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Data set for reporting of carcinoma of the adrenal cortex: Explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting (ICCR)
Human PATHOLOGY
Thomas J. Giordano, MD PhD, Daniel Berney, MA MB B Chir FRCPath, Ronald R. de Krijger, MD PhD, Lori Erickson, MD, Martin Fassnacht, MD, Ozgur Mete, MD, FRCPC, Thomas Papathomas, MD PhD FRCPath, Mauro Papotti, MD, Hironobu Sasano, MD PhD, Lester D.R. Thompson, MD, Marco Volante, MD PhD, Anthony J. Gill, MBBS MD FRCPA
| PII: | S0046-8177(20)30199-4 |
| DOI: | https://doi.org/10.1016/j.humpath.2020.10.001 |
| Reference: | YHUPA 5068 |
| To appear in: | Human Pathology |
| Received Date: | 28 September 2020 |
| Accepted Date: | 3 October 2020 |
Please cite this article as: Giordano TJ, Berney D, de Krijger RR, Erickson L, Fassnacht M, Mete O, Papathomas T, Papotti M, Sasano H, Thompson LDR, Volante M, Gill AJ, Data set for reporting of carcinoma of the adrenal cortex: Explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting (ICCR), Human Pathology, https://doi.org/10.1016/ j.humpath.2020.10.001.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
@ 2020 Published by Elsevier Inc.
Data set for reporting of carcinoma of the adrenal cortex: Explanations and recommendations of the guidelines from the International Collaboration on Cancer Reporting (ICCR)
Thomas J. Giordano MD PhDa, Daniel Berney MA MB B Chir FRCPathb, Ronald R. de Krijger MD PhDC, Lori Erickson MDd, Martin Fassnacht MDe, Ozgur Mete MD, FRCPCf, Thomas Papathomas MD PhD FRCPath8, Mauro Papotti MDh, Hironobu Sasano MD PhD’, Lester D. R. Thompson MD’, Marco Volante MD PhDk, Anthony J. Gill MBBS MD FRCPA1,m,n
a. Department of Pathology and Clinical Laboratories, University of Michigan, Michigan, 48109-5602, USA. Email: giordano@med.umich.edu
b. Department of Cellular Pathology, The Royal London Hospital, Barts Health NHS Trust, London, E1 1BB, UK. Email: Daniel.Berney@bartshealth.nhs.uk
c. Department of Pathology, University Medical Centre and Princess Maxima Centre for pediatric oncology, 3584 CS Utrecht, The Netherlands. Email: r.r.dekrijger@umcutrecht.nl
d. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Email: Erickson.Lori@mayo.edu
e. Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany. Email: fassnacht_m@ukw.de
f. Department of Pathology, Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, M5G 2M9, Canada. Email: Ozgur.Mete2@uhn.ca
g. Institute of Metabolism and Systems Research, University of Birmingham, B15 2TT, England, UK. Email: thomaspapathomas@nhs.net
h. Department of Oncology, University of Turin at Molinette Hospital, Turin, Italy. Email: mauro.papotti@unito.it
i. Department of Pathology, Tohoku University School of Medicine, Sendai, Japan. Email: hsasano@patholo2.med.tohoku.ac.jp
j. Southern California Permanente Medical Group, Woodland Hills Medical Center, Woodland Hills, California, 91364, USA. Email: Lester.D.Thompson@kp.org
k. Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy. Email: marco.volante@unito.it
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l. University of Sydney, Sydney, New South Wales, 2006, Australia.
m. Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards NSW, 2065, Australia.
n. NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia. Email: affgill@med.usyd.edu.au
Keywords: Checklist; data set; synoptic reporting; structured report; adrenal cortical carcinoma; ICCR,
Short running title: ICCR data set adrenal cortical carcinoma
Disclosures: The authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare no conflict of interest
Word count = 3526
Corresponding author: Thomas J. Giordano Henry Clay Bryant Professor of Pathology/Director of Molecular and Genomic Pathology Department of Pathology and Clinical Laboratories 4520D MSRB I 1150 W. Medical Center Drive Ann Arbor, MI 48109-5602, USA Tel: 1-213-734-615-4470 E-mail: giordano@med.umich.edu
Abstract
Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common and in individual cases the long term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies.
The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include: diagnosis according to the current World Health Organization (WHO) classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status and pathological stage. Tumors were dichotomized into low grade (<20 mitoses per 10 mm2) and high grade (>20 mitoses per 10 mm2). Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and AFIP scores/algorithms).
This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.
Introduction
Adrenal cortical carcinoma (ACC) is a relatively rare malignancy with a reported annual incidence ranging from 0.7 to 2 per million (1, 2). There is a bimodal age distribution with a small peak before the age of 5 years (greater in areas with a high incidence of germline TP53 mutation) and a second much larger peak in middle age (3, 4). Complete surgical excision is the mainstay of treatment (5, 6). However, the majority of patients recur, even with adjuvant therapy which is usually based on mitotane, and the 5-year survival for patients with stage IV disease is in the order of 5 to 15% (7, 8).
a
The pathological assessment of ACC resection specimens is complex (9). Although the majority of cases, which are either metastatic or invade outside the adrenal at presentation, are diagnostically straightforward, the distinction between benign and malignant disease in organ confined (stage I, stage II) adrenal cortical tumors may be challenging and is often based on one or more of several multiparameter scoring systems, some of which may be prone to interobserver discordance (9). Indeed, the very existence of several ‘competing’ systems is itself evidence of the difficulty of definitive pathological differential diagnosis and risk assessment in organ confined disease, and proof that no individual system is ideal. Clearly, an internationally accepted and uniform approach to the pathological assessment of ACC would assist risk assessment for individual patients, particularly if it recorded most of the individual components of these multiparameter systems, and may help to facilitate multinational translational research studies.
The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organisation that strives to produce standardized evidence-based data sets for pathology reporting. It is sponsored by major professional bodies including the Royal College of Pathologists of
Australasia and the United Kingdom, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the College of American Pathologists, the American Society of Clinical Pathology, and the Faculty of Pathology, Royal College of Physicians of Ireland. The ICCR produces data sets with a consistent style and content which are freely available from the ICCR website at http://www.iccr-cancer.org. In this publication we provide a brief commentary on the development of the data set for reporting ACCs now available at http://www.iccr- cancer.org/datasets/published-datasets/endocrine/adrenal-cortex.
1. Methods
Under the chairmanship of Dr. Thomas Giordano, the ICCR convened a 12 member Dataset Authoring Committee (DAC), to critically review the published evidence and develop a draft data set which, after open consultation and feedback, was published in December 2019.
2. Area of application
The data set was developed for the pathology reporting of resection specimens of malignant adrenal cortical tumors in both adults and children. Further, the authors intended that adrenal cortical tumors of low/uncertain malignant potential should also be reported using this data set. Neuroblastoma, phaeochromocytoma, sarcoma, metastases to the adrenal, and lymphoma are excluded from this data set. It should not be used for core needle or incisional biopsies.
3. Core elements
The data set includes 23 ‘core’ elements which are listed in Table 1. The core elements are defined as those that are essential for the clinical management, staging or prognosis of the cancer. These elements have evidentiary support at level III-2 or above (10), or were otherwise viewed by the DAC to represent the minimum reporting standard in clinical practice. The core elements are summarised below.
4.1 Clinical information
Relevant clinical information that should be provided includes the presence of symptoms or signs suggesting endocrine dysfunction (e.g., hypertension, change in body habitus, virilisation); the presence of clinical syndromes (e.g., Cushing’s or primary aldosteronism); a history of prior malignancy; a familial predisposition to cancer (e.g., Li-Fraumeni, Beckwith- Wiedemann, MEN1, FAP, and Lynch syndromes); the results of any previous biopsy or resection; and the details of any prior treatment.
4.2 Operative procedure, Specimen(s) submitted, Tumor site
The type of surgery (open versus laparoscopic; and partial versus total adrenalectomy) should be recorded. Laparoscopic surgery is prone to disruption of the gland which may cause difficulty in assessing tumor size, integrity of the capsule and adequacy of resection. The
resection of any other organs (e.g., liver or kidney) and regional (para-aortic and peri-aortic) lymph node removal should be reported. Tumor site (laterality) is an essential data point for fully characterizing any neoplasm even though there is no evidence that it affects prognosis.
4.3 Specimen integrity
Documentation of specimen integrity is essential, especially as laparoscopic surgery is being used with increasing frequency and may lead to disruption of the tumor capsule. There are options to record the specimen as intact, mostly intact but with a disrupted capsule, or fragmented.
4.4 Tumor dimensions
The largest single dimension in any direction measured in millimeters is considered a core item. The recording of all three dimensions, whilst useful to determine volume, is considered optional (noncore). The greatest dimension is necessary because it is a critical component of staging and some diagnostic systems include tumor size.
4.5 Tumor weight
Accurate determination of tumor weight is essential for complete diagnostic assessment and some scoring systems use tumor weight as a key element (11). Tumor weight should be determined after other organs are removed and adipose tissue is trimmed as much as possible without affecting the histological assessment of invasive growth.
4.6 Histological tumor type
All carcinomas of the adrenal cortex should be categorized based on the current World Health Organization (WHO) Classification of Tumors of Endocrine Organs (12). Diagnostic categories include adrenal cortical carcinoma not otherwise specified (NOS); adrenal cortical carcinoma, oncocytic type (Figure 1); adrenal cortical carcinoma, myxoid type (Figure 2); and adrenal cortical carcinoma, sarcomatoid type. Adrenal cortical neoplasm of uncertain
malignant potential is also a valid category for rare cases. Recognition of histological variants of ACCs is vital because some tumor types have distinct diagnostic systems. For example, oncocytic tumors are lipid-poor by definition and therefore should not be evaluated by the Weiss system (13, 14). Furthermore, knowledge of the morphological type can assist with future diagnostic assessments if there is recurrence.
4.7 Extent of invasion, Capsular invasion
Tumor extension is pathologically distinct from tumor capsular invasion. Tumor extension is a component of pathological staging and assesses the extent of growth beyond the adrenal gland and whether adjacent structures and organs such as the kidney, liver, and pancreas are directly involved. Almost all ACCs that involve adjacent structures are unencapsulated in the area of invasion. In contrast, almost all organ confined ACCs are encapsulated but may show capsular invasion. There is no accepted definition of what constitutes capsular invasion, with some authorities accepting invasion into, but not through, the capsule while others require full thickness penetration (11).
4.8 Tumor architecture
In contrast to adrenal cortical adenomas, ACCs are typically characterized by diffuse tumor architecture, which is defined as solid or pattern-less sheets of tumor cells. Non-diffuse growth patterns include trabecular, alveolar and nested. The assessment of tumor architecture is a component of many multifactorial scoring systems (15).
4.9 Lipid rich cells
Lipid rich cells, or clear cells, are a marker of adrenal cortical differentiation and should be record as ≤25% or >25% as the assessment of percentage of lipid-rich or clear cells, is a component of some scoring systems, and the 25% cut-off is used by the Weiss approach (15).
4.10 Lymphatic invasion
The assessment of lymphatic (sinusoidal) invasion should be evaluated at the periphery of the tumor in, and around, the tumor capsule and not within the tumor itself. It was the opinion of the expert committee that immunohistochemical markers are usually not useful in this evaluation. The assessment of lymphatic (sinusoidal) invasion is a component of several multifactorial scoring systems.
4.11 Vascular invasion
The distinction between small vessel invasion (capillaries) and invasion of large vessels (i.e., venous) should be determined, as invasion of large vessels is associated with a worse prognosis (16). Smooth muscle in the wall is a useful adjunct to recognize large vessel invasion. Intravascular tumor cells, admixed with thrombus, are thought to be the most reliable marker of vascular invasion with established prognostic significance (Figure 3). The assessment of venous invasion is a component of several multifactorial scoring systems.
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4.12 Atypical mitotic figures
The collective genomic studies of ACC to date indicate the presence of widespread genomic instability with significant copy number changes (17, 18). These genomic alterations can be reflected by the presence of atypical mitoses, which should be documented even when only a single unequivocal atypical mitotic figure is identified (Figure 1). The assessment of atypical mitotic figures is a component of several multifactorial scoring systems.
4.13 Necrosis
Whilst it may be beneficial to distinguish between focal and extensive necrosis, there are no accepted definitions. As such, the estimation of the extent of necrosis is considered optional (noncore) but noting the presence or absence of necrosis is considered core. It is emphasized
that infarct type necrosis, degenerative type changes with hyalinization, and haemorrhage or blood extravasation, as often seen centrally in adrenal cortical adenomas, should not be considered tumor necrosis and should be distinguished from true tumor type (usually coagulative) necrosis-a distinction that can sometimes be difficult (Figure 4).
4.14 Nuclear grade
Nuclear grade is a component of the Weiss multifactorial scoring system (15), using a grading system similar to the ISUP (and older Fuhrman) criteria for renal cancer (11). Using the Weiss criteria, grade is assigned based on the most atypical area. A rough rule of thumb is that if nucleoli are readily visible with a 10x objective (100 times magnification) a high nuclear grade should be ascribed (Figure5).
4.15 Mitotic count and histological tumor grade
The mitotic count should be recorded per 10 mm2. The literature commonly refers to mitotic count per 50 high power fields (HPFs) without always defining the diameter of the HPFs. The estimate of 50 HPFs equating to 10 mm2 is commonly used as this reflects many modern microscopes. However, it is emphasized that reporting pathologists must know their field diameter when calculating mitotic count and that on different microscopes fewer or more HPFs are equivalent to 10 mm2.
Architectural grading of ACC is not possible. Instead, tumor grade is based on tumor cell proliferation, initially determined by mitotic count and refined with the Ki-67 proliferative index. Mitotic count is essential for the diagnostic and prognostic evaluation of adrenal cortical tumors and should be reported in all cases. The mitotic count is also a component of all multifactorial scoring systems. While mitotic count is a continuous variable, one of the initial and most established mitotic grading schemes dichotomizes the count into two classes; low grade carcinomas contain ≤20 mitoses/50 HPF (presumed to be 10 mm2) and high grade
carcinomas contain >20 mitoses/50 HPF/10 mm2 (19). Assessment of mitotic count is prone to reproducibility issues(20), largely due to variation in interpretation amongst pathologists of what constitutes a mitotic figure and variation between microscopes without appropriate correction for different field diameters. To reduce this variation, only unequivocal mitotic figures should be counted. Pyknotic nuclei from apoptotic bodies should not be counted.
4.16 Ki-67 proliferation index
Significant evidence has accumulated that ACC is a proliferation-driven neoplasm (16-18, 21) and the Ki-67 proliferation index, determined immunohistochemically using the Mib-1 antibody (22) is an important independent prognostic factor (23-26). Assessment of the Ki-67 proliferation index should be performed on the area of tumor with the highest proliferative activity (so called ‘hot spots’). It is important that the Ki-67 proliferation index should be determined as accurately as possible, preferably using image analysis (Figure 6) or manual counting if resources permit (27). Although estimating the Ki-67 by simple inspection (‘eyeballing’) is generally not recommended, it has been shown to have some prognostic significance and may be used when image analysis and manual counting is not possible (28). The Ki-67 proliferative index is a continuous variable. Cut-offs to subcategorize tumors into different grades are not fully established, but some centers use a 3-tiered system based on the following cut-offs: ≤15% (low grade), >15 to ≤30 (intermediate grade), and >30% (high grade)(29). It is hoped that the information derived from this data set may inform future practice, but until there is consensus on Ki-67 cut-offs for individual grades, the absolute Ki- 67 proliferative index should be recorded.
4.17 Margin status
The presence of a clear (R0), microscopically involved (R1) or grossly transected (R2) margin is considered a core element and large tumors should be generously sampled to
adequately assess margin status. Assessment of tumor margins is essential because incomplete resection has been associated with local recurrence (30), and may be an indication for local radiation therapy (31). In completely excised (R0) tumors, the distance to the nearest margin may provide prognostic information, but until supported by definitive evidence, the distance is considered noncore. The location of any involved margin may be difficult to accurately determine pathologically and is also considered noncore. Margin assessment may be difficult or impossible in fragmented specimens; “cannot be assessed” is often the most appropriate option in this setting.
4.18 Lymph node status
The number of lymph nodes resected and the number positive for malignancy are considered core elements; however, the presence or absence of extranodal extension is noncore. At this time, size of tumor deposits have not been sufficiently well studied to be included.
4.19 Histologically confirmed distant metastases
The presence of histologically confirmed distant metastases is a critical component of pathological staging and should be recorded (32).
4.20 Pathological staging
The Union for International Cancer Control (UICC) has adopted the staging system proposed by The European Network for the Study of Adrenal Tumors (ENSAT), as outlined in Table 2 (33). It is emphasized that venous tumor thrombus qualifies as pT4 disease. Although the ENSAT stage grouping is not considered mandatory, it is listed in Table 2 for reference.
4.21 Reticulin framework
Histochemical staining to highlight the reticulin framework is illustrated in Figure 7. Although reticulin assessment has diagnostic utility and has been incorporated into a
multiparameter algorithm (34, 35), it is not needed in all cases and is therefore considered noncore.
4. Multifactorial scoring systems
Several multifactorial scoring systems have been developed for assessment of the malignant potential of adrenal cortical neoplasms. These are not always needed for diagnosis, and are therefore considered noncore. As there is ongoing debate around the validation and reproducibility of these systems the ICCR does not recommend any particular approach. Instead the ICCR recommends that pathologists should use their judgement to select the appropriate system(s) (if any) for use in their practice for individual tumor types. The selection of the core items described above was heavily influenced by the desire to ensure that pathologists record as consistently as possible the individual data items that contribute to the scoring systems in the hope that they may be further refined. The more commonly used systems are presented below, along with their intended uses. However it is noted that other systems, most notably the van Slooten System (36), may be useful in specific circumstances (37).
5.1 Weiss system (15, 19) for conventional adrenal cortical neoplasms
· High-nuclear grade (yes/no)
· Mitotic count of >5 mitoses per 50 HPFs (yes/no)
· Presence of atypical mitotic figures (yes/no)
” <25% lipid-rich (clear) cells (yes/no)
· Presence of diffuse architecture (yes/no)
” Presence of tumor necrosis (yes/no)
· Presence of venous invasion (yes/no)
” Presence of lymphatic (sinusoidal) invasion (yes/no)
” Presence of capsular invasion (yes/no)
The Weiss system (15, 19) can be used for the majority of conventional adrenal cortical tumors in adults, but should not be used for oncocytic tumors because they consistently display densely eosinophilic cytoplasm, a diffuse architecture and high nuclear grade. The Weiss system consists of 9 elements, each worth one point. Tumors with Weiss scores ≥3 are considered to possess malignant potential and are considered ACCs under the current form of this system (19).
5.2 Modified Weiss system (Aubert) (38) for conventional adrenal cortical neoplasms
· 2 x Mitotic count of >5 mitoses per 50 HPFs (yes/no)
· 2 x <25% lipid-rich (clear) cells (yes/no)
· Presence of atypical mitotic figures (yes/no)
” Presence of tumor necrosis (yes/no)
” Presence of capsular invasion (yes/no)
The modified Weiss system (38) can be also deployed for the majority of conventional adrenal cortical tumors, but should not be used for oncocytic tumors. The modified Weiss system places twice the weight on mitotic rate and percent lipid-rich cells and eliminates nuclear grade, architecture, venous invasion and lymphatic invasion. Tumors are thereby graded from 0 to 7, with those tumors scoring ≥3 possessing malignant potential. The modified Weiss system is highly correlated with the original Weiss system (38).
5.3 Lin-Weiss-Bisceglia system (14) for oncocytic adrenal cortical neoplasms
Major criteria
· Mitotic count of >5 mitoses per 50 HPFs (yes/no)
· Presence of atypical mitotic figures (yes/no)
· Presence of venous invasion (yes/no)
Minor criteria
· Tumor size >10 cm and/or weight <200 g (yes/no)
· Presence of tumor necrosis (yes/no)
· Presence of lymphatic (sinusoidal) invasion (yes/no)
· Presence of capsular invasion (yes/no)
The Lin-Weiss-Bisceglia system (14) is used specifically for oncocytic adrenal cortical neoplasms. This system should only be applied to adrenal cortical tumors that are ‘purely’ oncocytic. Although there are no widely accepted criteria for how much oncocytic differentiation constitutes pure differentiation, one commonly used definition requires that more than 90% of the tumor should be oncocytes (39). Under the Lin-Weiss-Bisceglia system, pathologic features are divided into Major and Minor criteria. The presence of any Major criterion indicates malignant potential and connotes the diagnosis of ACC, oncocytic variant. In the absence of Major criteria, the presence of any Minor criteria connotes the diagnosis of an adrenal cortical neoplasm of uncertain malignant potential, oncocytic variant. If no major or minor criteria are present, the diagnosis of oncocytic adrenal cortical adenoma (‘oncocytoma’) is usually appropriate (benign and therefore not reported with this dataset).
5.4 Helsinki system (40) for diagnosis and prognosis of conventional and oncocytic adrenal cortical neoplasms
· 3 x Mitotic count of >5 mitoses per 50 HPFs (yes/no) added to
· 5 x Presence of tumor necrosis (yes/no)
added to
” Ki-67 proliferation index (percentage)
The Helsinki system (40) is a weighted tumor score combining these results. A Helsinki score >8.5 is associated with metastatic potential and warrants the diagnosis of ACC. The Helsinki score has been evaluated and validated for both conventional ACCs and oncocytic tumors (41).
5.5 Reticulin algorithm (34, 35) for the diagnosis of conventional and oncocytic adrenal cortical neoplasms
· Abnormal/absent Reticulin framework (yes/no)
” Presence of tumor necrosis (yes/no)
” Mitotic rate of >5 mitoses per 50 HPFs (yes/no)
” Presence of venous invasion (yes/no)
The Reticulin algorithm (34, 35) employs a two-step process. First, the reticulin framework is evaluated by silver-based histochemical staining for reticulin. If disruption of the framework is observed (Figure 7), then the tumor is evaluated for the presence of the criteria above. Tumors with both disrupted reticulin framework and at least one of the other diagnostic criteria are considered to possess metastatic potential and can be diagnosed as ACC.
5.6 Armed Forces Institute of Pathology (AFIP) algorithm for paediatric adrenal cortical
neoplasms from Wieneke et al (42)
” Tumor weight >400 g (yes/no)
” Tumor size >10.5 cm (yes/no)
” Extra-adrenal extension (yes/no)
· Invasion into vena cava (yes/no)
· Presence of venous invasion (yes/no)
” Presence of capsular invasion (yes/no)
” Presence of tumor necrosis (yes/no)
” Mitotic count of >15 mitoses per 20 HPFs (yes/no)
” Presence of atypical mitotic figures (yes/no)
The Wieneke/Armed Forces Institute of Pathology (AFIP) algorithm (42) was developed for paediatric adrenal cortical neoplasms and reflects the observation that these tumors have a much lower risk of recurrence than their adult counterparts despite similar histologic features, which also may reflect their different genomic landscapes (43). Although there is no clean breakpoint above or below which patients can be definitively classified as benign or malignant with complete confidence, 0 to 2 criteria are associated with a benign long term clinical outcome; the presence of 3 criteria is considered indeterminate for malignancy (uncertain malignant potential); and four or more criteria connotes a high risk of poor outcome and can be considered ACC. Additional efforts to include the Ki-67 proliferation index into the evaluation of paediatric tumors are ongoing (43, 44).
5. Ancillary studies and other noncore elements
Increasingly, patients with ACC are undergoing significant ancillary testing. Some of these markers are immunohistochemical and are used to confirm primary adrenal cortical origin (e.g., SF-1, Melan-A, calretinin) (Figure 8), or to assist in the distinction between benign and malignant disease (e.g., IGF2, P53) (Figure 9) (45, 46, 47). Similar to p53 overexpression, diffuse nuclear beta-catenin expression also correlates with aggressive tumor molecular clusters (48). Phosphohistone H3 (PHH3) has been used by some to reduce the interobserver variability in the assessment of mitotic count (49). Next-generation sequencing (NGS)-based panel genotyping is increasingly being used. The significance of such testing should be interpreted in the general context of the specific case. Given the recent recognition that a small percentage of ACC patients have Lynch syndrome (32, 50), screening for mismatch repair protein defects by immunohistochemistry is encouraged (Figure 9D).
6. Conclusion
The goal of the ICCR in producing the data set for ACC was to improve patient management, facilitate national and international benchmarking, and enable multicentre research through standardized data collection. It is hoped that this data set will harmonize the pathological reporting of this rare malignancy and that this commentary has provided an explanation and rationale for the core and noncore elements selected.
Acknowledgements
The authors recognize the sponsoring societies and organizations. They particularly acknowledge Fleur Webster for her exceptional organizational and editing contributions. The views expressed are solely those of the authors.
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Figure and Table legends
Fig. 1. Oncocytic Adrenal Cortical Carcinoma
Oncocytic adrenal cortical carcinomas are composed of tumor cells with oncocytic change. The identification of one of three major criteria of the Lin-Weiss-Bisceglia system justifies the diagnosis of carcinoma in ‘pure’ oncocytic adrenal cortical neoplasms. (Provided by Dr Ozgur Mete)
Fig. 2. Myxoid Adrenal Cortical Carcinoma
Myxoid adrenal cortical carcinomas are distinguished with the presence of variable myxoid change in the tumor stroma. (Provided by Dr. Ozgur Mete)
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Fig. 3. Vascular Invasion
Venous invasion characterized by intravascular tumor cells admixed with thrombus in the adrenal capsule. (Provided by Dr Ozgur Mete)
Fig. 4 Necrosis
A) Coagulative necrosis, which can be defined as a necrosis showing an abrupt transition from viable to necrotic cells without granulation or fibrous tissue, is always significant and should be distinguished from B) infarct type necrosis where the ghosted outlines of tumor cells often remain visible. (Provided by Dr Thomas Giordano)
Fig. 5 Cytological Atypia
The assessment of cytologic atypia may be subjective. A) When the tumor is composed of a monotonous population of relatively uniform cells lacking prominent nucleoli, the cytological atypia is considered absent. B) When there is considerable nuclear atypia usually with discernible nucleoli visible with a 10x objective then cytological atypia is considered present. (Provided by Dr Thomas Giordano)
Fig. 6 Assessment of the tumor proliferation using Ki67/Mib-1
Assessment of the Ki-67 proliferation index should be performed on the area of tumor with the highest proliferative activity. Manual counting or the use of image analysis systems are strongly encouraged over eyeballing. This photomicrograph illustrates pathologist driven automated MIB1 image analysis in a hot spot. The MIB1 labeling index is 23.53% in 3217 tumor cells. (Provided by Dr Ozgur Mete)
Fig. 7 Reticulin Histochemistry
Assessment of reticulin histochemistry. A) When the reticulin framework is intact, reticulin surrounds individual nests of cells B) The presence of a disrupted reticulin framework is defined by the loss of continuity of reticulin fibers across one high power field. The original approach is that if an imaginary pathway can be drawn across a full high power field without ever being interrupted by a reticulin boundary, then the framework is disrupted (35). More recently the concept of a qualitative alteration in the reticulin framework has been introduced (34). (Provided by Dr Thomas Giordano)
Fig. 8 Confirmation of the Adrenal Cortical Origin
SF-1 (Steroidogenic factor-1) stands out as the most specific biomarker for the confirmation of the adrenal cortical origin of a neoplasm (Provided by Dr Ozgur Mete).
Fig. 9 Additional Immunohistochemical markers
A) Positive staining for IGF2 supports the diagnosis of adrenal cortical carcinoma over adenoma. Characteristically IGF2 shows paranuclear ‘dot-like’ cytoplasmic expression or accentuation. B) P53 overexpression is useful in the distinction of carcinoma from adenoma in the appropriate clinicopathologic context. C) Nuclear beta-catenin expression is enriched in a subset of aggressive adrenal cortical carcinomas. D) Given the established link with Lynch Syndrome (32, 50), and the potential to guide therapy, microsatellite instability testing or mismatch repair marker (MLH1, MSH2, MSH6 and PMS2) immunohistochemistry is encouraged. The photomicrograph illustrates a MSH2 immunodeficient adrenal cortical carcinoma (Provided by Dr Ozgur Mete).
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Table 1 Core and noncore elements for the pathology reporting of carcinoma of the adrenal cortex
Table 2 ENSAT stage groupings for adrenocortical carcinoma (33)
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Journal Pre - Tre loumalelolol pathologe-
| CORE | NON-CORE |
|---|---|
| Clinical information | Tumour dimensions Additional dimensions (largest tumor) |
| Operative procedure | Necrosis Extent |
| Specimen(s) submitted | Reticulin framework |
| Tumor site | Multifactorial scoring systems |
| Specimen integrity | Margin status Distance of tumour to closest margin |
| Tumor dimensions | Lymph node status Extranodal extension (ENE) |
| Tumor weight | Coexistent pathology |
| Histological tumor type | Ancillary studies |
| Extent of invasion | |
| Tumor architecture | |
| Lipid rich cells | |
| Capsular invasion | |
| Lymphatic invasion | |
| Vascular invasion | |
| Atypical mitotic figures | |
| Necrosis | |
| Nuclear grade | |
| Mitotic count and histological tumor grade | |
| Ki-67 proliferation index | |
| Margin status | |
| Lymph node status | |
| Histologically confirmed distant metastases | |
| Pathological staging |
| ENSAT stage | Definition |
|---|---|
| I | T1, N0, M0 |
| II | T2, N0, M0 |
| III | T1-T2, N1, M0 T3-T4, N0-N1, M0 |
| IV | any T, any N, M1 |
T1, tumor ≤5 cm; T2, tumor >5 cm; T3, tumor infiltration into surrounding tissue; T4, tumor invasion into adjacent organs or venous tumor thrombus in vena cava or renal vein;
NO, no positive lymph nodes; N1, positive lymph node(s);
MO, no distant metastases; M1, presence of distant metastasis.
Journal Préfmetade,
Jour
®
Journal
A
B
Journal Pre-proo
A
B
Journal Pre-pro
Percent Positive Nuck 23 5312
*
Region
Length fun Avea lun2)
Test
Percent Positive Nuc
Intensity Score
3
.
1
648754
23 5312
[)+] Percent Nuclei
13 8638
[+] Percent Nuclei
4 97358
(1+] Percent Nuclei
4.69381
(+) Percent Nuclei
76 4588
Average Positive Inter 158 345
Average Negative Inte 228 295
[+] Nuclei
446
(+) Nuclei
100
(1+] Nuclei
151
(0+) Nuclei
2490
Total Nuclei
3217
#
Average Nuclea RIG8 148.057
Average Nuclea See 242 845
Average Nuclew Soe 60.6386
Area of Analysis [Pixel: 2508309
Area of Analysis |nes”: 0.6263249830478099
Algorithes Inpulls = Algorithm Inputs ***
Algorithes
Nuclear v9
Version
9.1
View Width
1000
View Height
1000
Overlap Sce 100
Image Zoom
1.
Classler
None
Class Lift
Classifier Neighborhoo 0
Piel Sce fun) 0.4997
Avmaging Radun |um’ 1.
Avmaging Radus Pio 2
Curvature Threshold 25
Segmentation Type 2
Threshold Type
1
Lower Intensity Theest O
Upper Intensity Theedt 230
Min Nuclear Sie |um” 20
Min Nuclear Sie Pixe 80
Max Nuclear See [un’ 1.e+006
.
.
-
Journal Pre
B.
Journal Pre-pr
200um
Journal Pre
A
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