase in tumor size after 4 weeks. Suppression of E-cadherin expression and loss of its function fundamentally modified squamous cell carcinoma progression by activating a highly invasive, aggressive tumor phenotype, whereas maintenance of E-cadherin prevented invasion in vitro and limited tumor progression in vivo.

Localized Longitudinal Erythronychia

Longitudinal erythronychia (LE) is a term for red streaks in the nail. We describe the range of diseases manifested by localized (single or bifid) LE and explain the underlying physical changes. Longitudinal erythronychia can be multiple or localized. Multiple lesions typically indicate an inflammatory disease such as lichen planus. When localized, they may be a single or bifid streak arising through a benign or malignant neoplasm, scarring of the dermis or epidermis, or the first stage of an inflammatory process that may evolve into multiple LE. Excision of a localized LE may provide a diagnosis and cure. Incisional matrix biopsy of multiple LE may provide a diagnosis. Clinical manifestation of LE arises through reduced compression of the nail bed due to loss of bulk of the nail plate with a groove on the undersurface. A streak of thinned nail then allows an enhanced view of a corresponding streak of engorged nail bed. The reduction in nail thickness renders it more fragile with a tendency to split distally. Understanding LE can assist in diagnosis and explanation to the patient. Localized LE may represent a focal tumor or dysplastic process.

Tumour seeding in peritoneal wound sites in relation to growth-factor expression in early granulation tissue

The purpose of these experiments was to identify growth factors produced during the formation of a peritoneal wound in relation to tumour cell seeding and stimulated growth in granulation tissue. Gelfoam© gelatin sponge was implanted in the mesenteric fan of nude mice to initiate the granulation process. Human HT29 colon carcinoma cells were inoculated intraperitoneally at various times after sponge implantation and tumour growth in granulation tissue was determined. RNA isolated from granulation tissue was used for polymerase chain reaction analysis of the expression of specific growth factors and receptors [vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and lysophosphatic acid (LPA)], and for microarray analysis of differentially expressed genes in early vs. late granulation tissue. Inflammatory cells infiltrated the sponge within 1 day, followed by fibroblasts and the formation of an extracellular matrix. Tumour cell inoculation at 8 h to 3 days after sponge implantation resulted in extensive tumour formation in all cases. Inoculation at 10–28 days resulted in focal tumour growth in only 16–33% of the sponges. Low amounts of VEGF, TGF-β 1−3, TGF-β RIII and LPA receptors 1,2 were detected in early granulation tissue, with increased expression from day 10. Microarray analysis identified additional differentially expressed genes that may stimulate tumour take and growth in early granulation tissue.

Occurrence of avian leukosis virus subgroup J in commercial layer flocks in China

Mortality from myeloid leukosis was observed in commercial layers from 12 farms in northern China. Affected chickens were extremely thin and dehydrated, bleeding occurred in feather follicles and claws, combs were pale and anaemic, phalanges were swollen, and many yellowish–white tumours were seen on the visceral surface of the sternum. Focal tumour cells, with spherical eosinophilic granules in the cytoplasm, were found in the liver, spleen, kidney, ovary, oviduct, lung, bone marrow, proventriculus and gut by histopathological examination. Immunohistochemical studies with a monoclonal antibody to gp85 of avian leukosis virus subgroup J (ALV-J) revealed antigen in all organs examined. Polymerase chain reaction tests using a pair of ALV-J-specific primers H5/H7 (Smith et al., 1998) produced a 545 basepair fragment. The sequence of the Polymerase chain reaction product was compared with that of the ALV-J HPRS-103 prototype strain. The identity of nucleotides and predicted amino acids was 97.4% and 96.1%, respectively. On this basis the disease in the egg-type chickens was diagnosed as an ALV-J infection. This is the first report of field cases of myeloid leukosis caused by ALV-J in commercial egg-type chickens.

From the Editors

SummaryDear colleagues,Interstitial therapies have been introduced in the spectrum of minimally invasive cancer treatments for a decade, meanwhile a standardization has been introduced in the field of image-guided tumor ablation. This is an important criterion for facilitating effective ideas and for performing appropriate comparisons between treatments with different technologies. Tumor ablation and interstitial therapies are defined as a direct application of chemical or thermal therapies to a specific focal tumor in an attempt to achieve eradication or substantial tumor destruction. Via the term “direct” these therapies are defined as a “direct” differentiation from those therapies which are applied orally or via an intravascular approach.In this issue on “Interstitial Therapies” different technologies are presented which are based on well-known groups of different authors who have presented their experience in image-guided interstitial therapies for the treatment of lung, liver, and head and neck neoplasms. Although at present there are many technologies under investigation, the present issue aims at showing that image-guided tumor ablation has become an integrated part in modern oncology, opening the field of interventional oncology for the future.We do wish to inspire the reader to get involved in this field of interstitial therapies, which is, in fact, one of the most fascinating, exciting and rapidly growing ones.Thomas J. VoglNahum Goldberg

Stereotactic radiosurgery for brain metastases from gastrointestinal tract cancer

Background Outcomes in patients with brain metastases from gastrointestinal tract cancers are not well defined. In this study we used precise, single-session, focal tumor irradiation (radiosurgery) in patients with brain metastases and evaluated the results. Methods Thirty-nine patients had brain metastases from gastrointestinal tract cancer and were treated with radiosurgery. Thirty-two also had whole brain radiotherapy. Primary lesions included colorectal cancer ( n = 25), esophageal cancer ( n = 11), cholangiocarcinoma ( n = 1), duodenal cancer ( n = 1), and jejunal cancer ( n = 1). Seventy-two tumors were treated. Results The overall median survival was 9 months after diagnosis of metastatic brain disease and 5 months after radiosurgery. The 1-year survival rate after radiosurgery was 19%. The last imaging study of 49 tumors showed complete remission (CR) in 3 tumors (6.1%), partial remission (PR) in 27 tumors (55.1%), no change (NC) in 11 tumors (22.4%), and progression in 8 tumors (16.3%). The local tumor control rate (CR, PR, NC) was 84%. Two patients (5.1%) had a new or worsening neurologic deficit after radiosurgery. Conclusions Stereotactic radiosurgery provides reasonable local control of brain metastases from gastrointestinal tract cancer with few side effects. However, it should be used judiciously in patients with active extracranial cancers since the expected survival may be limited.

Commentary

BACKGROUND Outcomes in patients with brain metastases from gastrointestinal tract cancers are not well defined. In this study we used precise, single-session, focal tumor irradiation (radiosurgery) in patients with brain metastases and evaluated the results. METHODS Thirty-nine patients had brain metastases from gastrointestinal tract cancer and were treated with radiosurgery. Thirty-two also had whole brain radiotherapy. Primary lesions included colorectal cancer (n = 25), esophageal cancer (n = 11), cholangiocarcinoma (n = 1), duodenal cancer (n = 1), and jejunal cancer (n = 1). Seventy-two tumors were treated. RESULTS The overall median survival was 9 months after diagnosis of metastatic brain disease and 5 months after radiosurgery. The 1-year survival rate after radiosurgery was 19%. The last imaging study of 49 tumors showed complete remission (CR) in 3 tumors (6.1%), partial remission (PR) in 27 tumors (55.1%), no change (NC) in 11 tumors (22.4%), and progression in 8 tumors (16.3%). The local tumor control rate (CR, PR, NC) was 84%. Two patients (5.1%) had a new or worsening neurologic deficit after radiosurgery. CONCLUSIONS Stereotactic radiosurgery provides reasonable local control of brain metastases from gastrointestinal tract cancer with few side effects. However, it should be used judiciously in patients with active extracranial cancers since the expected survival may be limited.

Feasibility of Magnetic Resonance Imaging–guided Focused Ultrasound Surgery as an Adjunct to Tamoxifen Therapy in High-risk Surgical Patients with Breast Carcinoma

To evaluate the feasibility of treating breast neoplasms with use of magnetic resonance (MR) imaging-guided focused ultrasound (US) surgery. Twenty-four female patients, each with a single biopsy-proven breast carcinoma, who were considered to be at increased surgical risk or who had refused surgery underwent MR imaging-guided focused US surgery as an adjunct to their chemotherapeutic regimen of tamoxifen. Follow-up included routine studies to rule out metastatic disease and MR studies with and without contrast material infusion in the treated breast (10 days and 1, 3, and 6 months after the treatment session). Percutaneous biopsy was performed after 6-month follow-up, and if residual tumor was present, a second MR imaging-guided focused US surgery treatment session was performed, followed by repeat biopsy 1 month later. Twenty-three of 24 patients completed the protocol, with only one minor complication associated with the treatment sessions (second-degree skin burn resolved with local treatment). Follow-up MR studies demonstrated a varying hypointense treatment margin (range, 1-11 mm), which represents destruction of tissue beyond the visible tumor. Absence of enhancement may be an indicator of tumor destruction (18 of 19 patients with negative biopsy results) whereas persistent enhancement suggested tumor residue (three of five patients with residual tumor). Overall, 19 of 24 patients (79%) had negative biopsy results after one or two treatment sessions. MR imaging-guided focused US surgery of breast tumors is a safe, repeatable, and promising method of focal tumor destruction.

CT and MR Imaging Findings of Endometrial Stromal Sarcomas

Purpose: To evaluate the imaging findings of endometrial stromal sarcoma (ESS) according to histopathologic grade. Materials and Methods: Six patients with pathologically proven ESS were included in this study. The histopathologic diagnosis was low-grade ESS for three patients and high-grade ESS for the three others. Preoperative CT or MR images were evaluated in terms of tumor size, location, growth pattern, the presence of hemorrhage or necrosis, status of the endometrial cavity, and invasion of surrounding structures. The imaging features of ESSs, which varied according to their histopathologic grade, were compared. Results: The mean maximal diameter of low-and high-grade ESSs was 6 cm and 11.2 cm, respectively. All three low-grade ESSs were located mainly in the myometrium, but two high-grade ESSs were situated in the endometrial cavity and associated with focal tumor extension into the myometrium. One high-grade ESS had completely replaced the uterus. Low-grade ESSs were relatively well-defined, but high-grade ESSs had an irregular and lobulated margin. Intratumoral hemorrhage and necrosis were, respectively, found in two and three high-grade ESSs. Widening of the endometrial cavity was noted in all three high-grade ESSs, and lymph node metastasis had occurred in one. Conclusion: The imaging findings of ESS vary from a well-defined intramural mass to a bulky infiltrating mass, and depend on their histopathologic grade.

Polyclonal anti-PSA is more sensitive but less specific than monoclonal anti-PSA: Implications for diagnostic prostatic pathology.

Prostate-specific antigen (PSA) production by nonprostatic tissues has been reported, casting doubts on its specificity. The immunohistochemical relative specificity and sensitivity of PSA expression using monoclonal and polyclonal anti-PSA was analyzed on 60 prostate carcinomas, 40 normal seminal vesicles, and 310 nonprostatic tumors. All nonprostatic tumors proved negative with both antibodies. However, 13 (32%) seminal vesicles showed immunoreactivity with polyclonal anti-PSA, but none showed immunoreactivity with the monoclonal antibody. The sensitivity of the 2 antibodies for prostate cancer varied with tumor grade. In Gleason pattern 3, both antibodies showed diffuse immunostaining in all cases. In Gleason pattern 5, polyclonal anti-PSA showed diffuse (>95%) tumor cell positivity in 18 cases (90%), while with the monoclonal antibody, 7 cases (35%) showed only focal (<10%) tumor cell immunoreactivity. Thus, monoclonal anti-PSA seems to be useful in small gland proliferations in which the differential diagnosis includes seminal vesicle, while for poorly differentiated neoplasms, polyclonal anti-PSA is considered superior. Sections of high-grade prostate cancer should be included as positive controls for PSA immunostaining.

ADAPTIVE SIMULATED ANNEALING FOR CT IMAGE CLASSIFICATION

We present a pattern classification method that combines the classical Perceptron algorithm with simulated annealing. For a sample set S of n-dimensional patterns labeled as positive and negative, our algorithm computes threshold circuits of small depth where the linear threshold functions of the first layer are calculated by simulated annealing with the logarithmic cooling schedule c(k) = Γ(k)/ ln (k + 2). The parameter Γ depends on the sample set and changes in time, and the neighborhood relation is determined by the Perceptron algorithm. We apply the approach to the recognition of focal liver tumours. From 400 positive (focal liver tumour) and 400 negative (normal liver tissue) examples a depth-six threshold circuit is calculated. The examples are of size n = 14161 = 119 × 119 and they are presented in the DICOM format. On test sets of 100 + 100 examples (disjoint from the learning set) we obtain a correct classification of more than 98%.

Mn-DPDP-enhanced MR Imaging: the Optimal Pulse Sequence for Detection of Focal Hepatic Tumor

Purpose: To assess the diagnostic value of Mn-DPDP for the detection of focal hepatic tumors on MR images and to determine the optimal pulse sequence to maximize its effect. Materials and Methods: Twenty-three patients with 32 focal hepatic tumors were examined by means of 1.5-T MRI. Before and after the intravenous administration of Mn-DPDP, five pulse sequences were used to obtain T1-weighted images: two-dimensional fast low-angle shot (2D FLASH) with/without fat saturation (FS), spinecho (SE), and three-dimensional fast low angle shot reconstruction (3D FLASH) with/without FS. Quantitative assessment involved determination of the signal-to-noise ratio (SNR) of the liver and the tumor, the percentage signal enhancement ratio (PSER) of the liver, and tumor-to-liver contrast to noise ratio (CNR). Pulse sequences were also evaluated subjectively for tumor conspicuity, delineation, and image artifact. In addition, two experienced radiologists compared tumor detection rates between precontrast and postcontrast images. Results: Mn-DPDP had a marked effect on liver SNR and absolute CNR at all pulse sequences (p

No Significant Association of Epstein-Barr Virus Infection with Invasive Breast Carcinoma

We studied 48 cases of invasive breast carcinoma for evidence of Epstein-Barr virus (EBV), which is associated with many human malignancies. In situ hybridization studies to detect the presence of EBV-encoded small nonpolyadenylated RNA (EBER)-1 were performed in paraffin sections. Immunohistochemical studies to detect EBV nuclear antigen (EBNA)-1, latent membrane protein (LMP)-1, and the transactivating immediate-early BZLF1 (ZEBRA) protein were also performed in paraffin sections. The presence of EBV genomic DNA was studied by polymerase chain reaction (PCR) amplification using sets of primers flanking the EBNA-4 and the EBV-LMP-1 genes in frozen tissues. Southern blot analysis using a probe flanking the EBV terminal repeat region was then attempted in cases that were PCR-positive. Five of 48 cases (10%) of breast carcinoma showed focal EBER-positive tumor cells. Twelve cases (25%) were positive for EBNA-1 by immunohistochemistry, all but one different from the EBER-positive cases. None of the cases were positive for LMP-1 or ZEBRA protein by immunohistochemistry. PCR studies for EBNA-4 and LMP-1 were each positive in five cases (including three cases in common). However, Southern blot studies successfully performed in all but one of the PCR-positive cases were completely negative. The identification of EBV by any methodology was not correlated with tumor size, grade, or lymph node status. This study demonstrated evidence of EBV infection in tissues involved by invasive breast carcinomas in a significant subset of cases. However, the lack of localization of EBV infection to a significant population of the tumor cells in any case, the negativity by Southern blot hybridization, and the lack of expression of multiple antigens in any case strongly argue against a significant role for EBV in the pathogenesis of breast carcinoma.

Anti-tumor effects of human peripheral gammadelta T cells in a mouse tumor model.

Peripheral gammadelta T cells derived from healthy donors were found to exhibit cytotoxicity against a variety of tumor cell lines in vitro, including CNE2, which was established from nasopharyngeal carcinoma (NPC). The anti-tumor effects were further studied in a mouse model. Control nude mice inoculated s.c. with 5 x 10(6) CNE2 cells regularly developed hypodermal tumors, which progressively increased in size, and animals had a mean survival of 35 +/- 3.4 days. Tumor growth was arrested and tumor size was reduced after animals were infused with 5 x 10(7) gammadelta T cells derived from a healthy donor. The anti-tumor effects were temporary, however, and tumor growth was resumed after about 1 week in a group of the animals that had been given a single dose of gammadelta T cells. In another group of animals given 2 doses of gammadelta cells 1 week apart, resumption of tumor growth was delayed for a further week. Mean survival of the 2 groups was increased to 61 +/- 15.7 and 74 +/- 12.9 days, respectively. Immunohistology revealed an accumulation of infused cells in tumors attended by focal tumor necrosis in specimens taken 2 days after infusion. Infiltrative cells virtually disappeared from tumor tissues 6 days after infusion, accompanied by increased mitotic indices of tumor cells. These temporal relationships suggested that the accumulation of infused gammadelta T cells in hypodermal tumors was responsible for the observed anti-tumor effects.

Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer

Angiogenesis is esential for tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and is an important component of the angiogenic stimulus in a range of human neoplasias. In addition to its mitogenic activities, VEGF has also been found to stimulate migration in macrophages via the flt-1 VEGF receptor. It has previously been shown that increased focal tumour macrophage infiltration is associated with increased angiogenesis and worsened relapse-free and overall survival in breast cancer. Macrophages are able to stimulate angiogenesis by their production of a range of factors including VEGF, tumour necrosis factor-α (TNF-α), and thymidine phosphorylase (TP). Thus, in breast cancer, VEGF could have a dual role in the regulation of angiogenesis, by direct mitogenic stimulation of endothelial cells, and also indirectly by attracting macrophages into avascular tumours. The purpose of this study was to localize VEGF protein in a series of 96 consecutive primary breast carcinomas and to determine its relationship to focal macrophage infiltration (macrophage index). These two variables were also compared with the pathological features of the tumours, as well as oestrogen receptor (ER), epidermal growth factor receptor (EGFR), microvessel density, macrophage index, and survival. An inverse relationship (p=0.0006) was noted between VEGF and EGFR, with high VEGF expression correlating with low EGFR levels. In the EGFR-negative group of cases (n=56), positive associations were observed between VEGF expression and macrophage index (p=0.005), ER (p=0.05), p53 (p=0.006), tumour grade (p=0.02), and tumour necrosis (p=0.03). Macrophage counts were higher in EGFR-positive tumours (p=0.0006) and no associations were found between VEGF expression and increased microvessel density. These results show that in breast cancers there are two types of macrophage infiltrates, one associated with the presence of EGFR and low VEGF expression in tumours and the other with high VEGF expression in EGFR-negative tumours. VEGF expression may be an important factor in the recruitment of tumour-associated macrophages into breast carcinomas and may thus have an additional, indirect, pathway of angiogenic stimulation in this type of tumour. Copyright © 2000 John Wiley & Sons, Ltd.