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Out of a total of 24 ERNs, three are specifically dedicated to rare tumors: EURACAN (rare solid tumors of adults, including brain tumors), EuroBloodNet (hematological diseases and rare hematological tumors) and PaedCan (rare pediatric tumors). Within EURACAN, domain 10 is dedicated to brain tumors. |
## 7. Conclusions and Future Directions |
MB is a very rare tumor in the post-pubertal and adult population, with a distinctly unique profile from a clinical, molecular, prognostic and therapeutic point of view. |
Despite the relevant innovations in the pathology and molecular biology field emerging from the recent 2021 WHO classification for the MB diagnosis, practice-changing clinical trials modifying medical treatments and radiotherapy options, especially in adult MB, are still lacking. |
Irrespective of the individual risk and of the molecular subgroup, the standard of care remains surgery followed by craniospinal irradiation and multi-agent chemotherapy, with a wide spectrum of short and long-term toxicities of various types, such as hematological, neurocognitive and endocrinological. A large proporti... |
Lessons from the use of personalized targeted therapies in oncology have shown the advantage of considering the molecular profile as the primary criteria for the clinical trial design. Future research dedicated to adult MB should move forward in the direction of personalized treatments, stratifying patients by age and ... |
This will require consistent academic and financial investments from third-party funders as well as the pharmaceutical industry, research institutes and scientific societies. |
## Author Contributions |
Conceptualization, E.F., P.H.; writing—original draft preparation, E.F., C.G., J.F., K.W.P., S.A., R.G., C.S., L.G. and P.H.; writing—review and editing, E.F., P.H. and L.G.; supervision, P.H. All authors have read and agreed to the published version of the manuscript. |
## Conflicts of Interest |
The authors declare no conflict of interest. |
## Funding Statement |
This research received no external funding. |
## Footnotes |
## References |
b188e128f45ad086cdc94bc9c9fd7681409554d6d314e645f55c66901af04915 pmc9367316.txt |
PMCID: PMC9406596 |
TITLE: Are Columnar Cell Lesions the Earliest Non-Obligate Precursor in the Low-Grade Breast Neoplasia Pathway? |
LICENSE: https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
ABSTRACT: Columnar cell lesions (CCLs) of the breast comprise a spectrum of morphologic alterations of the terminal duct lobular unit involving variably dilated and enlarged acini lined by columnar epithelial cells. The World Health Organization currently classifies CCLs without atypia as columnar cell change (CCC) and... |
## 1. Introduction |
Columnar cell lesions (CCLs) of the breast comprise a spectrum of morphologic alterations of the terminal duct lobular unit (TDLU) involving variably dilated and enlarged acini lined by columnar epithelial cells. While CCLs have historically been described using a variety of terms, the World Health Organization current... |
In part due to the implementation of widespread screening mammography, CCLs have been increasingly recognized in stereotactic core needle biopsies (CNB) performed for the assessment of calcifications [2,3,4,5]. CCLs have been postulated to represent the earliest non-obligate precursor of low-grade invasive breast carci... |
## 2. Historical Overview and Terminology |
CCLs have long been recognized by pathologists but have been previously described using a wide assortment of names, including blunt duct adenosis [21], columnar alteration of lobules [6], columnar cell alterations with atypical snouts [6], atypical cystic lobules [7], atypical lobule of type A [22], hyperplastic enlarg... |
In 2003, Drs. S. Schnitt and A. Vincent-Salomon grouped CCLs into two categories-CCC and CCH, both of which should lack significant cytologic atypia. In contrast, the presence of high-grade nuclear features, even if present in a single cell layer, merits the designation of high-grade DCIS, while complex architectural p... |
Blunt duct adenosis (BDA) was first described by Foote and Stewart [21], and has previously been considered a synonym of CCL without atypia [31,32]. Other authors, however, describe morphologic differences between BDA and CCL, including flattened branching configurations, irregular ducts, conspicuous myoepithelial cell... |
The current 5th edition of the WHO classification of tumors of the breast from 2019 classifies CCLs without atypia as CCC and CCH. FEA is the recommended term for CCLs with atypia, although acceptable terminology also includes CCC with atypia and CCH with atypia [1]. |
## 3. Radiologic Findings |
CCLs are most frequently identified in CNBs performed for mammographically detected calcifications. While the majority of CCLs manifest as grouped amorphous calcifications, fine pleomorphic or punctate calcifications can also be observed [2,3,6,8,9,10,32,38,39,40,41,42,43,44,45,46,47,48,49]. The calcifications associat... |
Sonographically, CCLs with and without atypia may present as cystic or solid lesions as well as a mass with irregular, microlobulated or indistinct borders and hypoechoic or complex echotexture [2,38,39,43,45,46]. There are no reported specific mammographic or ultrasound features which aid in the distinction of patient... |
Although there is a dearth of literature with regards to magnetic resonance imaging (MRI) features in CCLs, findings described include non-mass enhancement (NME) [38,51] and irregular clumped enhancement [46]. Santucci et al. describe a series of 139 patients with histologic borderline (B3) lesions, of which 31 (14.39%... |
Approximately 40% of women in breast screening programs have mammographically dense breasts. Percent mammographic density (PMD) of the breast reflects variations in the number of non-epithelial and epithelial cells, and collagen. Extensive PMD or elevated mammographic density (MBD) is associated with an increased risk ... |
## 4. Histologic Features |
The simplest form of CCL is CCC which is characterized by variably dilated acini with relatively smooth contours lined by one to two layers of columnar epithelial cells (Figure 1a,c). The lesional cells of CCC exhibit ovoid to elongated nuclei that are oriented perpendicular to the basement membrane in a regular fashio... |
CCH is composed of variably dilated acini lined by columnar cells with cytologic features similar to CCC but with cellular stratification of more than two cell layers (Figure 2a,c,e,f). Crowding or overlapping of the nuclei may give the appearance of nuclear hyperchromasia, and the proliferating cells may form small mo... |
FEA now encompasses the term for CCLs with low-grade (monomorphic) cytologic atypia resembling the nuclei of low-grade DCIS. FEA has architectural features of CCC or CCH (Figure 3a,c), but with superimposed cytologic atypia characterized by the presence of rounded or ovoid nuclei with loss of polarity, mildly increased... |
Several authors have examined morphometric nuclear features in order to aid in the distinction of FEA from CCC. Using whole slide imaging and ImageJ software Katayama et al. compared morphologic parameters of 12 cases of CCC and FEA [60]. While cells in CCC had greater mean maximum Feret’s diameter (defined as the meas... |
Another point that merits consideration when discussing the histologic features of CCLs is their diagnostic reproducibility. Samples et al. assessed interobserver agreement of 29–30 pathologists for the diagnosis of six reference cases of FEA [63]. The rate of agreement with the reference diagnosis ranged from 17% to 5... |
Following training tutorials and with well-defined criteria for FEA, O’Malley et al. found an overall agreement of 91.8% for 30 cases of CCLs including complete agreement among all eight pathologists in 24 (80%) cases (k = 0.83) [66]. Darvishian’s group similarly found a kappa value of 0.85 when evaluating the reproduc... |
## 5. Cytologic Features |
With the widespread use of CNB sampling, the cytologic features of CCLs are less relevant in the day-to-day work of practicing pathologists. Nevertheless, they have been described in several small cohorts. In a series of 20 fine needle aspirations (FNAs) with subsequent histologic diagnoses of CCLs, Saqi et al. describ... |
## 6. Immunohistochemical Markers |
The immunohistochemical features of CCLs have been investigated in order to examine their relationship to other breast lesions and explore their etiology. Similar to other low-grade clonal proliferations such as ADH and low-grade DCIS, CCLs are usually diffusely positive for estrogen and progesterone receptors [7,11,23... |
Noel et al. investigated the proliferative rate in CCLs and found that the Ki-67 index was low (<1%) in CCC and CCH without atypia [77]. While the proliferative index was significantly higher (mean 8.2%) in FEA, it was lower than that of intermediate to high-grade DCIS (mean 25.4%). Paradoxically, the Ki-67 proliferati... |
When examining a series of breast biopsies performed for mammographically detected calcifications, Fraser et al. described a spectrum of lesions in the TDLU characterized by columnar epithelial cells with prominent apical snouts, intraluminal secretions, varying degrees of cytologic and architectural atypia and associa... |
## 7. Molecular Alterations |
Breast cancer is a diverse group of diseases with respect to morphologic features, clinical behavior and molecular profile. Low-grade invasive breast carcinomas frequently show recurrent chromosomal aberrations including loss of chromosome 16q and gain of 1q, while high-grade tumors are genetically complex lesions. Giv... |
In the process of breast carcinogenesis, epigenetic abnormalities such as promoter CpG islands are considered to be an early event and may lead to inactivation of tumor suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. Park et al. previously demonstrated that promoter CpG islands were... |
Further studies employing other molecular techniques such as loss of heterozygosity (LOH) [81,82], comparative genomic hybridization [29], in situ hybridization [83], microRNA (miRNA) in situ hybridization [84], mitochondrial DNA sequencing [82], multiplex ligation-dependent probe amplification [36], and allelic imbala... |
Using the designation “clinging carcinoma in situ” with monomorphic features, Moinfar et al. investigated possible genetic alterations in 22 cases of pure flat lesions as well as cases with concurrent conventional DCIS and invasive carcinoma [81]. LOH was identified in 17/22 (77%) of cases at a minimum of one locus, in... |
Using comparative genomic hybridization, Simpson et al. studied 81 lesions from 18 patients with CCLs co-existing with DCIS or invasive carcinoma of no special type [29]. All categories of CCLs exhibited a range of chromosomal copy number gains and losses and the recurrent changes included 16q, 17p or X loss, and 15q, ... |
Aulmann et al. sought to investigate the relationship of extensive FEA spanning greater than two TDLUs with associated low-grade DCIS using comparative allelotyping and loss of heterozygosity markers. Similar to localized FEA, in most cases the different foci of FEA and DCIS shared the same LOHs in most cases; however,... |
Lastly, Verschuur-Maes et al. examined gene copy number of 17 breast cancer-related genes in CCLs, paired DCIS and invasive carcinoma using multiplex ligation-dependent probe amplification (MLPA) [88]. No high-level gene amplifications were observed in CCLs but copy number gains in C11orf30, MYC, CPD, MTDH, CCND1, CCNE... |
Overall, these molecular observations demonstrate genetic commonality between CCLs and other members of the low-grade breast neoplasia pathway supporting the notion that CCLs are clonal precursor lesions. Further studies are required to elucidate factors that determine the rate of progression to in situ and invasive ma... |
## 8. Columnar Cell Lesions in the Male Breast |
Several studies have assessed the presence of CCLs in the male breast. Ni et al. examined consecutively excised male breast specimens and described “columnar cell-like” lesions composed of dilated ducts with intact surrounding myoepithelial cells and an inner layer of columnar luminal cells and apical snouts in 54% of ... |
Lastly, in a retrospective joint analysis of the International Male Breast Cancer Program central pathology review was performed for 1328 male breast cancer patients [92]. Although pathology review was limited to one representative formalin-fixed-paraffin-embedded tissue block per case, a columnar cell-like lesion was ... |
## 9. Clinical Significance |
CCLs are commonly identified in association with lobular carcinoma in situ or atypical lobular hyperplasia, low-grade DCIS and tubular carcinoma [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Although morphologic, immunohistochemical and molecular evidence supports that FEA is a non-obligate precursor to low-grade DCIS an... |
In regards to overall breast cancer risk associated with CCLs, Boulos et al. evaluated the cancer risk for 1261 biopsies with CCLs [93]. They observed that the presence of CCL alone was associated with a mild increase in overall breast cancer risk (relative risk 1.47, 95% CI, 1.0–2.2). Other authors have found that FEA... |
As suggested by Drs. S. Schnitt and A. Vincent-Salomom, when CCC or CCH are encountered in a CNB specimen, no additional work-up or excision is required [28]. In contrast, when pure FEA is encountered in CNB, the optimal management is less clear due to a wide range of reported upgrade rates. The reported incidence of p... |
In order to provide a more robust evaluation, several recent systemic reviews and meta-analyses have been performed in order to identify the pooled upgrade rates of pure FEA to malignancy. Wahab et al. reviewed 2482 cases of pure FEA over 42 studies published from 2004–2020 managed either by surgical excision or imagin... |
Given the lack of consensus recommendations for the management of FEA, it is not surprising that the approach to their management is heterogeneous. In an audience response survey at the 2010 and 2011 annual meetings of the American Roentgen Ray Society, radiologists were asked about the clinical management of various h... |
If one turns to national and international societies, guidelines for the management of FEA are scant. The American Society of Breast Surgeons currently recommends observation with clinical and imaging follow-up if pure FEA or CCL is diagnosed on CNB but excision in the presence of concurrent ADH [134]. As for Europe, t... |
The latest edition of the WHO classification of tumors of the breast states that the need for routine surgical excision after a diagnosis of FEA on CNB is uncertain. Furthermore, surgical excision may not be necessary if a post-biopsy mammogram shows that all of the radiographic lesion has been removed. Radiologic-path... |
## 10. Conclusions |
Immunohistochemical and molecular studies suggest that CCLs represent the earliest non-obligate precursor of low-grade breast carcinoma. Nevertheless, the risk of local recurrence and progression to carcinoma is low. Management recommendations when pure FEA is diagnosed on CNB are heterogeneous, although recent meta-an... |
a1005077971e8e6c8de8702e539bfa63a40219d87725e399f2f81ec7489bbde4 pmc9406596.txt |
PMCID: PMC9422988 |
TITLE: Sudden death associated with lipoma of the cerebellopontine angle |
LICENSE: This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
ABSTRACT: ABSTRACTIntracranial lipomas are rare benign tumors considered exceptional when localized in the cerebellopontine angle (CPA), with an incidence of 0.1% of the total number of expansive processes located in this area. We present a case of the sudden death of a 26-year-old young woman in which an unencapsulate... |
## INTRODUCTION |
Intracranial lipomas are rare benign lesions with an incidence at autopsy of 0.08%.1,2 Lacking cellular atypia, dysplasia, and other malignancy indices, these lipomas are considered embryonic developmental disorders rather than neoplasms.3,4-5 Frequently, intracranial lipomas are localized on the midline above the corp... |
In this report, we present the case of an unexpected death of a young woman affected by cerebellopontine lipoma. |
## CASE REPORT |
A 26-year-old girl was found dead in her home. Her family members reported they had seen her alive a few hours before and that she occasionally suffered from migraine, which was never medically investigated and treated with over-the-counter analgesics. They declined alcohol or drug abuse. The autopsy was ordered by the... |
During the autopsy investigation, fragments of viscera and biological fluids were sampled for the usual chemical-toxicological analyses, as well as the brain and heart in toto and samples of the lung, liver, kidneys, and spleen for subsequent histopathological study. The latter were conducted using standard post-fixati... |
Toxicological analyses were negative for determining Blood Alcohol Concentration (BAC), narcotics, and psychotropic substances. On the other hand, histopathological investigations of the viscera and the cerebellopontine neoformation showed a formation composed by mature adipocytes, allowing to define it as an intracran... |
No evidence of malignancy was observed. Areas of acute neuronal hypoxic distress in the bulbar site (olive) and diffuse cerebral edema of a severe degree, mainly in the right hemisphere, were also documented (Figure 4). |
Histological examinations of all other viscera revealed no pathological findings. In detail, the heart, which was taken entirely, was studied carefully with numerous histological samples, and sudden death from cardiac causes was ruled out. |
Therefore, based on the concordance and convergence of the data that emerged at autopsy examination and laboratory testing, we attributed the cause of death of the young woman to acute cardiocirculatory failure secondary to supratentorial herniation (right uncal) from lipoma of the cerebellopontine angle with diffuse c... |
## DISCUSSION |
Intracranial lipomas (ILs) are benign, slow-growing neoplasms that typically cause progressive neurological symptoms with loss of hearing ability, dizziness, tinnitus, trigeminal neuralgia, and occasionally, involvement of the facial6 and trigeminal nerves.10,11,12-13 Macroscopically, although presenting as well-define... |
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