Histological Patterns and Mammographic Presentation of Invasive Lobular Carcinoma Show No Obvious Associations.

Invasive lobular carcinoma of the breast has different mammographic appearances, including spiculated or lobulated masses, architectural distortion, increased breast density, and the possibility of also being occult. Histologically, the morphology is also variable, as several patterns have been described beside the classical one, including the solid, the alveolar, the trabecular, the one with tubular elements, and others. Of 146 ILC cases, 141 were reviewed for mammographic appearance and 136 for histological patterns by two radiologist and two pathologists, respectively; 132 common cases were analyzed for possible associations between mammographic presentation and the histological patterns. Interobserver agreement on the presence or absence of a given mammographic morphology ranged from 45% (increased density) to 95% (occult lesion); the most common radiomorphology was that of a spiculated mass. Interobserver agreement on the presence or absence of a given histological pattern ranged between 79% (solid) and 99% (classical) but was worse when semi-quantification was also included. The mammography-pathology correlation was less than optimal. Multifocality was more commonly detected by histology. The identification of a mammographic mass lesion often coincided with a mass-like lesion on the histological slides and vice versa, but nearly half of the mammographically occult lesions were felt to have masses on histological slides assessed grossly. Histological patterns showed no obvious associations with one or the other mammographic appearance.

[Interobserver reproducibility of Gleason grading in prostate biopsy samples]. / A Gleason-osztályozás reprodukálhatóságának vizsgálata prosztata-tubiopsziás mintákban.

INTRODUCTION: Gleason grading is the most common method of prostate cancer classification. AIM: The aim of the authors was to assess the reproducibility of Gleason grading among pathologists using the same needle biopsy samples. METHOD: 23 pathologists examined 37 prostate cancer biopsies stained with hematoxylin and eosin. Gleason scores were categorised into 4 groups (2-4, 5-6, 7 and 8-10). Kappa statistics were used to reflect interobserver agreement. RESULTS: Considering all participating pathologists, grouping into one of the 4 categories resulted in an overall kappa value of 0.49. For the individual categories, the worst agreement (kappa = 0.15) was seen with well differentiated carcinomas, and the best (kappa = 0.65) with poorly differentiated ones. CONCLUSIONS: These results suggest that Gleason grading in biopsy samples is moderately reproducible. The kappa values vary according to the differentiation of the cancer, and there is not much difference between the results of the present study and those published in the literature. To increase reproducibility, trainings should be organised, and this could improve the quality of grading.

ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

ONEST (Observers Needed to Evaluate Subjective Tests) suggests four or more observers for a reliable assessment of the consistency of histological grading of invasive breast carcinoma: A reproducibility study with a retrospective view on previous studies.

Histological grade is one of the most important prognosticators of breast cancer which is available for nearly all cases. It also makes part of several multivariable analysis derived combined prognostic profiles despite concerns about its reproducibility. The aims included a reproducibility study of grading in the light of a recently described statistical approach, ONEST (Observers Needed to Evaluate Subjective Tests) and review earlier reproducibility studies in the light of the ONEST analysis. Nine pathologists reviewed 50 core needle biopsies and 50 slides from different excision specimens and recorded the scores for gland (tubule) formation, nuclear pleomorphism and mitotic activity as well as histological grade. Overall percent agreement, Fleiss kappa and the intraclass correlation coefficient (ICC) were used for the analysis of reproducibility. ONEST data and curves were generated from 100 random permutations of the participants. ONEST suggested a minimum of 4 observers for the reliable evaluation of reproducibility for both the scored components and grade in either type of specimen. Our results suggested moderate or moderate to good reproducibility of grading (kappa values of 0.51 for excisions, and 0.54 for biopsies and ICCs of 0.70 and 0.69, respectively) with gland formation being the most and nuclear pleomorphism the worst consistently evaluated feature. In studies with sufficient participants (at least 4) and non-pairwise comparisons in the analysis, the reproducibility of histological grading is fair to moderate, whereas studies with fewer participants or pairwise kappa analysis suggest moderate to almost prefect agreement of the results. ONEST is a valuable complementation of reproducibility analyses.

The additional value of ONEST (Observers Needed to Evaluate Subjective Tests) in assessing reproducibility of oestrogen receptor, progesterone receptor, and Ki67 classification in breast cancer.

The reproducibility of assessing potential biomarkers is crucial for their implementation. ONEST (Observers Needed to Evaluate Subjective Tests) has been recently introduced as a new additive evaluation method for the assessment of reliability, by demonstrating how the number of observers impact on interobserver agreement. Oestrogen receptor (ER), progesterone receptor (PR), and Ki67 proliferation marker immunohistochemical stainings were assessed on 50 core needle biopsy and 50 excision samples from breast cancers by 9 pathologists according to daily practice. ER and PR statuses based on the percentages of stained nuclei were the most consistently assessed parameters (intraclass correlation coefficients, ICC 0.918-0.996), whereas Ki67 with 5 different theoretical or St Gallen Consensus Conference-proposed cut-off values demonstrated moderate to good reproducibility (ICC: 0.625-0.760). ONEST highlighted that consistent tests like ER and PR assessment needed only 2 or 3 observers for optimal evaluation of reproducibility, and the width between plots of the best and worst overall percent agreement values for 100 randomly selected permutations of observers was narrow. In contrast, with less consistently evaluated tests of Ki67 categorization, ONEST suggested at least 5 observers required for more trustful assessment of reliability, and the bandwidth of the best and worst plots was wider (up to 34% difference between two observers). ONEST has additional value to traditional calculations of the interobserver agreement by not only highlighting the number of observers needed to trustfully evaluate reproducibility but also by highlighting the rate of agreement with an increasing number of observers and disagreement between the better and worse ratings.

[Laparoscopic and open complete mesocolic excision in right-sided colon cancer compared with open and laparoscopic surgery]. / Laparoszkópos és nyitott komplett mezokólikus excízió összehasonlítása nyitott és laparoszkópos konvencionális mutéttel jobb oldali vastagbéldaganatoknál ­ retrospektív feldolgozás, kezdeti tapasztalatok.

Introduction: In 2009, Hohenberger translated the concept of total mesorectal excision to colon cancer surgery and he named it complete mesocolic excision (CME). The principle of CME is based on wide mesenteric excision in the embriologic plane to remove mesenteric lymph nodes, central vascular ligation without damage of the peritoneal layer. CME can be performed by laparoscopic and open methods. Aim: To make sure that we are capable of performing right laparoscopic hemicolectomy with similar results to the open method. Results: A cohort of 156 consecutive patients were operated on with malignant right-sided colon tumours from 01.09.2016 to 30.06.2019. 143 curative resections were performed in 63 men and 80 women. The average age of men and women were 71.5 and 72.75 years, respectively. 84 laparoscopic and 59 open operations were performed. 84 patients underwent CME surgery and 56 conventional resections. The average length of the specimen was 22.34 cm in the conventional and 24.97 cm in CME surgery (p = 0.18) and the average lymph node number were 15.4 and 16.9, respectively (p = 0.24). The average duration of the operation was 111 minutes for the conventional and 136 minutes for the CME group (p = 0.0014), while the average length of stay were 7.47 days and 5.65 days (p = 0.0004) respectively for the cases without complications. Conclusion: We are yet in the learning period, but based on the early results, it might be concluded that the operation can be performed by laparoscopic methods as well with similar results to the open operation but with shorter length of stay.

Basal phenotype in breast carcinoma occurring in women aged 35 or younger.

Breast cancer in the young is considered a special clinical presentation of the disease. Sixty-nine breast cancer cases diagnosed at or before the age of 35 were analyzed for common morphological and immunophenotypical features of basal-like carcinomas. Sixteen carcinomas displayed the immunophenotypical characteristics (estrogen receptor and HER2 negativity and positivity for at least one of the following basal markers: cytokeratin 5 or 14, epidermal growth factor receptor, p63) of basal-like carcinomas, and most of them demonstrated characteristic histological features (pushing borders, lymphocytic peritumoral infiltrate, central hypocellular zone or necrosis, high mitotic rate) too. These tumors were more likely to be high-molecular-weight cytokeratin: 34betaE12 and p53 positive by immunohistochemistry. The presence of a basal-like phenotype can be important as concerns systemic treatment issues and could theoretically be associated with a higher rate of BRCA1 mutations in the young, because of the overlap of BRCA1 mutation associated breast carcinomas and the basal-like phenotype.

[Analysis of predictive tools for further axillary involvement in patients with sentinel-lymph-node-positive, small (< or =15 mm) invasive breast cancer]. / A hónalji nyirokcsomók további érintettségére vonatkozó modellek elemzése kisméretu (< / =15 mm) ôrszemnyirokcsomó-áttétes emlôrákokban.

Small breast cancers often require different treatment than larger ones. The frequency and predictability of further nodal involvement was evaluated in patients with positive sentinel lymph nodes and breast cancers < or =15 mm by means of 8 different predictive tools. Of 506 patients with such small tumors 138 with positive sentinel nodes underwent axillary dissection and 39 of these had non-sentinel node involvement too. The Stanford nomogram and the micrometastatic nomogram were the predictive tools identifying a small group of patients with low probability of further axillary involvement that might not require completion axillary lymph node dissection. Our data also suggest that the Tenon score can separate subsets of patients with a low and a higher risk of non-sentinel node metastasis. Predictive tools based on multivariate models can help in omitting completion axillary dissection in patients with low risk of non-sentinel lymph node metastasis based on their small tumor size.

Sentinel lymph node biopsy and non-sentinel node involvement in special type breast carcinomas with a good prognosis.

This study aimed at identifying factors related to sentinel lymph node (SLN) involvement in patients with tubular, cribriform, mucinous or papillary breast carcinoma and those related to non-SLN metastases if an SLN was positive. Multivariate analyses involved logistic and stepwise regressions. The SLNs harboured metastases in 85 of 572 cases, 78 of whom underwent axillary dissection; 19 presented non-SLN positive disease. Lack of lymphovascular invasion, a tumour size < or = 10 mm and a single SLN removed were the factors predicting an SLN metastasis rate <10%, and patients with these features could be candidates for no surgical axillary staging. A positive SLN proportion of < or = 50% and no lymphovascular invasion were associated with a <10% rate of non-SLN invasion; patients with a positive SLN and these features could be candidates for the omission of completion axillary dissection. The opposite presentation of these factors would mandate SLN biopsy and axillary dissection, respectively.

Sentinel lymph node biopsy in staging small (up to 15 mm) breast carcinomas. Results from a European multi-institutional study.

Sentinel lymph node (SLN) biopsy has become the preferred method for the nodal staging of early breast cancer, but controversy exists regarding its universal use and consequences in small tumors. 2929 cases of breast carcinomas not larger than 15 mm and staged with SLN biopsy with or without axillary dissection were collected from the authors' institutions. The pathology of the SLNs included multilevel hematoxylin and eosin (HE) staining. Cytokeratin immunohistochemistry (IHC) was commonly used for cases negative with HE staining. Variables influencing SLN involvement and non-SLN involvement were studied with logistic regression. Factors that influenced SLN involvement included tumor size, multifocality, grade and age. Small tumors up to 4 mm (including in situ and microinvasive carcinomas) seem to have SLN involvement in less than 10%. Non-SLN metastases were associated with tumor grade, the ratio of involved SLNs and SLN involvement type. Isolated tumor cells were not likely to be associated with further nodal load, whereas micrometastases had some subsets with low risk of non-SLN involvement and subsets with higher proportion of further nodal spread. In situ and microinvasive carcinomas have a very low risk of SLN involvement, therefore, these tumors might not need SLN biopsy for staging, and this may be the approach used for very small invasive carcinomas. If an SLN is involved, isolated tumor cells are rarely if ever associated with non-SLN metastases, and subsets of micrometastatic SLN involvement may be approached similarly. With macrometastases the risk of non-SLN involvement increases, and further axillary treatment should be generally indicated.

Divergences in diagnosing nodular breast lesions of noncarcinomatous nature.

Nodular breast lesions of noncarcinomatous origin are often of fibroepithelial origin. They may cause classification problems when they are hypocellular or hypercellular; the latter setting may also raise the differential diagnosis of phyllodes tumors. Thirty equivocal nodular breast lesions were collected and one hematoxylin and eosin slide from each was assessed by six pathologists with special interest in breast pathology. The overall reproducibility of classifying these lesions into categories of fibroadenoma, phyllodes tumor or anything else was moderate (kappa value: 0.48). The lack of a uniform nomenclature was not felt disturbing for hypocellular lesions, but the discordant diagnosis of tumors resembling or representing phyllodes tumors was acknowledged to require intervention, such as more obvious implication of guidelines and quality assurance programs aiming at assessing diagnoses and prognostic parameters.

[Sentinel lymph node biopsy for in situ carcinoma of the breast. Experience at the Bács-Kiskun County Hospital and review of the literature]. / Orszemnyirokcsomó-biopszia in situ emlorákban. A Bács-Kiskun Megyei Onkormányzat Kórházának tapasztalatai és irodalmi összefoglalás.

UNLABELLED: Sentinel node biopsy (SNB) is controversial for in situ breast cancers. We reviewed our experience with in situ and microinvasive carcinomas and surveyed the literature. METHODS: SNB was performed with intraparenchymal administration of vital dye alone or combined with radiocolloid. The SNs were assessed histologically with haematoxylin eosin staining and cytokeratin immunohistochemistry. RESULTS: Patients with in situ (36) or microinvasive (20) carcinomas underwent SNB: 59 axillary and 1 parasternal, and 39 axillary and 1 parasternal SNs were recovered, respectively. The SNs were positive in 4 patients and 1 patient, respectively: 1 micrometastasis and 3 isolated tumour cells, and 1 micrometastasis in the respective groups. No further axillary nodes were found positive after dissection. Further 21 invasive carcinomas (often with extensive intraductal component) had an in situ carcinoma diagnosis preoperatively: of 39 axillary and 3 parasternal SNs 10 patients had nodal involvement in 13 axillary SNs; 5 patients also had further lymph nodes involved after dissection. CONCLUSIONS: The definitive diagnosis of in situ carcinoma does not warrant SNB. This procedure should be considered if the tumour is to be removed by mastectomy, or if the diagnosis is preoperative and there are associated high-risk factors for the subsequent diagnosis of invasive cancer.

The role of sentinel node biopsy in male breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a standard procedure in women with breast cancer. The risk of morbidity related to axillary lymph node dissection (ALND) is similar for men and women with breast cancer and SLNB could minimize this risk. METHODS: Between January 2004 and August 2013, 25 men with primary breast cancer were operated on at the Bács-Kiskun County Teaching Hospital. These were reviewed retrospectively. SLNB was performed following lymphoscintigraphy with intraoperative gamma probe detection and blue dye mapping. RESULTS: SLNB was successful in all 16 male patients (100 %), in whom it was attempted. The SLNs were negative in 4 cases (25 %) and were involved in 12. Intraoperative imprint cytology was positive in 9 of the 12 involved cases (75 %) and resulted immediate completion ALND. In 7 patients, the intraoperative imprint cytology was negative, with 3 false-negative results that resulted in delayed completion ALND. After a median follow-up of 48 months, there was only one axillary recurrence after ALND and none in the SLNB group. CONCLUSIONS: SLNB is successful and accurate in male breast cancer patients too. Although compared to women a larger proportion of men have positive nodes, for men with negative nodes, ALND-related morbidity may be reduced by SLNB. We recommend SLNB in male patients with breast cancer and clinically negative axilla.

The Petersen prognostic index revisited in Dukes B colon cancer--Inter-institutional differences.

A prognostic index (Petersen index, PI) was created for patients with pT3-4 pN0 M0 (Stage II, Dukes' B) colon cancers to distinguish between patients with better and worse outcome, and to help in recommending adjuvant chemotherapy for high risk patients in this stage. The prognostic value of the PI was evaluated in two independent retrospective series of stage II (Dukes' B) colon cancer patients. The parameters defining the PI (venous invasion, peritoneal involvement, circumferential margin involvement, perforation through the tumour) and performance of the PI were compared in two institutions. The two series of patients consisted of 127 and 87 patients. Venous invasion was more frequently detected at one of the centres (p<0.01) and tumour perforation was more frequent at the other (p<0.01). There were no significant differences in the 5-year survival estimates of all patients (p=0.19), and of either the low PI value groups (p=0.52) or that of the high PI value groups (p=0.99) between the two sites. In contrast, there were significant differences in the survival estimates between patients of the low PI category and those of the high PI category altogether (p<0.01) and in either centre. Although, it was expected that differences in the frequency of the parameters involved in the PI would influence its performance, this was not confirmed by the data. Our results suggest that using the PI may be of value in prognostic factor based therapy selection of colon carcinoma patients.

[Eosinophilic gastritis simulating gastric carcinoma]. / Eosinophil gastritis gyomorrákot utánozó formája.

A case of eosinophilic gastritis is reported in a 65-year-old woman. The disease presented with signs of delayed emptying, vomiting and substantial thickening of the antrum. Partial gastrectomy was performed because of the suspicion of gastric cancer and pyloric stenosis. Histopathology established the diagnosis of eosinophilic gastritis of mural type. Clinicopathological features of the disease, as well as its differential diagnosis are summarised in the discussion.

[Sentinel lymph node mapping in colorectal cancer]. / Orszem nyirokcsomó meghatározása vastag- és végbélrák esetén.

UNLABELLED: Sentinel lymph node mapping has already been accepted as part of the treatment for malignant melanomas of the skin and in breast carcinomas. The status of lymph nodes is an important prognostic marker in colorectal carcinoma as well. The authors tried the feasibility of this technique in colorectal carcinomas. The technique is analogous to the one used in breast cancer and melanoma: 2 ml of 2.5% Patentblau dye was given subserosally around the tumor. After resection the specimen was immediately sent to pathology where the lymph nodes were removed. This technique has been tried on 31 patients, 22 with colonic and 9 with rectal tumors. Of these patients, 15 were Dukes stage C, 14 were Dukes stage B and 2 were Dukes stage A. An average 4.3 blue lymph nodes were found in colon tumors and 5.4 in rectal tumors and an average 14 unstained lymph nodes were found in colon tumors, and 7 in rectal tumors. The blue nodes were predictive of the nodal status in 9 of the 15 Dukes stage C patients. In these cases the blue lymph nodes contained metastases and there were 2 cases where metastases were limited to the blue lymph nodes. SUMMARY: The authors found a high false negative rate for lymphatic mapping with the vital dye technique, therefore they try to change the method according to that used by Saha et al. The aim of sentinel node identification in colorectal carcinomas would be improved staging rather than reducing of the extent of lymphadenectomy. The role of lymphatic mapping in large bowel cancers needs further investigations. Until the results are reliable, as many lymph nodes as possible have to be excited and sent for histology.

[A rare case of tumor-to-tumor metastasis: secondary deposits of pulmonary adenocarcinoma in a secretory meningioma]. / Tumorba való áttétképzôdés ritka esete: a tüdôrák áttéte secretoros meningeomába.

OBJECTIVE: To report a rare case of tumour-to-tumour metastasis with differential diagnostic considerations. METHODS AND RESULTS: We report the operation of a Sylvian fissure secretory meningioma in a 48 year-old woman. The tumour was suspicious of a metastasis related to a pulmonary adenocarcinoma operated 4 months before. Histopathology confirmed metastatic adenocarcinoma in a secretory meningioma. CONCLUSIONS: Both secretory meningioma and tumour-to-tumour metastasis are rare, and to our knowledge this is the first report of such a rare coincidence. Secretory meningioma can simulate metastases both clinically (extensive oedema, space occupation, carcinoembryonic antigen secretion) and pathologically (secretory inclusions, positivity for cytokeratin 7 and carcinoembryonic antigen and negativity for vimentin), and therefore may cause a special differential diagnostic dilemma.

Multi-institutional comparison of non-sentinel lymph node predictive tools in breast cancer patients with high predicted risk of further axillary metastasis.

Although axillary lymph node dissection (ALND) has been the standard intervention in breast cancer patients with sentinel lymph node (SLN) metastasis, only a small proportion of patients benefit from this operation, because most do not harbor additional metastases in the axilla. Several predictive tools have been constructed to identify patients with low risk of non-SLN metastasis who could be candidates for the omission of ALND. In the present work, predictive nomograms were used to predict a high (>50 %) risk of non-SLN metastasis in order to identify patients who would most probably benefit from further axillary treatment. Data of 1000 breast cancer patients with SLN metastasis and completion ALND from 5 institutions were tested in 4 nomograms. A subset of 313 patients with micrometastatic SLNs were also tested in 3 different nomograms devised for the micrometastatic population (the high risk cut-off being 20 %). Patients with a high predicted risk of non-SLN metastasis had higher rates of metastasis in the non-SLNs than patients with low predicted risk. The positive predictive values of the nomograms ranged from 44 % to 64 % with relevant inter-institutional variability. The nomograms for micrometastatic SLNs performed much better in identifying patients with low risk of non-SLN involvement than in high-risk-patients; for the latter, the positive predictive values ranged from 13 % to 20 %. The nomograms show inter-institutional differences in their predictive values and behave differently in different settings. They are worse in identifying high risk patients than low-risk ones, creating a need for new predictive models to identify high-risk patients.

Limited lymph-node recovery based on lymph-node localisation is sufficient for accurate staging.

AIMS: To assess the reliability of nodal staging in colorectal carcinomas (CRCs) when only lymph nodes close to the tumour are recovered and examined histologically. METHODS: Lymph nodes from CRC resection specimens were recovered into two fractions: one from around the tumour and the 3 cm sidelong bowel segment associated with it in the proximal and distal directions, and another from the remaining part of the resection specimen. RESULTS: Of the 762 CRCs (239 right colon, 251 left colon, 257 rectum, 15 unspecified localisation) there were 393 node-negative and 369 node-positive cases. The median number of LNs examined was 18. The assessment of the LNs located in the close fraction (median 13) yielded an adequate qualitative nodal status in 756 patients (99.2%). In four cases (two rectal and two right colic), no LN metastases could be identified in the close-fraction lymph nodes, but nodes from the distant fraction contained metastases. Of the node-positive carcinomas which had at least one positive lymph node in the close fraction, 203 belonged to the pN1 category and 162 to the pN2 category of the Tumour Node Metastasis staging system. Only 14 cases (10 rectal, two right and two left colic tumours) were misclassified as pN1 (on the basis of lymph nodes recovered from the close fraction) although they were of the pN2 category. CONCLUSIONS: In general, nodal status of CRCs may be adequately assessed by examining the lymph nodes from the close fraction around the tumour and the 3 cm sidelong bowel segment in both directions.

Venous invasion demonstrated by orcein staining of colorectal carcinoma specimens is associated with the development of distant metastasis.

AIMS: To assess venous invasion (VI) and its relation to distant metastases in colorectal cancer (CRC). METHODS: Primary untreated CRC cases were assessed for VI. All tumour blocks were stained with H&E and orcein. The presence of VI and nodal status were then correlated with the presence of synchronous or metachronous distant metastases. RESULTS: VI was detected more frequently with the orcein stain (18% versus 71%). Eleven tumours (nine node-positive tumours, all VI positive) were associated with synchronous distant metastasis. During a median follow-up of 17 months nine further cases were diagnosed with distant metastasis (six node-positive tumours, all VI positive). The specificity and sensitivity of the presence of nodal metastasis for predicting distant metastasis were 0.56 and 0.75, respectively. The same values for orcein-detected VI were 0.39 and 1, respectively. CONCLUSIONS: Elastic stains such as the orcein stain enable the detection of clinically relevant VI with greater frequency than conventionally stained histological slides. If nodal involvement is an indication for systemic chemotherapy, the data presented here suggest that VI detected by the orcein stain should also be an indication for systemic chemotherapy.