Lymphatic and Blood Vessels in Basal and Triple-negative Breast Cancers

Characteristics And Prognostic Significance

Rabab AA Mohammed; Ian O Ellis; Ali M Mahmmod; E Claire Hawkes; Andrew R Green; Emad A Rakha; Stewart G Martin

Disclosures

Mod Pathol. 2011;24(6):774-785. 

In This Article

Discussion

Breast cancers with basal-like and triple-negative phenotypes are recently identified tumour subtypes characterised by aggressive behaviour and poor prognosis. Tumour lymphatics and blood vessels are known to have an important role in tumour progression in many tumour types, including breast cancer. The aims of this study were to examine the vascular characteristics, lymph-vessel density, microvessel density and vascular invasion, both lymphatic and blood vascular invasion, in basal-like and in triple-negative phenotypes and to study the association of these features with the different clinicopathological criteria and patient prognosis. Previous work has demonstrated that basal-like tumours show a specific pattern of distant metastasis with an increased propensity for visceral metastases to the brain and lung and that they are less likely to metastasise to the bone and liver, suggesting that such tumours might also possess a distinct mechanism of metastatic spread from non-basal-like tumours.[36,37] Therefore, it was of interest to examine whether these vascular characteristics differed in basal compared with non-basal tumours and in triple-negative compared with non-triple-negative tumours, which may contribute to the difference in metastatic spread pattern. It was also of interest to investigate whether this difference, if present, contributes to biological and clinical features and, if so, whether they could be used to aid in the determination of prognosis in these two tumour subtypes.

Numerous studies have examined the vascular characteristics of breast cancers; however, no study has previously examined these characteristics, including lymphatics, in basal-like or triple-negative subtypes.

Lymph vessels have, following the characterisation of specific markers, been a focus of attention over the last decade.[38,39] Similar to previous findings from studies on breast cancer of mixed phenotypes,[40,41] we found that the majority of lymphatics in the basal phenotype group were located in the peritumoral and the peripheral areas with few tumours having lymphatics within the tumour core. Breast cancers with high lymph-vessel density have been found, in some studies, to be associated with higher risk of lymph-node metastasis and with tumours with negative hormonal-receptor status. However, such associations were not found in other studies.[41] The significance of high lymph-vessel density as a factor indicating poor prognosis is also controversial. In the study by Kato et al,[41] lymph-vessel density was not associated with overall survival or disease-free interval. In recent studies, from the current authors, high lymph-vessel density was significantly associated with the presence of lymph-node and distant metastases and hence with poorer Nottingham prognostic index and tumour stage. In univariate survival analysis, high lymph-vessel density was associated with poorer survival, but this did not retain significance in multivariate analysis.[20] In the current study, high lymph-vessel density in lymph node-negative basal-like or triple-negative phenotypes was not associated with any of the clinicopathological characteristics or with overall survival or disease-free interval. The difference in such findings may be due to the fact that all current specimens were lymph node negative, whereas those in the previous study were non-selected cases of both lymph node-negative and lymph node-positive specimens. It is generally accepted that lymphatic vessels are a key route for tumour cell dissemination. It is logical to assume that the presence of more vessels may increase the chance of vascular invasion occurring and therefore influence prognosis. When lymph-vessel density in the basal-like was compared with that in the non-basal-like, no difference was found. The same applies to triple-negative and non-triple-negative types. Such data suggest that the density of lymph vessels, itself, may not be of clinical or prognostic significance in either basal-like or triple-negative breast cancer.

As mentioned previously, the clinical and prognostic significance of microvessel density has been examined extensively in breast cancer; however, its use in practice is still fraught with difficulties because of the difference in methods of assessment and the presence of significant inter- and intra-observer variation.[42] Controversy exists regarding the usefulness of microvessel density as a prognostic factor.[17] Breast cancers with high microvessel density have, in certain studies, been found to have significant association with larger tumour size, high grade, lymph-node metastasis and poor prognosis;[16,18,43,44] however, no such association was detected with pathological criteria or patient survival in other studies.[45,46] In the current study, microvessel density, in both basal-like and triple-negative phenotypes, was significantly higher than in non-basal-like and non-triple-negative types. In basal-like breast cancers, high microvessel density was significantly associated with larger tumour size (>1.5 cm), high grade, ER negativity and PR negativity. Previous studies have reported that basal-like breast cancers are generally characterised by being of high grade and of large tumour size.[4] In the current study, in 197 basal-like breast cancers, 71% of the tumours were grade III and 71% were >1.5 cm in size, which may explain the association between high microvessel density and basal-like phenotype when compared with non-basal-like tumours. The same was found with triple-negative phenotypes in which the triple negative was associated with high microvessel density when compared with non-triple negative; however, unlike the basal-like phenotype, high microvessel density was not associated with tumour size or grade in the triple-negative group. The same explanation, as in basal-like cancers, can be applied here as the majority of triple-negative cases were of high grade and of large size. Overall, 88% of tumours in the current cohort of triple-negative specimens were grade III and 80% were >1.5 cm. The fact that high microvessel density was not associated with clinicopathological characteristics may be due to the heterogeneous nature of this group. Recently, it was found that triple-negative breast cancers encompass a biologically heterogeneous group of tumours with a proportion of them expressing basal markers.[13]

From survival analyses, microvessel density was not associated with either overall survival or disease-free interval, in basal-like or in triple-negative tumours. Such data suggest that although blood vessels are important for tumour growth and development, they have a little part in the initial dissemination of cancer. It could be hypothesised that such groups may preferentially benefit from anti-angiogenic therapy in terms of primary tumour response. Lymphatic vascular invasion data would suggest, however, that there would be little impact on metastatic dissemination and overall survival. It is interesting, in this light, to reflect on recent work that reports anti-angiogenic therapies reducing primary tumour growth and microvessel density but accelerating invasion and metastasis.[47,48]

The current study, as with our and others' previous findings,[20,27,40] shows that blood vascular and lymphatic characteristics do not correlate, in either phenotype, in that specimens having high microvessel density do not necessarily have high lymph-vessel density and vice versa, suggesting distinct biological regulatory mechanisms.

Vascular invasion, including both lymphatic and blood vascular invasion, has been generally accepted, for some time, as a risk factor for development of recurrence and death from the disease. With the development of specific blood and lymphatic vascular markers, it has become possible to identify and distinguish lymphatic and blood vascular invasion. In a previous study, the current authors found that, in a cohort of 177 non-selected cases, vascular invasion in breast cancer was almost entirely lymphatic vascular invasion;[29] such results are currently being validated using 1000 lymph node-negative specimens. Basal-like breast cancers have been reported to show preferable metastatic dissemination to sites such as the brain and liver, and less to the bone.[5,49,50] These distinctive metastatic patterns have been interpreted as a distinctive ability of basal-like breast cancers for early blood-borne metastasis. It was assumed, from such observations, that the frequency of blood vascular invasion would be higher in basal-like than in the non-basal-like group. Vascular invasion was detected in 27% of the basal-like tumours compared with 21% in the non-basal-like group and was 26% in the triple-negative group compared with 22% in the non-triple-negative group. In both basal-like and triple-negative cancers, vascular invasion was, interestingly, almost entirely invasion of lymph vessels. Such findings show that both triple-negative and basal-like breast cancers are no different, in terms of initial route of dissemination, from non-basal-like or non-triple-negative types in that such dissemination occurs through lymph vessels and not blood vessels. The distinct metastatic pattern mentioned earlier, to the brain and lung, may be due to other pathomolecular features in basal-like breast cancers and, perhaps, due to other tissue-specific factors in the remote sites themselves that attract basal-like cancer cells to extravasate and to grow. The haematogenous spread of breast cancer cells may occur distal to the primary tumour.

It was interesting to find that the presence of vascular invasion stratified patients, in both basal-like and in triple-negative phenotypes, into separate prognostic groups. Such findings emphasise the role of vascular invasion as an independent poor prognostic factor in both tumour phenotypes. Additional studies are required to explore the pathomolecular mechanisms that underlie the highly invasive nature of basal-like breast cancers and the mechanisms of the reported haematogenous metastatic pattern of this subgroup. Such understanding is essential for the optimal management of patients with breast cancer and for finding the appropriate tailored therapy for each patient.

In conclusion, although basal-like and triple-negative breast cancers have been reported, haematogenous patterns of metastatic spread vascular invasion was, with both groups, almost entirely invasion of lymph vessels. Results show that both triple-negative and basal-like cancers are no different, in terms of the initial route of dissemination, from non-basal-like or non-triple-negative types in that such dissemination occurs through lymph vessels and not blood vessels. Similarly, lymph vessel-density in breast cancer with basal or triple-negative phenotypes was no different from those in non-basal or non-triple-negative groups. Basal-like and triple-negative tumours did, however, exhibit higher microvessel density, a finding that may have implications for the use of anti-angiogenic therapy, for local control, in both tumour phenotypes. The presence of vascular invasion is an independent poor prognostic factor for overall survival and can be used to stratify basal-like and triple-negative phenotypes into distinct subgroups.

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