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Clinically, OGS may present with nonspecific symptoms such as headache, hyposmia or anosmia, and, less commonly, visual disturbances when mass effect involves the optic pathway [2,6,7]. In our case, the patient presented with transient visual disturbances over several months and a recent onset of intense headache. No s... |
Other anterior skull base tumors may induce pressure damage of the olfactory system causing unilateral olfactory dysfunction, such as olfactory groove meningioma. Welge-Luessen and colleagues observed that four out of 12 patients had ipsilateral olfactory dysfunction with clear asymmetry in three of them, while four ha... |
The radiological appearance of OGS is variable and often misleading, posing a diagnostic challenge. On MRI, OGSs typically present as well-circumscribed, extra-axial masses with heterogeneous enhancement after gadolinium administration. They may contain both solid and cystic components and frequently exhibit mass effec... |
In this context, histopathology and immunoprofiling play a decisive role: these tumors typically display a biphasic pattern with Antoni A and B areas as well as Verocay bodies. Immunohistochemically, they show strong positivity for S100 protein and are negative for EMA, GFAP, and neuroendocrine markers, supporting thei... |
Surgical resection remains the gold-standard treatment for OGS, with the choice of the surgical approach dictated primarily by the tumor’s location and degree of extension. Indeed, when the lesion is limited to the intracranial compartment, a single transcranial route—typically via a pterional or interhemispheric appro... |
Outcomes in the literature are generally favorable when gross total resection is achieved, and recurrence is rare. However, long-term follow-up remains essential [5,18]. We confirmed previously observed improvement of olfactory function in olfactory groove schwannoma postoperatively. Unlike esthesioneuroblastoma, which... |
## Author Contributions |
Conceptualization: L.A., P.E.C., J.W.H. and P.B. Methodology: L.A., J.W.H. and P.E.C. Surgery: L.A., P.E.C., J.W.H., B.N.L. and P.B. Pathological analyses: K.E. Writing—original draft preparation: L.A., P.E.C. and J.W.H. Writing—review and editing: A.L., P.E.C., J.W.H., P.B. and B.N.L. Supervision: J.W.H. and P.E.C. Al... |
## Institutional Review Board Statement |
Ethical review and approval were waived for this study due to the retrospective nature of the patient case report, which did not involve any experimental intervention. |
## Informed Consent Statement |
Informed consent for publication was obtained from the patient for the illustrative case, and all identifying information has been anonymized. |
## Data Availability Statement |
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors. |
## Conflicts of Interest |
The authors declare no conflicts of interest. |
## Funding Statement |
This research received no external funding. |
## Footnotes |
## References |
## Associated Data |
### Data Availability Statement |
The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors. |
f34cab3c0aabca53b0ffef0f9c2d0a20007b3eee1ddf770dff05307b08d52efb pmc13605746.txt |
PMCID: PMC3357964 |
TITLE: Intraductal Proliferative Lesions of the Breast—Terminology and Biology Matter: Premalignant Lesions or Preinvasive Cancer? |
LICENSE: This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
ABSTRACT: AbstractMorphological criteria for the diagnosis of intraductal proliferative lesions of the breast have been an object of research and much controversy, and its terminology is rather confusing. Knowledge of the molecular aspects of this disease probably necessitates further research to clarify if these entit... |
## 1. Introduction |
Intraductal proliferative lesions (IPLs) of the breast are confined to the duct-lobular system, originating from the terminal duct-lobular unit (TDLU) with different cytological and architectural patterns of proliferation. They are characterized by an increase in the number of cells perpendicular to the basement membra... |
Both a lobular and a ductal type of epithelial proliferation of TDLU are recognized. While the first type is quite monomorphic, intraductal proliferations show a wide variety of heterogeneous cytological aspects and architectural patterns. |
In the past several decades, there has been a wide discussion among pathologists worldwide regarding classification and grading of IPLs, with the aim to establish various risk categories. Despite these efforts, a high interobserver variability among pathologists regarding the diagnosis of IPLs as well established [2]. |
Criteria for diagnosis of IPLs by morphological means (Hematoxylin and Eosin and immunohistochemistry stains) are both qualitative (cytological and architectural changes), and quantitative. Diagnostic variability is not only due to interpretation of different patterns, but also to the difficulty in recognizing atypical... |
In this regard, there are several open questions in the literature, including the minimum threshold for grading, the risk of progression for different type of lesions, and the relationships between normal epithelium, IPLs, and invasive ductal carcinoma (IDC). Furthermore, it is unclear whether different types of IPLs a... |
These issues are of great interest not only to those involved in basic research, but also to the clinicians, because each type of lesion has different propensity for progression to local relapse and invasive disease. Therefore, understanding the biology of these lesions is paramount, and will contribute to a better del... |
## 2. Terminology and Historical Aspects |
The term utilized by Azzopardi [3] for benign epithelial hyperplasia was epitheliosis. This term found little agreement among pathologists and has gained much wider acceptance in Europe than in North America. The alternative terms in the past were papillary proliferation and papillomatosis, because it can form “tongue-... |
Epitheliosis is a condition that has to be distinguished from in situ well-differentiated, low-grade carcinoma (LG-DCIS). The criteria for diagnosis have been well described by Azzopardi [3]. Two cell types are distinguishable in epitheliosis, epithelial, and myoepithelial, which have divergent differentiation. Immunoh... |
The hallmarks of LG-DCIS are architectural and cytological aspects. Myoepithelial cells cover the neoplastic ducts but are not present in the neoplastic proliferation (Figures 3(a) and 3(b)). Intraluminal or intraepithelial calcification, as calcific bodies, are frequent. The solid form of LG-DCIS has the same cytology... |
A “borderline” entity, between UDH and LG-DCIS, is controversial. Historically, there are two opposing approaches. The first viewpoint entails sharp demarcation between UDH and LG-DCIS, without intermediate lesions. Azzopardi said “…names like atypical hyperplasia should be avoided as far as possible.” The second viewp... |
Intermediate grade DCIS (IG-DCIS) and high-grade DCIS (HG-DCIS) are obvious neoplastic lesions, graded by nuclear grade, necrosis, and architectural patterns. IG-DCIS has solid, papillary, or cribriform growth patterns, cytologically similar to those of LG-DCIS but with intraluminal necrosis (Figure 4(a)) or with inter... |
Rosai [2] proposed a terminology such as mammary intraepithelial neoplasia (MIN), like CIN of uterine cervix, for subjectivity and high degree of variability in interpretation of IPLs, disagreement about the criteria for definition of borderline lesions, and risk of progression of all types of IPLs. Afterwards this con... |
## 3. DIN System |
Tavassoli [1] proposed to comprise all the IPLs in a single category, termed DIN, with various subtypes. This initial work by Tavassoli included epitheliosis or intraductal hyperplasia as DIN1a, because the risk of developing an invasive carcinoma was 1.5–2 times higher than in the general population. In the WHO book [... |
[TABLE] Terminology of IPLs. |
DIN system | Traditional terminology |
Usual ductal hyperplasia (UDH) | EpitheliosisInfiltrating epitheliosisPapillomatosisSclerosing adenosis with pseudoinfiltrationSclerosing papillary proliferation |
DIN1a | Clinging carcinoma monomorphus or type 2Flat epithelial atypiaAtypical cystic lobulesAtypical lobules type AAtypical columnar change |
DIN1b | Atypical ductal hyperplasia (ADH) |
DIN1c | Low-grade ductal carcinoma in situ (LG-DCIS) DCIS grade 1 |
DIN2 | Intermediate-grade ductal carcinoma in situ (IG-DCIS) DCIS grade 2 |
DIN3 | High-grade ductal carcinoma in situ (HG-DCIS) DCIS grade 3 |
DIN System has some advantages. It diminishes the dualism cancer/no cancer, retains separation of all different subcategories but places LG-DCIS in the same group of ADH, because it considers the differences between these lesions quantitative, not qualitative. It eliminates the term cancer, diminishing the associated a... |
The majority of the participants in the WHO Working Group were in favour of maintaining the traditional terminology with the new DIN System [4]. This fact shows well the disagreement and scepticism of pathologists. |
## 4. Genetic and Molecular Findings |
In the last twenty years, there have been numerous studies to search for genetic and molecular differences or similarities between the various forms of IPLs, heterogeneous in their cytological and architectural characteristics, and between IPLs and normal TDLU and IDC. Sometimes the results seem conflicting, but a more... |
A multitude of methods have been utilized: immunohistochemistry (IHC), in situ hibridization (ISH), analysis of loss of heterozygosity and allelic imbalance (AI), Comparative Genomic hybridization (CGH), cDNA microarrays (MA), and Proteomics Analysis (PA). The purposes of these methods are the study of growth character... |
### 4.1. Growth Characteristics |
The growth of any hyperplastic or neoplastic lesion is a balance between proliferation and cell death (apoptosis). Many researchers have studied the Proliferation Index (PI) with IHC, using antibodies marking cellular proliferative cycle like Ki67 [13]. In premenopausal women, the PI of the normal TDLU varies in differ... |
ADH has a lower rate of apoptosis (0,3% versus 0,6%) and higher PI than normal TDLU; DCIS has higher apoptosis (5%) and PI than normal TDLU and ADH. Apoptosis varies from 1% to 5% among LG-DCIS and HG-DCIS, and it represents a continuous variable [14]. Higher cellular death in high-grade lesions means that the growth i... |
### 4.2. Sex Hormones, Oncogenes, and Tumor Suppressor Genes |
Estrogens, through Estrogen Receptor (ER), play a central role in growth and differentiation of normal TDLU epithelium, stimulating cell proliferation and regulating expression of other genes, like Progesteron Receptor (PgR) [15]. Two types of ER are described: ERα and ERβ. ERα is the more studied molecule. 90% of norm... |
Many molecules are studied in IPLs, but the majority of studies have not been validated [17]. Exceptions are c-erbB2 (neu) and p53. |
In IDC, c-erbB2 (neu) is overexpressed or amplified in 10–20% of cases, generally HG-IDC. It plays a role in cell proliferation, is related to poor clinical outcome, is a predictive marker for responsiveness to various therapies, and promotes cell mobility [18]. In recent years, it has been one of the more studied mark... |
The more utilized method to detect expression of p53 is IHC, which is a surrogate assay for detecting mutations, because a gene with missense mutations codifies for inactivate protein. This abnormal inactive protein is accumulated in very high levels in the nucleus of neoplastic cells, and it is detectable by IHC [20].... |
Clark et al. [22] found by IHC analysis on tissue microarray (TMA) the same molecular classes in DCIS as in IDC [23, 24], but with different frequency. Basal-like phenotype is rare in DCIS; c-erbB2 is more frequently expressed in Luminal-like DCIS than in IDC (13,2% versus 5,2%). The mitochondrial antiapoptotic protein... |
Other genes and proteins are studied in IPLs and compared with IDC. |
Ma et al. [27] studied five genes with quantitative RT-PCR in ADH and DCIS, upregulated or downregulated in IDC. These genes were altered in the same rate in ADH, DCIS, and IDC: for example, CRIP1 was upregulated in 7/8 ADH, in 27/30 DCIS and in 23/25 IDC, and ELF5 was downregulated in 7/8 ADH, in 28/30 DCIS and 25/25 ... |
Gillett et al. [29] studied expression of Cyclin D1 in ADH and DCIS. In IDC, expression of Cyclin D1 is more frequent in well differentiated and ER+ cases. ADH does not express Cyclin D1, but it is ER+ like LG-DCIS: in DCIS Cyclin D1 is over-expressed in 64% of cases, and it is not related to grade or to ER expression. |
Schuetz et al. [30] studied genes of epithelial mesenchymal Transition (EMT) and other genes candidates to cause invasion and metastases [31]. These genes (Twist1, SPARC, MMP13, MMP11, BPAG1) are markers of transition from DCIS to IDC. Some of the proteins codified by these genes are very interesting: for example, BPAG... |
Porter et al. [32] and Kretschmer et al. [33] found several genes of IDC up-regulated in DCIS using SAGE (Serial Analysis of Gene Expression), TMA, quantitative RT-PCR, and IHC. Some of these genes are not related to differentiation grade (MUC1, SBP1) and probably play a role in early cancerogenesis. Other proteins, li... |
### 4.3. LOH and Allelic Imbalance (AI) |
Two types of studies are performed: the first on IPLs in their pure form and the second on IPLs with synchronous IDC in the same breast. The strategy of the last type is to identify alterations, which may be important in the invasiveness [17]. Generally, IPLs with synchronous invasive cancer share more frequent genetic... |
There are numerous studies on LOH in IPLs without invasive cancer. |
Allelic Imbalance in UDH is rare: Lakhani et al. [39] found alterations in 0–13% of studied loci, frequently in 17q; Deng et al. [35] found alterations in different loci in 0–15%. |
Moinfar et al. [40] found AI on 77% of FEA, at least in one locus 11q, 16q, and 3p. 11q and 16q are frequently involved in tubular carcinoma. |
Morphological overlap between ADH and LG-DCIS is reflected at molecular level. Up to 50% of ADH contains one or more AIs among 30 genetic loci [35, 39], and they are the same of DCIS. |
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