Case Of Endometrial Stromal Sarcoma Research Articles

Endometrial stromal neoplasia: An uncommon tumor at a tertiary health centre in coastal India

Introduction and Aim: Stromal malignancies of uterus are rare and accounts for 1-3% of all female genital tract malignancies. They are known to pose a diagnostic challenge to the clinicians and the pathologists. They show non-specific clinical features, gross appearance, varying histological and immunohistochemical features. This study highlights the important clinical, morphologic and immunohistochemical features of these tumors. Methodology: Histopathologically diagnosed cases of endometrial stromal neoplasia over a period of 5 years from 2013 to 2017 were retrieved. The cases were analysed based on age, tumor size and histological types. Immunohistochemistry (IHC) was done whenever feasible. Results: During the study period, we found 25 cases of endometrial stromal neoplasia. They were composed of four cases of endometrial stromal nodule (ESN), six cases of low grade endometrial stromal sarcoma (ESS) and three cases of ESS with smooth muscle differentiation. Twelve cases of carcinosarcomas and adenosarcomas and a single case of undifferentiated uterine sarcoma were seen. The mean age at presentation of Mixed epithelial stromal sarcoma (Carcinosarcoma) was 61 years while that of ESS and ESN was 46 and 47 years respectively. The mean size of ESN was 3.6cm (1.5-6cm), ESS was 4.5 cm (2-9.9 cm) and carcinosarcomas was 4.9 cm (2.5-16 cm). Conclusion: Endometrial stromal neoplasia should be diagnosed after proper evaluation of gross morphology, histological features and immunohistochemical findings in correlation with the clinical presentation. In addition, genetic profiling is useful as an ancillary test. The spectrum of endometrial stromal neoplasia is a beginner’s ordeal if not aware of.

Endometrial Stromal Sarcoma - A Rare Gynecological Malignancy

Endometrial stromal sarcoma is rare gynecological malignancy. A proper preoperative diagnosis is difficult and most of cases diagnosed on histopathology. This is case of endometrial stromal sarcoma infiltrating to both ovaries that is stage II A.A 44year old female presented with complaint of irregular heavy vaginal bleeding and history of loss of weight, appetite and altered bowel habits. Clinical diagnosis of Leiomyosarcoma was in mind but on histopathology endometrial stromal sarcoma infiltrating to both ovaries confirmed.

JAZF1, YWHAE and BCOR gene translocation in primary extrauterine low-grade and high-grade endometrial stromal sarcomas.

JAZF1 translocation is the most common genetic change in low-grade (LG) endometrial stromal sarcoma (ESS), and YWHAE and BCOR translocations are common in high-grade (HG) ESS. Primary extrauterine ESS is rare, and there are limited data on molecular alterations in these tumours. Cases of primary extrauterine ESS, comprising eight LG-ESS cases and five HG-ESS cases were collected. Haematoxylin and eosin and immunohistochemical staining were used to observe the histomorphology and analyse related protein expression. JAZF1, YWHAE and BCOR rearrangements were explored with fluorescence in-situ hybridisation (FISH). In LG-ESS, the tumour cells resembled normal proliferative-phase endometrial stromal cells; CD10, oestrogen receptor and progesterone receptor were expressed in all eight cases. In HG-ESS, the tumour cells had uniform HG round and/or spindle morphology, sometimes with an LG component; CD10 was fully expressed in one case and focally expressed in four cases; BCOR was expressed in all five cases, and cyclin D1 in four of five cases. FISH analysis showed JAZF1 translocation in one of eight LG-ESS cases (12.5%). YWHAE translocation occurred in four of five HG-ESS cases, with a positivity rate of 80%. BCOR translocation was absent in all five cases. In extrauterine LG-ESS, the rate of JAZF1 rearrangement was significantly lower than in uterine LG-ESS. This result limited the value of JAZF1 translocation for diagnosis. YWHAE rearrangement is a common genetic change in extrauterine HG-ESS. Further studies are required to confirm these findings, especially in LG-ESS.

A case of endometrial stromal sarcoma treated with additional laparoscopic surgery using a wound from robot-assisted laparoscopic total hysterectomy

A case of endometrial stromal sarcoma treated with additional laparoscopic surgery using a wound from robot-assisted laparoscopic total hysterectomy

Ossifying low grade endometrial stromal sarcoma with PHF1-BRD8 fusion

Low-grade endometrial stromal sarcoma and ossifying fibromyxoid tumors are two types of mesenchymal tumors that share no similarities in terms of site, sex, and morphological characteristics. They are rare, low grade tumors of uncertain lineage, with no definite immunological markers. Interestingly, a common PHF1 gene- related rearrangement was observed in these two tumors. Here, we report a case of endometrial stromal sarcoma with distinct ossification. Microscopically, the tumor is composed of bland-looking ovoid cells with low cellularity in the fibromyxoid stroma. Foci of metaplastic bone formation were noted. Using a combination of FISH, transcriptome sequencing, and molecular techniques, we identified a new PHF1-BRD8 fusion transcript, which was previously described, but in its reciprocal fusion form. This case expands the current understanding of low-grade endometrial stromal sarcoma and emphasizes the importance of molecular characterization of unique fusion, which may be related to its distinct morphological features and the possibly chemosensitive target.

Endometrial Stromal Sarcoma in the Young

Endometrial stromal sarcoma (ESS) represents a very rare group of malignant tumors comprising less than 10% of all uterine sarcomas but only around 0.2% of all uterine cancer. In developing countries, the prevalence of ESS is approximately two in a million perimenopausal women between ages of 45 and 50 years. The occurrence in younger women is rare and the diagnosis frequently delayed due to low index of suspicion. Two cases of ESS diagnosed in women in the 20s age group were documented in a tertiary hospital. Both patients presented with abnormal vaginal bleeding associated with hypogastric pain and rapid abdominal enlargement. Surgery was the primary treatment modality and histopathologic examination confirmed the diagnosis. Adjuvant therapy remains controversial. ESS is a rare pathological entity, more so in the young. However, the diagnosis of a malignancy should not be missed despite rarity of occurrence in this age group. J Clin Gynecol Obstet. 2020;9(3):73-77 doi: https://doi.org/10.14740/jcgo647

Endometrial stromal sarcoma and variants: A study of four cases with review of literature and immunohistochemistry

Endometrial stromal Sarcoma (ESS) is a rare malignant neoplasm of uterus occurring in perimenopausal age group. The annual incidence of ESS is 1–2 per million women. ESSs are morphologically heterogeneous. The distinction between uterine smooth muscle tumors such as myxoid leiomyosarcoma and low-grade ESS can be difficult when stromal sarcomas have abundant myxoid stroma. A definitive diagnosis of stromal sarcoma can be made if myometrial invasion is present, but hysterectomy is usually required for definitive diagnosis. We report four cases of ESS encountered in a period of one year all of which was confirmed by immunohistochemistry.

Genomic profiling of BCOR-rearranged uterine sarcomas reveals novel gene fusion partners, frequent CDK4 amplification and CDKN2A loss

ObjectiveGenomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. MethodsA retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. ResultsWe identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. ConclusionsAlterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.

Retrospective analysis of clinical, pathological characteristics and prognosis of the patients with endometrial stromal sarcomas

Objective: Endometrial stromal sarcoma (ESS) is a rare mesenchymal tumor of the uterus.Literature has limited data about the ESS. The aim of the present study was to contribute to literature by reporting the histo-pathological findings, clinical characteristics of ESS patients and the data about the accuracy of preoperative diagnosis and prognosis.
 Material and Methods: A total of 33 patients who were diagnosed and followed up with ESS at Department of Gynecology and Obstetrics of Bursa Uludağ University between 2007 and 2017 were retrospectively analyzed with regard to clinical and pathologic characteristics, surgical procedures they underwent and survival.
 Results: Mean age of the patients was 49.5 years and 60.2 years for low grade ESS (LG-ESS) and high grade ESS (HG-ESS) (p=0,01). Post-menopausal hemorrhage was the most common complaint on admission. Correct histological diagnosis was made in only 72.7% of the patients from whom pre-operative endometrial biopsy was obtained. Twelve out of 16 cases (75%) were in Stage 1. While all patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH+BSO), 14 underwent pelvic and para-aortic lymphadenectomy for surgical staging. Lymph node involvement was detected in no patients who underwent lymphadenectomy. The patients with LG-ESS were found to have a good prognosis however the ones with HG-ESS had a high mortality rate even in the early stages (mean survival of 10 months).
 Conclusion: High grade ESS cases show different clinical characteristics and prognosis than LG-HSS. Diagnostic accuracy of endometrial sampling is much lower when compared to epithelial uterine malignancies. Metastasis of pelvic-paraaortic lymph nodes of which removal is reported which not to contribute to survival is rare.

Endometrial stromal sarcoma: Retrospective analysis of a tertiary care experience from India

Background: Endometrial stromal tumors are rare tumors of mesenchymal origin, conventionally classified as low-grade and high-grade tumors based on the mitotic count. Objective: In this study, our objective was to analyze the clinical characteristics and outcomes of patients with endometrial stromal sarcomas (ESS) treated at our institute.Materials and Methods: Records of histologically proven cases of ESS treated at out institute between January 2011 and July 2015 were studied. The data were reviewed to ascertain the patient and disease characteristics and the treatment received before and after coming to the tertiary care hospital. Overall survival (OS) was assessed using the Kaplan–Meier method, and the differences were evaluated using the log-rank test.Results: A total of 25 patients with ESS were identified, and the data for 23 of these were analyzed; 15 (65%) patients had low-grade tumors, and eight (35%) had high-grade tumors. About 53% of the patients with low-grade ESS (LG-ESS) had early stage disease, and 75% of those with high-grade ESS had Stage III/IV disease. All patients underwent at least a total abdominal hysterectomy. Adjuvant radiation and chemotherapy were given to 11 and 7 with LG-ESS and HG-ESS patients, respectively. Nine (39.1%) patients received hormonal therapy. Fifteen (65%) patients received some form of treatment before reporting at our institute. At the median follow-up of 22 months (range, 5–62 months), four patients died because of disease progression. The median OS for patients with high-grade tumors was 25 months; it was not reached for patients with low-grade tumors.Conclusions: LG-ESS present at an earlier stage and have a better outcome than high-grade ESS, which receive more aggressive treatment. However, the general lack of awareness among practitioners has led to many patients not receiving standard treatment and counseling. Therefore, the treating oncologists must properly assess the risk management strategies before instituting treatment.

A case of endometrial stromal sarcoma presenting at very young age

Uterine sarcomas are heterogeneous group of malignancies both clinically as well as pathologically. Lieomyosarcoma contributes for majority of uterine sarcomas (30-40%) with the peak incidence in postmenopausal women (50-60 years). Endometrial Stromal Sarcoma accounts for 10% of uterine malignancies, generally an indolent disease with long natural history. It presents in relatively young age. ESS tumors have high incidence of oestrogen and progesterone receptor expression, and are hormonally responsive. We present a case of a endometrial stromal sarcoma in a 28 years old patient who presented with heavy menstrual bleeding and secondary subfertility. Ultrasound scan revealed a typical appearance of a leiomyoma. However, later diagnosed a ESS and had undergone surgical management by gynaecological oncosurgical team. Preoperative diagnosis of uterine sarcoma in a young patient is always a challenge. Surgery is the mainstay of treatment. However, due to high expression of hormone receptors peri-operative hormonal suppression plays a vital role in prevention of recurrence and treatment of advanced cancers.

Cystic and solitary nodular pulmonary metastases in a patient with low-grade endometrial stromal sarcoma: A case report and literature review.

Pulmonary metastases of endometrial stromal sarcoma (ESS) are uncommon and can be difficult to diagnose. The aims of the present study were to investigate the clinical and pathological features, and enhance the awareness of pulmonary metastases in patients with low-grade ESS. The study reports a case of low-grade ESS that resulted in cystic and nodular pulmonary metastases. Furthermore, the PubMed database was searched using ‘pulmonary metastases of low-grade endometrial stromal sarcoma’ as the key phrase. The literature on pulmonary metastases of low-grade ESS was reviewed and 35 cases were included in the present study. The clinical manifestations, imaging data, pathological features, treatment and prognosis of the 35 previously reported cases and the current case were retrospectively analyzed. The age range of the 36 patients diagnosed with low-grade ESS was 28–65 years. The time period from confirmation of ESS to lung metastases was 1.5–27 years. In 50% of the patients, the pulmonary metastases were asymptomatic. The most common pulmonary symptom was dyspnea, followed by chest pain, pneumothorax and coughing. The most common chest imaging presentation was multiple pulmonary nodules, followed by a solitary nodule or mass. Histology was used to identify that the pulmonary metastases had the pathological features of low-grade ESS. The immunohistochemical results demonstrated strong diffuse immunoreactivity for cluster of differentiation 10, estrogen receptor and progesterone receptor in almost all the specimens. The review of the literature revealed that pulmonary metastases from low-grade ESS are rare but not negligible. Furthermore, the detailed clinical information, imaging findings and immunohistochemical detection are important for making a diagnosis.

A Case of Endometrial Stromal Sarcoma Revealed by Lung Metastasis 7 Years after Hysterectomy which Led to Histological Diagnosis of Uterine Fibroid

A Case of Endometrial Stromal Sarcoma Revealed by Lung Metastasis 7 Years after Hysterectomy which Led to Histological Diagnosis of Uterine Fibroid

Occult uterine malignancy during laparoscopic supracervical hysterectomy.

To estimate the incidence of occult uterine malignancies during laparoscopic supracervical hysterectomy (LSH). Retrospective cohort study based on archival data (2010-2016) of the Department of Gynecology and Oncology, Jagiellonian University. Medical records of 696 women, who underwent LSH were analyzed. Two occult sarcomas (2/696; 0.29%, 0.003, 95% CI: 0.001 to 0.01), including one case of low-grade endometrial stromal sarcoma (ESS) with co-occurring atypical endometrial hyperplasia (AH) and one case of high-grade ESS were found postoperatively. One case of invasive primary fallopian tube cancer (1/696; 0.14%, 0.001, 95% CI: 0.00 to 0.008) and additional three cases of AH (3/696; 0.57%, 0.004, 95% CI: 0.001 to 0.013) were also identified. No case of EC was documented. One hundred sixty nine (24.3%) women of 696 had an endometrial sampling prior LSH including these with ESS. We did not observe worsening of the prognosis and all patients with confirmed malignancy are still alive and free from recurrence in 2-5 years of observations. Most commonly the occult malignancy would have not been recognized if the surgery had not been conducted. When appropriate diagnostics is conducted, rare incidents of malignant tissue morcellation should not be considered as a professional misconduct but as a possible adverse event. Patients should be informed about the risk of malignancy according to available estimations and that endometrial sampling cannot eliminate such a risk. A consensus regarding safe indications, required diagnostics, and justifiability of mandatory use of contained morcellation for LSH should be developed.

Extrapelvic Metastases in Endometrial Stromal Sarcomas: A Clinicopathological Review With Immunohistochemical and Molecular Characterization.

Endometrial stromal sarcoma is a rare uterine tumor associated with favorable outcomes despite its ability to recur and metastasize to distant sites. Most recurrences are local, being limited to the abdomen/pelvis, but distant metastases can occur. Metastatic endometrial stromal sarcoma can occur many months to years after the original diagnosis or may present prior to the primary, potentially creating a diagnostic challenge. We report a bi-institutional review of 10 cases of endometrial stromal sarcoma with extrapelvic metastases without a prior history of endometriosis. The histologic, immunophenotypic, and molecular characteristics of these tumors are analyzed in the context of a relevant literature review.

Extrauterine endometrial stromal sarcoma arising in a background of endometriosis following prior total abdominal hysterectomy

This article describes a case of endometrial stromal sarcoma arising in a background of endometriosis presenting several years after total abdominal hysterectomy. Discussion of endometrial stromal sarcoma ensues as well as review of pertinent imaging findings.

IFITM1 Outperforms CD10 in Differentiating Low-grade Endometrial Stromal Sarcomas From Smooth Muscle Neoplasms of the Uterus.

Distinguishing between uterine neoplasms of smooth muscle and endometrial stromal origin is a frequent diagnostic challenge. We investigated the staining pattern of interferon-induced transmembrane protein-1 (IFITM1), a novel endometrial stromal marker, in endometrial and smooth muscle uterine neoplasms and compared it with CD10 in its ability to differentiate between these two groups. Immunohistochemistry for IFITM1 and CD10 was performed in 20 cases of smooth muscle neoplasms (10 cases leiomyoma, 10 cases leiomyosarcoma), 14 cases of endometrial stromal sarcoma (ESS) (12 cases of low grade and 2 cases of high grade) and 12 cases of carcinosarcoma. Staining was scored in terms of intensity and distribution (0=absent, 1=weak/<50%, 2=moderate/50%-75%, 3=strong/>75%). A total score was obtained by adding intensity and distribution scores and classified as positive (score 3-6) or negative (score 0-2). IFITM1 was positive in 10 of 12 (83%) low-grade ESSs, 6 of 20 (30%) smooth muscle tumors (leiomyomas and leiomyosarcomas) and 11 of 12 carcinosarcomas (91.6%). The 2 cases of high-grade ESS were IFITM1 negative. While both IFITM1 (83%) and CD10 (91%) had high sensitivity in differentiating low-grade ESSs from smooth muscle neoplasms, IFITM1 (70%) had higher specificity compared with CD10 (45%). In this study IFITM1 appears to be a more specific marker of endometrial stromal differentiation compared with CD10 in differentiating low-grade ESSs from smooth muscle neoplasms. Thus, IFITM1 may be a valuable tool as part of an immunohistochemical evaluation panel in this diagnostic scenario.

Pulmonary metastases of uterine endometrial stromal sarcoma in a young patient: An extreme rarity

Endometrial stromal sarcoma (ESS) is a rare malignant tumor of the endometrium, usually seen in perimenopausal females. We report a case of ESS in a 24 year old woman, presenting as rapid enlargement of a uterine fibroid associated with irregular and excessive vaginal bleeding along with a lung nodule. Hysterectomy was performed. Histopathological examination and immunohistochemistry confirmed ESS. A proper preoperative diagnosis is difficult and in most cases the diagnosis is confirmed after hysterectomy for a presumed benign disease. Simultaneous pulmonary metastasis of ESS is an extremely rare event. As the tumor is rarely encountered, management protocols are still questionable. Although rare, ESS should be considered in the differential diagnosis of all women who present with a rapid enlargement of a uterine leiomyoma. This report is aimed to present a case of endometrial stromal tumor in a young female with simultaneous lung metastasis because of its rare existence and difficulties in establishing histological diagnosis.

The JAZF1-SUZ12 fusion protein disrupts PRC2 complexes and impairs chromatin repression during human endometrial stromal tumorogenesis.

The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17). Co-transient transfection assay indicated JAZF1-SUZ12 destabilized PRC2 components EZH2 and EED, resulting in decreased histone methyl transferase (HMT) activity, which was confirmed by in vitro studies using reconstituted PRC2 and nucleosome array substrates. We also demonstrated the PRC2 containing the fusion protein decreased the binding affinity to target chromatin loci. In addition, we found that trimethylation of H3K27 was decreased in ESS samples with the t(7;17), but there was no detectable change in H3K9 in these tissues. Moreover, re-expression of SUZ12 in Suz12 (−/−) ES cells rescued the neuronal differentiation while the fusion protein failed to restore this function and enhanced cell proliferation. In summary, our studies reveal that JAZF1-SUZ12 fusion protein disrupts the PRC2 complex, abolishes HMT activity and subsequently activates chromatin/genes normally repressed by PRC2. Such dyesfunction of PRC2 inhibits normal neural differentiation of ES cell and increases cell proliferation. Related changes induced by the JAZF-SUZ12 protein in endometrial stromal cells may explain the oncogenic effect of the t(7;17) in ESS.

Endometrial stromal sarcoma: morphologic features and detection of JAZF1-SUZ12 and YWHAE FAM22 fusion genes

To study the morphologic features, immunophenotype and significance of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in endometrial stromal sarcoma (ESS). Fifty-three cases of ESS were retrieved and the pathologic features were reviewed. Immunohistochemical study for estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon were carried out using tissue microarray technology. Reverse transcription-polymerase chain reaction (RT-PCR) was applied for detection of expression of JAZF1-SUZ12 and YWHAE-FAM22 fusion genes in 47 cases of ESS and 12 cases of other spindle cell neoplasia in uterus (including 2 cases of undifferentiated sarcoma, 3 cases of leiomyosarcoma, 3 cases of leiomyoma, 4 cases of adenosarcoma and 2 cases of uterine tumor resembling ovarian sex cord tumor). The 53 cases of ESS studied included 43 cases of low-grade ESS and 10 cases of high-grade ESS. As for low-grade ESS, in addition to the classic morphologic features, smooth muscle differentiation was present in 7 cases (16.3%), sex cord-like differentiation in 2 cases (4.7%), rhabdoid differentiation in 1 case (2.3%), clear cell changes in 1 case (2.3%) and schwannoma-like palisading pattern in 1 case (2.3%). As for high-grade ESS, sex cord-like differentiation (1 case), mucinous microcystic changes (1 case) and focal clear cell changes (1 case) were also observed. The expression rate of estrogen receptor, progesterone receptor, CD10, cyclin D1, smooth muscle actin, desmin and H-caldesmon was 86.0%, 81.4%, 74.4%, 2.3%, 23.3%, 23.3% and 4.7% in low-grade ESS, respectively, and was 1/10, 6/10, 6/10, 7/10, 1/10, 1/10 and 0 in high-grade ESS, respectively. RNA extraction was successful in 47 cases of ESS, including 39 cases of low-grade ESS and 8 cases of high-grade ESS. The positive rate of JAZF1-SUZ12 fusion gene was 30.8% (12/39) in low-grade ESS. The positive rate of YWHAE-FAM22 fusion gene was 12.5% (1/8) in high-grade ESS. The 14 control cases were all negative for JAZF1-SUZ12 and YWHAE-FAM22 fusion genes. As uncommon pathologic pattern may occur in both low-grade ESS and high-grade ESS, detection of JAZF1-SUZ1 and YWHAE-FAM22 fusion genes by RT-PCR would be helpful in diagnosis and differential diagnosis of ESS, especially for those tumors which lack typical morphologic features.