NTRK Fusions in a Sarcomas Series: Pathology, Molecular and Clinical Aspects.

Targeting molecular alterations has been proven to be an inflecting point in tumor treatment. Especially in recent years, inhibitors that target the tyrosine receptor kinase show excellent response rates and durable effects in all kind of tumors that harbor fusions of one of the three neurotrophic tyrosine receptor kinase genes (NTRK1, NTRK2 and NTRK3). Today, the therapeutic options in most metastatic sarcomas are rather limited. Therefore, identifying which sarcoma types are more likely to harbor these targetable NTRK fusions is of paramount importance. At the moment, identification of these fusions is solely based on immunohistochemistry and confirmed by molecular techniques. However, a first attempt has been made to describe the histomorphology of NTRK-fusion positive sarcomas, in order to pinpoint which of these tumors are the best candidates for testing. In this study, we investigate the immunohistochemical expression of pan-TRK in 70 soft tissue and bone sarcomas. The pan-TRK positive cases were further investigated with molecular techniques for the presence of a NTRK fusion. Seven out of the 70 cases showed positivity for pan-TRK, whereas two of these seven cases presented an NTRK3 fusion. Further analysis of the fused sarcomas revealed some unique histological, molecular and clinical findings. The goal of this study is to expand the histomorphological spectrum of the NTRK-fused sarcomas, to identify their fusion partners and to correlate these parameters with the clinical outcome of the disease. In addition, we evaluated the immunohistochemical expression pattern of the pan-TRK and its correlation with the involved NTRK gene.

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.

High-grade serous cancer of undetermined primary origin presenting as solitary inguinal lymph node enlargement.

A 62-year-old woman presented with unilateral inguinal lymphadenopathy, existing for several months. As it was initially thought to be lymphoma, the lymph node was resected. Pathology, however, revealed a metastasis of a high-grade papillary serous cancer, according to its stainings, most likely ovarian in origin. Further staging showed lymphadenopathies in the inguinofemoral, para-aortic and mediastinal regions. Consequently, the multidisciplinary oncologic meeting advised a diagnostic laparoscopy which showed no macroscopic spread within the abdomen. Pathological examination of biopsies as well as both ovaries showed no sign of ovarian cancer. The patient received standard chemotherapy, that is, carbo-Taxol-Avastin, to which she showed complete response after three cycles as shown on positron emission tomography-CT. A review of existing literature showed that this is a very unusual case of high-grade serous carcinoma, where no site of origin could be found.

Interobserver variability in upfront dichotomous histopathological assessment of ductal carcinoma in situ of the breast: the DCISion study.

Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.

Presacral extramedullary haematopoiesis: A diagnostic update and case report of a late diagnosis.

INTRODUCTION: We report a rare case of presacral extramedullary haematopoiesis, which manifested as a tumoural mass on a routine ultrasonography in a patient presenting with symptoms of cholecystitis. Since Ask-Upmark in 1945 reported 3 cases of pelvic extramedullary haematopoiesis, we are aware of only published 14 additional cases. PRESENTATION OF CASE: A 73-year-old female patient presented with abdominal pain in the right hypochondrium. An abdominal ultrasonography revealed cholecystitis with cholecystolithiasis and a coincidental hyperreflective mass of 9.5cm was visualised behind the bladder. A clinical examination identified a mass in the pelvis that could be palpated vaginally. A computerised tomography scan showed a large presacral, inhomogeneous, multilobular and nodular tumour. The patient was admitted for laparoscopic resection of the gall bladder and laparoscopic exploration of the presacral mass. An anatomopathological examination of the tissue revealed the presence of extramedullary haematopoietic tissue. A postoperative haematological investigation indicated that the extramedullary haematopoiesis was idiopathic. DISCUSSION: Presacral EMH may occasionally present with symptoms of nerve compression. Symptoms of haematologic disorders may accompany EMH. Barium enema, abdominal ultrasound, CT scan, MRI and radionuclide bone marrow imaging have all been used by previous authors in establishing the diagnosis. Tissue samples may be misdiagnosed when atypical megakaryocytes are misinterpreted as malignant cells, which occurred in this case. Misdiagnosis can occur even more often when EMH is not considered in the differential diagnosis due to its rare occurrence. In this case, the final diagnosis was made tissue sampling after surgery. Treatment of EMH is only necessary when it is symptomatic. CONCLUSION: This case report shows that extramedullary haematopoiesis is very rare and that it is a difficult diagnostic challenge when its location is unusual and when it is not associated with a haematologic disorder. Together with this case report, we present an update of the available diagnostic methods.

An intracerebral intraparenchymatous triton tumor in a man with neurofibromatosis.

We report the second case of a cerebral intraparenchymatous malignant nerve sheath tumor, triton tumor variant. It is the first case associated with neurofibromatosis reported in literature thus far. The therapy of these aggressive tumors is rather disappointing as recurrence of the tumor despite complete surgical resection and even adjuvant radiotherapy and/or chemotherapy is seen in most patients. It is still unknown if survival is influenced by tumor localization, size or malignancy grade. In this case therapy also proved to be unsuccessful.