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## 5. Ductal Carcinoma In Situ |
### 5.1. Histomorphology and Grading |
Morphologically, the involved ductal lobular units have neoplastic ductal epithelial proliferation arranged in a complex architecture. The architecture could be cribriform (with fenestrations) (Figure 4A), solid (Figure 4B), micropapillary (club-shaped) (Figure 4C), papillary (Figure 4D), comedo (Figure 4E), or clingin... |
There are many grading systems for DCIS [66]; the most commonly used are the consensus conference on the classification of DCIS [67]; Lagios’ nuclear grading systems for DCIS [68]; DCIS grading according to the College of American Pathologists [69]; and the United Kingdom’s National Health Service/breast screening prog... |
The WHO classifies DCIS into three grades (low, intermediate, or high). Low-grade DCIS is composed of small monomorphic cells arranged in a complex growth pattern (cribriform, micropapillary, or less often solid). The nuclei are uniform in size and shape with irregular chromatin and indistinct nucleoli. The nuclei meas... |
### 5.2. Natural History and Prognostic Tools for Ductal Carcinoma In Situ |
The natural history of DCIS is unclear, owing to the clinical practice in which a diagnosis of any form of DCIS is routinely excised. There are only a few studies that evaluated the natural history of DCIS by reviewing those who declined surgical removal or were misdiagnosed as benign. In a small study population, up t... |
Defining the prognosis of DCIS after surgical removal has been an area of extensive research. Few models have been developed, including Memorial Sloan-Kettering Cancer Center (MSKCC) [75], Oncotype [76,77], and University of South Carolina Van Nuys Prognostic Index (USC-VNPI) [78]. While Oncotype examines DCIS at the m... |
## 6. Treatment |
### 6.1. Atypical Ductal Hyperplasia |
The National Comprehensive Cancer Network (NCCN) guidelines recommend surgical removal of the ADH lesion [80]. However, if the risk versus benefit of surgery comes into question, the treating physician can use published literature for guidance. Two nomograms have been published (see above), one for cases detected by sc... |
Since most of the iBC cases that develop in women with ADH are strongly positive for ER, it is logical to use selective estrogen receptor modulators (SERM) and aromatase inhibitors (AI) as a preventive measure. Several large breast chemoprevention clinical trials have shown risk reduction ranging from 41% to 79% [27]. ... |
### 6.2. Ductal Carcinoma In Situ |
The standard of treatment of DCIS is surgical removal of the lesion with or without RT, with or without HT. The extent of surgery (wide excision versus mastectomy) depends on the extent of the disease [8]. Mastectomy is indicated if the area of DCIS cannot be removed by oncologically acceptable excision (preserving cos... |
## 7. Challenges in the Active Surveillance Trials from Pathology Standpoint |
The inclusion criteria for COMET trial includes LG- and IG-DCIS with any degree of necrosis. LORIS trial includes LG-DCIS or lower half of IG-DCIS with no comedonecrosis. LORD trial accepts LG-DCIS or IG-DCIS with ER-positive/HER2-negative. LORETTA includes LG-DCIS or IG-DCIS with no comedonecrosis and must be ER-posit... |
### 7.1. Challenges in Grading Ductal Carcinoma In Situ and Their Consequences on Active Surveillance Trial |
As mentioned above, there are many grading systems for DCIS [66]. Moreover, cells with various nuclear grade could coexist in the same DCIS case (Figure 6A) with HG-DCIS (Figure 5B) and IG-DCIS (Figure 6C) and possibly within a single duct (Figure 7) [84]. This variation reflects the genetic heterogeneity of tumor cell... |
#### 7.1.1. Downgrading Low-Risk Ductal Carcinoma In Situ to Atypical Ductal Hyperplasia or Atypical Ductal Hyperplasia Bordering on Ductal Carcinoma In Situ |
As mentioned above, the diagnosis of some cases falls in between ADH and DCIS. The WHO recommends a more conservative approach. Following WHO recommendations, these cases are designated as severe ADH bordering on DCIS and treated conservatively with local excision. Paradoxically, if the case is designated as low-risk D... |
Tozbikian et al. found that most cases with a diagnosis of ADH bordering on DCIS were diagnosed as ADH after a review by a group of pathologists. With a median follow-up of 57 months, 3.8% developed subsequent ipsilateral carcinoma; interestingly, all in the ADH group [43]. Due to the lack of concrete diagnostic criter... |
#### 7.1.2. Low-Risk Ductal Carcinoma In Situ Versus High-Grade Ductal Carcinoma In Situ |
Distinguishing low-risk from HG-DCIS is crucial in the AS trials setting. If a HG-DCIS is mistakenly designated as low-risk and the patient is enrolled in the AS trial, it would have a negative impact for two reasons; first, the aim of studying the natural history of low-risk DCIS would be compromised; second, the pati... |
A recent study that included more than 5000 cases found that the proportion of LG-DCIS varies from 6% to 24% by department [62]. This means that the LORIS trial (before the amendment) may recruit patients from one center four times more than another, and the question always remains as to whether these cases are truly l... |
Machine learning could assist in overcoming the variation in grading DCIS. Two studies from the same group were performed on the same group of DCIS cases. In the first, DCIS was graded manually and there was no correlation with the clinical outcomes [90]. In the second, DCIS was graded using quantitative image cytometr... |
### 7.2. Comedonecrosis Controversy and Its Consequences on Active Surveillance Clinical Trials |
There is controversy on the definition of comedonecrosis. Comedo type DCIS was included in the 1997 classification as a subtype of DCIS besides cribriform, solid, micropapillary and papillary [67]. Then, the term “comedo” was used to describe central and expansile necrosis in any of the other four types [91]. CAP requi... |
The author examined whether comedonecrosis correlated with the upgrading to iBC. In this study, 129 cases that met the COMET trial criteria were investigated. The degree of comedonecrosis was measured by calculating the percentage of the ductal diameter occupied by necrosis, using image analysis. The degree of comedone... |
The role of comedonecrosis in the natural history of DCIS will be better evaluated by the COMET trial, but not by LORIS or LORETTA. However, the caveat is that a good proportion of these patients would already have iBC at the time of diagnosis. |
## 8. Conclusions |
There is significant overlap between ADH, LG-, IG- and HG-DCIS in terms of definition, histologic features/criteria, biology, and clinical significance. Distinguishing these lesions from each other has become more important with the introduction of the AS trials, particularly between ADH and LG-DCIS and between LG-DCIS... |
## Abbreviations |
[TABLE] |
ADH | Atypical ductal hyperplasia |
LG | Low-grade |
IG | Intermediate-grade |
HG | High-grade |
DCIS | Ductal carcinoma in situ |
AS | Active surveillance |
iBC | Invasive breast carcinoma |
ER | Estrogen receptor |
RT | Radiation therapy |
HT | Hormonal therapy |
COMET | Comparison of Operative to Monitoring and Endocrine Therapy |
LORIS | Low risk DCIS trial |
LORD | LOw Risk Dcis |
CNB | Core needle biopsy |
WHO | World Health Organization |
TILs | Tumor infiltrating lymphocytes |
AUC | Area under the curve |
MSKCC | Memorial Sloan-Kettering Cancer Center |
USC-VNPI | University of South Carolina Van Nuys Prognostic Index |
NCCN | National Comprehensive Cancer Network |
SERM | Selective estrogen receptor modulators |
NSABP | National surgical adjuvant breast and bowel project |
CAP | College of American pathologists |
UDH | Usual ductal hyperplasia |
## Funding |
This research received no external funding. |
## Conflicts of Interest |
Thaer Khoury serves as a pathology faculty advisor for HER2 testing in AstraZeneca. |
## Footnotes |
## References |
cd1f8f4b7b007931587fd62bef80551504d8c1b5e8163c2a46174df300094bd5 pmc8833401.txt |
PMCID: PMC9367316 |
TITLE: Adult Medulloblastoma: Updates on Current Management and Future Perspectives |
LICENSE: 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: AbstractSimple SummaryAdult medulloblastoma is an extremely rare tumor of the central nervous system. Standard multimodal treatment, comprising maximal safe surgical resection followed by craniospinal radiotherapy and multi-agent chemotherapy, can improve the prognosis of this disease, producing, however, imp... |
## 1. Introduction |
First described by Bailey and Cushing in 1925 [1], MB is a rare embryonic tumor of the posterior cranial fossa, grade 4 assigned by WHO classification, arising from the granule cell precursors in the external germinal layer of the developing cerebellum. |
Tumor growth starts in the fourth ventricle and has a propensity to spread to the cerebellar vermis and the brainstem, seeding the craniospinal axis through the subarachnoid system (the so-called “drop metastases”) [2,3]. |
Examining data from the Surveillance, Epidemiology, and End-Results (SEER) database from 1973 through 2007, MB is the second most common of all pediatric central nervous system (CNS) tumors (accounting for about 20% of the total CNS tumors in the pediatric age group), with a bimodal peak at age 3 to 4 years and at age ... |
In adult neuro-oncology practice, therefore, MB is a very rare condition, representing only 0.4–1% of all adult CNS tumors, with an incidence of 0.6–1 case per million per year [4]: this population, which is the topic of this review and for readability purposes will be called “adult MB”, is an “orphan” entity, being th... |
Current standard treatment involves a multimodal treatment comprising surgical resection followed by radio-chemotherapy, selected and adapted to patients on the basis of risk stratification [7]. This interdisciplinary management can achieve a 5-year survival rate between 50% to 90% [10,11,12,13,14,15]. |
However, regardless of long-term survival, treatment-related adverse effects, including neurological toxicity, hematological toxicity, polyneuropathies, endocrinopathies, and cognitive disorders remain a relevant issue, involving up to 80% of patients, thus representing a strong incitement for the search for more innov... |
MB is a heterogeneous disease, both clinically and molecularly. Current MB classification, according to the fourth (2016) and fifth (2021) edition of the WHO Classification of Tumors of the Central Nervous System (CNS) [16,17], includes both histological and molecular criteria, defining four molecular types (wingless-t... |
The diverse molecular types show significantly different age, molecular and clinical profiles [17,18,19,20,21,22,23,24,25,26,27]. WNT MB harbors deregulation of the WNT pathway, mostly caused by activating somatic mutations in the CTNNB1 gene, and exhibits the most favorable prognosis across all the subgroups, rarely b... |
The clinically meaningful contribution provided by the latest editions of the WHO classification lies in having finally opened the way to the development of molecularly adapted treatment strategies for MB patients. |
As a result, the landscape of clinical trials has significantly changed since the discovery of distinct molecular types, and multiple targeted agents are currently under investigation. SHH-activated adult MBs, particularly, have become a very appealing focus in research for the preliminary evidence of activity of the S... |
The challenges we encounter in clinical practice suggest that there are two primary research objectives for adult MB: first, to design clinical trials specifically stratified by age and tumor biology, to develop rationally personalized treatments; second, to identify new experimental agents with improved acute and chro... |
This review provides recommendations on the clinical management of adult MB, including basics on pathology, molecular biology, neuroradiology, neurosurgery, radiotherapy, chemotherapy and novel targeted therapies, as well as future perspectives. |
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