ABSTRACT
Objective To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). Methods This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. Results A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). Conclusions TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST (AU)
Subject(s)
Humans , Female , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Nucleic Acid Amplification Techniques , Sentinel Lymph Node/pathology , Lymphatic Metastasis , Neoadjuvant Therapy , Predictive Value of Tests , Retrospective Studies , Sentinel Lymph Node BiopsyABSTRACT
OBJECTIVE: To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). METHODS: This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. RESULTS: A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). CONCLUSIONS: TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Nucleic Acid Amplification Techniques , Sentinel Lymph Node/pathology , Tumor Burden , Female , Humans , Lymphatic Metastasis , Neoadjuvant Therapy , Predictive Value of Tests , Prognosis , Retrospective Studies , Sentinel Lymph Node BiopsyABSTRACT
BACKGROUND: Recently, microRNAs have been demonstrated to be potential non-invasive biomarkers for diagnosis, prognosis assessment or prediction of response to treatment in cancer. In this study, we evaluate the potential of miR-30b-5p as a biomarker for early diagnosis of breast cancer (BC) in tissue and plasma. METHODS: Expression of miR-30b-5p was determined in a series of 112 BC and 40 normal breast tissues. Circulating miR-30b-5p levels in plasma samples were determined in a discovery cohort of 38 BC patients and 40 healthy donors and in a validation cohort of 83 BC patients and 83 healthy volunteers. miR-30b-5p expression was measured by quantitative real-time PCR and receiver operating characteristics curve analysis was carried out. RESULTS: The miR-30b-5p expression was significantly lower in BC tissue than in healthy breast samples. In contrast, circulating miR-30b-5p levels were significantly higher in BC patients compared with healthy donors. Furthermore, circulating miR-30b-5p levels were significantly higher in patients with positive axillary lymph node and de novo metastatic patients. Receiver operating characteristics curve analysis demonstrated a good diagnostic potential of miR-30b-5p to detect BC even at an early stage of the disease. CONCLUSION: Thus, we highlight the potential of miR-30b-5p as a non-invasive, fast, reproducible and cost-effective diagnostic biomarker of BC.
Subject(s)
Breast Neoplasms , MicroRNAs , Biomarkers, Tumor/blood , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Early Detection of Cancer , Female , Humans , MicroRNAs/blood , PrognosisABSTRACT
Purpose. To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice. Materials and methods. A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling. Results. Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly. Conclusions. Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain (AU)
No disponible
Subject(s)
Humans , Female , Breast Neoplasms/pathology , Biopsy, Fine-Needle/methods , Neoadjuvant Therapy/methods , Clinical Protocols/standards , Breast Neoplasms/drug therapy , Practice Patterns, Physicians'ABSTRACT
PURPOSE: To compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice. MATERIALS AND METHODS: A modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling. RESULTS: Our survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly. CONCLUSIONS: Active participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain.
Subject(s)
Breast Neoplasms/diagnosis , Pathologists , Pathology, Clinical/standards , Specimen Handling/standards , Biopsy, Large-Core Needle , Breast Neoplasms/drug therapy , Delphi Technique , Female , Guideline Adherence/statistics & numerical data , Humans , Neoadjuvant Therapy , Pathology, Clinical/methods , Practice Patterns, Physicians'/standards , Spain , Specimen Handling/methods , Surveys and QuestionnairesABSTRACT
Objetivo. Nuestro objetivo fue analizar el rendimiento de la biopsia selectiva del ganglio centinela valorando la detección gammagráfica tras la administración intratumoral del radiofármaco en pacientes con cáncer de mama que recibieron quimioterapia neoadyuvante. Material y métodos. Sesenta pacientes con diagnóstico de carcinoma infiltrante de mama, estadios T1-T3, que recibieron tratamiento con quimioterapia neoadyuvante fueron sometidas posteriormente a cirugía mamaria y biopsia del ganglio centinela mediante administración intratumoral del radiofármaco. Resultados. Se consiguió la detección gammagráfica de algún ganglio centinela en 55/60 pacientes (91,6%). Cuando se excluyeron los casos con reinyección periareolar del radiofármaco por falta de migración, la detección fue del 70% (42/60). Cuando se comparó la detección o no del ganglio centinela en estas 42 pacientes, no se encontraron diferencias en función de la edad, lateralidad-localización de la lesión, tamaño pre y posquimioterapia, grado histológico del tumor o perfil inmunohistoquímico. Sí existieron diferencias significativas al comparar los grupos según el grado de respuesta patológica del tumor, valorado tanto con el sistema de Miller-Payne (no detección 44,4%-detección 16,7%, p = 0,003) como con el sistema residual cancer burden (72,2%-28,6%, p<0,01). Conclusiones. La detección gammagráfica del ganglio centinela tras administración intratumoral del radiofármaco en pacientes con cáncer de mama que recibieron quimioterapia neoadyuvante estuvo por debajo del valor óptimo, siendo necesaria en ocasiones la reinyección periareolar, lo que podría estar en relación con una alteración de las vías de drenaje linfático. Existió una significativa relación inversa entre detección del ganglio centinela y el grado de respuesta patológica tumoral (AU)
Purpose. Our objective was to analyse the accuracy of the sentinel node biopsy, taking into consideration the scintigraphy detection rate after the intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy. Materials and methods. The study included 60 patients with a diagnosis of invasive breast carcinoma, stage T1-T3, who received treatment with neoadjuvant chemotherapy, and were subsequently subjected to breast surgery and sentinel node biopsy after intra-tumour administration of the radiopharmaceutical. Results. Scintigraphic detection of some sentinel node was achieved in 55/60 patients (91.6%). When those cases that received a second injection of the radiopharmaceutical, performed peri-areolarly due to a lack of tracer migration, were excluded, the detection rate dropped to 70% (42/60). When the detection of sentinel node, or its absence, was compared in those 42 patients, no differences were found with age, laterality-location of the lesion, size pre- and post-neoadjuvant chemotherapy, histological grade, or immunohistochemical profile. There were significant differences when comparing the groups according to the degree of pathological tumour response, both with the Miller-Payne system (non-detection 44.4%-detection 16.7%, p = 0.003) as well as the residual cancer burden (72.2%-28.6%, p<0.01). Conclusions. The scintigraphic detection of the sentinel node after intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy was below the optimal value, and sometimes a further, peri-areolar, injection was necessary, probably in relation to an alteration in the lymphatic drainage pathways. There was a significant inverse relationship between the detection of the sentinel node and level of pathological tumour response (AU)
Subject(s)
Humans , Female , Middle Aged , Sentinel Lymph Node Biopsy , Breast Neoplasms , Breast Neoplasms/drug therapy , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/analysis , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis , Neoadjuvant Therapy/instrumentation , Neoadjuvant Therapy/methods , Neoadjuvant Therapy , Gated Blood-Pool Imaging/methods , Nuclear Medicine/methods , Nuclear Medicine/trends , Immunohistochemistry/methods , Immunohistochemistry , Retrospective StudiesABSTRACT
PURPOSE: Our objective was to analyse the accuracy of the sentinel node biopsy, taking into consideration the scintigraphy detection rate after the intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy. MATERIALS AND METHODS: The study included 60 patients with a diagnosis of invasive breast carcinoma, stage T1-T3, who received treatment with neoadjuvant chemotherapy, and were subsequently subjected to breast surgery and sentinel node biopsy after intra-tumour administration of the radiopharmaceutical. RESULTS: Scintigraphic detection of some sentinel node was achieved in 55/60 patients (91.6%). When those cases that received a second injection of the radiopharmaceutical, performed peri-areolarly due to a lack of tracer migration, were excluded, the detection rate dropped to 70% (42/60). When the detection of sentinel node, or its absence, was compared in those 42 patients, no differences were found with age, laterality-location of the lesion, size pre- and post-neoadjuvant chemotherapy, histological grade, or immunohistochemical profile. There were significant differences when comparing the groups according to the degree of pathological tumour response, both with the Miller-Payne system (non-detection 44.4%-detection 16.7%, p = 0.003) as well as the residual cancer burden (72.2%-28.6%, p<0.01). CONCLUSIONS: The scintigraphic detection of the sentinel node after intratumoural administration of the radiopharmaceutical in patients with breast cancer who received neoadjuvant chemotherapy was below the optimal value, and sometimes a further, peri-areolar, injection was necessary, probably in relation to an alteration in the lymphatic drainage pathways. There was a significant inverse relationship between the detection of the sentinel node and level of pathological tumour response.
Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Sentinel Lymph Node Biopsy , Technetium Tc 99m Aggregated Albumin/administration & dosage , Adult , Aged , Aged, 80 and over , Chemotherapy, Adjuvant , Female , Humans , Injections, Intralesional , Middle Aged , Neoadjuvant Therapy , Retrospective StudiesABSTRACT
BACKGROUND: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.
Subject(s)
Antineoplastic Agents/therapeutic use , Survival Analysis , Triple Negative Breast Neoplasms/drug therapy , Cohort Studies , Female , Humans , Middle Aged , Treatment Outcome , Triple Negative Breast Neoplasms/physiopathologyABSTRACT
BACKGROUND: The addition of trastuzumab (T) and lapatinib (L) to neoadjuvant chemotherapy increases the pathological complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We investigated the efficacy of T or L with neoadjuvant chemotherapy and specific efficacy biomarkers. METHODS: Patients with stages I-III (including inflammatory) HER2-positive breast cancer were randomised to receive epirubicin (E) plus cyclophosphamide (C) × 4 cycles followed by docetaxel (D) plus either T (EC-DT) or L (EC-DL). End points included pCR (primary), clinical response, toxicity, and pCR-predictive biomarkers. RESULTS: We randomised 102 patients to EC-DT (50) and EC-DL (52). Median age was 48, 56% were premenopausal and 58% had oestrogen receptor (ER)-positive tumours. Pathological complete response in breast was 52.1% (95% CI:38.0-66.2%) for EC-DT and 25.5% (95% CI:13.5-37.5%) for EC-DL (P=0.0065). Pathological complete response in breast and axilla was 47.9% for EC-DT and 23.5% for EC-DL (P=0.011). Grade 3-4 toxicity did not differ across treatments, except for diarrhoea (2% in EC-DT vs 13.5% in EC-DL, P=0.030). Multivariate analyses showed that treatment (P=0.036) and ER (P=0.014) were the only predictors of pCR in both groups. CONCLUSION: EC-DT exhibited higher efficacy and lower toxicity than EC-DL. Of the different biomarkers studied, only the absence of ER expression was associated with increased pCR.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2/biosynthesis , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Cyclophosphamide/administration & dosage , Docetaxel , Epirubicin/administration & dosage , Female , Humans , Lapatinib , Middle Aged , Neoadjuvant Therapy/methods , Quinazolines/administration & dosage , Receptor, ErbB-2/genetics , Taxoids/administration & dosage , TrastuzumabABSTRACT
BACKGROUND: This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations. PATIENTS AND METHODS: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient's RS. RESULTS: Treatment recommendation changed in 32% of 107 patients enrolled: in 21% from chemohormonal (CHT) to hormonal therapy (HT) and in 11% from HT to CHT. RS was associated with the likelihood of change from HT to CHT (P < 0.001) and from CHT to HT (P < 0.001). Confidence of oncologists in treatment recommendations increased for 60% of cases. Higher tumor grade (P = 0.007) and a high proliferative index (Ki-67) (P = 0.023) were significantly associated with a greater chance of changing from HT to CHT, while positive progesterone receptor status (P = 0.002) with a greater probability of changing from CHT to HT. CONCLUSIONS: Results from the first prospective European study are consistent with published experience and use of the RS as proposed in European clinical practice guidelines and provide evidence on how Oncotype DX and clinicopathological factors are complementary and patient selection may be improved.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Practice Patterns, Physicians'/statistics & numerical data , Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant/statistics & numerical data , Female , Guideline Adherence/statistics & numerical data , Hormone Antagonists/therapeutic use , Humans , Medical Oncology/standards , Medical Oncology/statistics & numerical data , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/genetics , Receptors, Estrogen/biosynthesis , Receptors, Estrogen/genetics , Risk FactorsABSTRACT
AIMS: The term perineurioma has been used to designate a variety of clinically and histologically different proliferations of perineurial cells based on immunohistochemical and/or ultrastructural characterization. There are two different groups of neoplasms derived from perineurial cells: extraneural or soft tissue perineuriomas, and intraneural perineuriomas. Recently, a sclerosing variant of cutaneous perineurioma has been described. METHODS AND RESULTS: We report a case of a cutaneous form of perineurioma, combining features of the intraneural and sclerosing varieties, as well as showing a Pacinian pattern of growth. In order to assess the neoplastic nature of the lesion, we performed fluorescence in-situ hybridization (FISH) analysis using a probe which maps to the chromosome band 22q11 and 22q13, allowing us to show deletion or loss of one chromosome 22 in the tumour cells. CONCLUSIONS: This case may be considered a new variant of perineurioma with Pacinian-like features, for which we propose the designation 'sclerosing Pacinian-like perineurioma'.
Subject(s)
Nerve Sheath Neoplasms/pathology , Skin Neoplasms/pathology , Adult , Chromosome Aberrations , Chromosomes, Human, Pair 22/genetics , Female , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Mucin-1/analysis , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/metabolism , Pacinian Corpuscles/pathology , Sclerosis/pathology , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Vimentin/analysisABSTRACT
Metastatic tumors in the small intestine are rare. The most commonly implicated primitive tumors are malignant melanoma, lung cancer and colon cancer. Few cases of metastasis to the intestine as the first manifestation of metastasis have been described. We present a case of metastasis to the intestine of lobular breast carcinoma 9 years after surgical resection of the primary tumor. Metastasis presented as anasarca. Ray small bowel series revealed ileal stenosis. Diagnosis was confirmed by histopathologic analysis following surgical resection of the affected intestinal segment.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Lobular/diagnosis , Carcinoma, Lobular/secondary , Edema/etiology , Ileal Neoplasms/diagnosis , Ileal Neoplasms/secondary , Intestinal Obstruction/etiology , Breast Neoplasms/surgery , Carcinoma, Lobular/surgery , Female , Humans , Middle AgedABSTRACT
We describe the case of a 62-year-old man with chronic irritation of the urinary bladder resulting in dysuria and hypogastric pain. Three neoplasms measuring 0.5, 1, and 1.5 cm, respectively, were observed by cystoscopy and removed by transurethral resection (TUR). Histologic examination showed a complex folding of squamous hyperplastic epithelium around a connective tissue core. The superficial epithelium contained numerous koilocytes. The double polymerase chain reaction (PCR) detected DNA of type 11 human papillomavirus (HPV). The diagnosis was condyloma acuminatum of bladder. Three months later the patient presented with fever, and a new cytoscopy demonstrated an ulcerated, exophytic 4.5 cm mass. Histopathology showed a squamous carcinoma with papillomatous structure, pronounced viral koilocytosis, and irregular invasive deep margin. HPV type 11 was found with double PCR. The diagnosis was warty carcinoma arising in condyloma acuminatum. To the best of our knowledge, this is the first case of warty carcinoma of the urinary bladder described in the literature. We discuss the relationship between the infection by HPV and the development of condyloma acuminatum, its evolution toward a well-differentiated squamous carcinoma, and its distinction from verrucous carcinoma. Int J Surg Pathol 8(3):253-259, 2000
ABSTRACT
A new case of hepatoid adenocarcinoma was diagnosed in fragments obtained at transurethral resection (TUR) from a 71-year-old man who had complained of haematuria. The tumour was composed of trabeculae and small solid nests of polygonal atypical cells simulating hepatocarcinoma, together with glandular areas of an otherwise typical adenocarcinoma. Immunohistochemistry showed cytoplasmic reactivity to AFP, AAT, albumin and CAM 5.2. Membrane reactivity was seen in EMA immunostaining, and there was also positivity to polyclonal CEA following a canalicular pattern. Immunoperoxidase studies of hepatocyte growth factor (HGF) and its receptor, c-met, were positive. Their expression may be related to the aggressive behaviour of this tumour.