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Histologic features of MTC. A, Coagulative necrosis. B, Incipient necrosis defined as clusters of cells showing nuclear pyknosis, karryhorexis, and cytoplasmic condensation. C, Spindle cell morphology. D, Sheet-like growth. E, High nuclear grade. F, Multinucleation. G, Prominent nucleoli defined as nucleoli visible at ×100 magnification. H, Fibrosis/amyloid deposition > 50% of tumor area (hematoxylin and eosin).
Source publication
We investigated the prognostic value of a range of histologic parameters in medullary thyroid carcinoma (MTC) to design a grading system to predict overall survival. We assessed 76 patients with MTCs undergoing primary tumor resection for age, sex, tumor size, vascular space invasion, lymph node metastasis, multiple endocrine neoplasia type 2 (MEN2...
Contexts in source publication
Context 1
... single hematoxylin and eosin-stained slide containing a representative section of tumor was evaluated by 1 pathologist who was blinded to all clinical and pathologic data. A number of histologic observations were recorded for each tumor and illustrated in Figure 1. These features comprised: mitotic count per 2 mm 2 (equivalent to 10 contiguous HPFs on many microscopes, assessed in the most mitotically active part [hotspot] of the tumor); proportion of cells with spindled morphology; the presence of a sheet-like growth pattern in > 10% of the tumor (illustrated in Fig. 1D); the presence of coagulative necrosis; the presence of incipient necrosis (defined as clusters or zones of cells showing nuclear pyknosis, karryhorexis, and cytoplasmic condensation suggesting impending ischemic infarction); nuclear grade (assessed semiquantitatively as low, moderate, or high grade based on the degree of nuclear pleomorphism); the presence of multinucleated cells; prominent nucleoli (defined as nucleoli visible at ×100 magnification similar to Fuhrman nuclear grade 3 in renal cell carcinoma); and the proportion of tumor fibrosis/amyloid deposition. ...
Context 2
... for each tumor and illustrated in Figure 1. These features comprised: mitotic count per 2 mm 2 (equivalent to 10 contiguous HPFs on many microscopes, assessed in the most mitotically active part [hotspot] of the tumor); proportion of cells with spindled morphology; the presence of a sheet-like growth pattern in > 10% of the tumor (illustrated in Fig. 1D); the presence of coagulative necrosis; the presence of incipient necrosis (defined as clusters or zones of cells showing nuclear pyknosis, karryhorexis, and cytoplasmic condensation suggesting impending ischemic infarction); nuclear grade (assessed semiquantitatively as low, moderate, or high grade based on the degree of nuclear ...
Context 3
... similar to Fuhrman nuclear grade 3 in renal cell carcinoma); and the proportion of tumor fibrosis/amyloid deposition. Fibrosis and amyloid deposition were assessed together as in specific areas of individual cases hyalinised fibrosis was difficult to distinguish from amyloid. The pattern of growth that we termed "sheet-like" (illustrated in Fig. 1D) bore a superficial resemblance to small cell carcinoma and an alternative term for this pattern could be "small cell like" as it was composed of smaller cells with diffuse growth and little cytoplasm (illustrated in Fig. 1D). However it is emphasized that this sheet-like growth pattern differed from true small cell carcinoma by the ...
Context 4
... fibrosis was difficult to distinguish from amyloid. The pattern of growth that we termed "sheet-like" (illustrated in Fig. 1D) bore a superficial resemblance to small cell carcinoma and an alternative term for this pattern could be "small cell like" as it was composed of smaller cells with diffuse growth and little cytoplasm (illustrated in Fig. 1D). However it is emphasized that this sheet-like growth pattern differed from true small cell carcinoma by the absence of the classic features of nuclear molding, intense mitotic activity, prominent apoptotic debris, and extremely high (usually > 50%) Ki-67 proliferative index. Necrosis thought to be attributable to preoperative fine ...
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Purpose
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Citations
... Like NET/NEC in other organs, the prognosis for MTC varies significantly from case to case. The proliferative activities of the tumor can stratify the long-term risk of MTC [24,25]. The WHO 5th recommended a two-tier risk assessment system based on the tumor's proliferative activity and necrosis [4]: (i) mitotic counts, ≥5 cells/2 mm 2 ; (ii) Ki67 labeling index, ≥5%; and (iii) presence of tumor necrosis (Table 3). ...
In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th), was published. Large-scale genomic analyses such as The Cancer Genome Atlas (TCGA) have revealed the importance of understanding the molecular genetics of thyroid tumors. Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on the cell of origin of tumors and their clinical risk. This paper outlines the following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDNs) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The framework for benign lesions has been revised. The WHO 5th introduces a new category: “developmental abnormalities”. Benign FDNs comprise “thyroid follicular nodular disease”, follicular thyroid adenoma (FTA), FTA with papillary architecture, and oncocytic adenoma (OA). “Hürthle cell adenoma/carcinoma” is renamed oncocytic adenoma/carcinoma of the thyroid (OA/OCA), which can be distinguished from FTA/FTC by its unique genetic background. 3. Low-risk tumors include NIFTP, TT-UMP, and HTT, and they have an extremely low malignant potential or an uncertain malignant potential. 4. PTC histological variants are reclassified as “subtypes” in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to their shared genetic and prognostic features. 7. Other miscellaneous tumors are categorized as salivary-gland-type carcinomas of the thyroid, thyroid tumors of uncertain histogenesis, thymic tumors within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on both genetic abnormalities and histomorphology. This approach aids in achieving accurate pathological diagnosis and facilitates the early selection of appropriate treatment options, including molecular targeted therapies.
... The name ʺHürthle cell tumorʺ is no longer used because it is inappropriate. OA/OCA were distinguished from FTA/FTC by their characteristic morphology as well as their unique genetic background [18,19]. Oxyphilic PTC is not included in OCA. 8 The criteria for differentiating OA from OCA are the same as for follicular tumors: the presence of capsular invasion and vascular invasion. ...
In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th) was published. The importance of understanding the molecular genetics of thyroid tumors as revealed by large-scale genomic analyses such as The Cancer Genome Atlas (TCGA). Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on tumor cell-of-origin and clinical risk. This paper outlines following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDN) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The Framework for benign lesions have revised. The WHO 5th introduces new categories such as "developmental abnormalities" and "thyroid follicular nodular disease" in benign FDN. 3. Low-Risk Tumors include NIFTP, TT-UMP, and HTT. 4. PTC histological variants are reclassified as "subtypes" in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to shared genetic and prognostic features. 7. Hürthle cell adenoma/carcinoma is renamed oncocytic thyroid adenoma/carcinoma. 8. Other miscellaneous tumors are classified into salivary gland-type carcinomas of the thyroid, thyroid tumours of uncertain histogenesis, thymic tumours within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on genetic abnormalities together with histomorphology, aiding in accurate pathological diagnosis and treatment selection, including molecular-targeted therapies.
... The mitotic activity is relatively low in the majority of cases. The histologic features associated with adverse outcomes include raised proliferative activity and necrosis [12][13][14][15][16][17]. Tumor cells possess abundant cytoplasm, varying from eosinophilic, amphophilic, or finely granular appearance. ...
... In the past, there was no widely accepted prognostically relevant pathologic grading system for MTC [17,18]. An International Medullary Thyroid Carcinoma Grading System has been designed to define high-grade MTC by combining proliferative activity and necrosis [12][13][14][15][16]. A two-tiered grading system has been introduced in the 2022 World Health Organization (WHO) classification (see Chap. 14). ...
Fine-needle aspiration (FNA) with ultrasound imaging remains the first-line modality for diagnosing medullary thyroid carcinoma (MTC). However, the diagnostic accuracy for MTC is less consistent than the follicular cell-derived thyroid tumors. The diverse appearances of MTC pose diagnostic difficulties due to morphologic overlap with other thyroid neoplasms. The major differential diagnosis includes follicular/oncocytic neoplasm, papillary carcinoma, poorly differentiated thyroid carcinoma, anaplastic carcinoma, and metastatic tumors. The characteristic cytologic features of MTC are sometimes misleading. The cytomorphologic clues and pitfalls for each cytopreparatory method, along with the differential diagnoses, are highlighted in this chapter.
... Ki-67 index in the majority of them is <1%, even then limited studies have suggested that Ki-67 alone or in combination with RET mutation has some prognostic significance. [11][12][13] According to the WHO 2004, pituitary tumors were divided into adenoma, atypical adenoma, and carcinoma. Atypical adenomas are those tumors having atypical morphological features suggestive of aggressive behavior such as invasion growth. ...
Background: Neuroendocrine tumors (NENs) are a group heterogenous group of tumors that can arise in any organ in the body and have a wide range of aggressiveness. Aims and Objective: To compare the frequency of NENs in our setup to those reported in the literature to age, site, and degree of differentiation by doing a retrospective study. Materials and Methods: Cases of NENs that were diagnosed in the Department of Pathology, in our hospital over the past 5 years were studied considering the age, location, and degree of differentiation. A fresh panel of immunohistochemistry (IHC) was conducted for those cases where IHC was not done. Results: A total of 46 cases of NENs were reviewed. About 56.5% (26 cases) were males and 43.5% (20 cases) were females, with a median age of 46 years. In our study, most of the tumors are found in the gastro-entero-pancreatico-hepatobilliary group followed by the NENs of the endocrine gland (21.7%) and broncho-pulmonary group (15.2%). NENs were graded based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis. In total 21 cases (45.7%) had G1 grading, 7 cases (15.2%) had G2 grading, 2 cases (4.3%) had a G3 grading, and 16 cases (34.7%) were graded as neuroendocrine carcinoma. Conclusion: As the majority of the studies do not include benign NENs and those arising from the endocrine glands, therefore comparison of our results can be difficult. This is the first attempt to study the NENs from North East India and to analyze their clinicopathological features.
... Ряд исследований показал рациональность двухуровневой классификации рисков, связанных с медуллярной карциномой щитовидной железы. Наличие одного из критериев, таких как некроз опухоли, количество митозов ≥5 на 2 мм 2 и/или индекс пролиферации Ki-67 ≥5%, считают независимым предиктором более агрессивных форм рака [66,67]. ...
... Demographics described in many studies across the globe have described a female predominance, however Indian literatures in reverse have reported male predominance [10][11][12][20][21][22]. We found a female predominance in our study. ...
... The mean age was 44.0 years, concordant with the other Indian studies [20][21][22]. Studies carried out outside the India, however, made note of the older age group [10][11][12]. ...
... Two independent studies were published in year 2020 by Fuchs et al. and Alzumaili et al. proposing the three tiered and two tiered grading system, respectively [11,12]. ...
Introduction
Medullary carcinoma (MTC) is a rare neuroendocrine thyroid neoplasm. The international medullary thyroid carcinoma grading scheme (IMTCGS), which has prognostic significance, has been introduced recently. The present study graded MTC cases using the IMTCGS and evaluated it in our study cohort.
Methods
All MTC thyroidectomy cases over 6 years were evaluated. Low-grade (LG) and high-grade (HG) were compared. Survival analysis included overall survival (OS), loco-regional free survival and distant metastasis free survival (DMFS).
Results
Of 32 cases, 31.25% were HG and 68.75% LG. The mean age was 44.0 years and M:F ratio 1:1.146. HG patients were older and had tumour cells with high-grade nuclear features and prominent nucleoli and showed distant metastasis. Necrosis was found more in patients with high grade nuclear features. There was discordance between the high Ki67 (60%) and increased mitotic activity (20%). Univariate survival analysis revealed poor DMFRS and OS in the cohorts with high grade, Ki67 > 5% and coagulative necrosis. The multivariate cox regression analysis showed IMTCGS significantly associated with overall survival (HR 28.30, p = 0.009) and DMFS (HR 15.70, p = 0.02).
Discussion and conclusion
This is the first Indian study evaluating IMTCGS, a very simple and convenient grading system that can be readily used in any tertiary health care centre. IHC for Ki 67 should mandatorily be done irrespective of the low mitotic activity on the HPE and necrosis should be diligently searched in cases with high-grade nuclear morphology. HG MTC cohorts were associated with poor OS as well as DMFRS.
... and pathological parameters to predict the outcome of MTC have been investigated. Fuchs et al.11 showed that Ki-67 LI ≥ 3, mitotic counts (per 2 mm 2 ) ≥3, and coagulative necrosis were all poor prognostic factors. Based on these findings, MTCs were assigned into three categories (low-, intermediate-, and highgrade).11 ...
... Fuchs et al.11 showed that Ki-67 LI ≥ 3, mitotic counts (per 2 mm 2 ) ≥3, and coagulative necrosis were all poor prognostic factors. Based on these findings, MTCs were assigned into three categories (low-, intermediate-, and highgrade).11 Alzumaili et al.10 reported that tumor necrosis and mitotic counts (5 mitosis/10 HPFs as the cutoff) were the only independent predictor, and proposed a two-grade system, as either low-grade (<5 mitosis/10 HPF and no tumor necrosis) or high-grade (≥5 mitosis/10 HPF and/or tumor necrosis). ...
Background:
Medullary thyroid carcinoma (MTC) with papillary-like nuclear features has not been previously described. Here, we aimed to describe the unique features of MTC and examine their prognostic value as markers of high-grade MTC.
Methods:
Of the 110 MTC patients reviewed, a total of five (4.5%) who exhibited MTC with papillary-like nuclear features based on observations from cytological preparations were included in this study. Papillary-like nuclear features were defined as exhibiting all of the following characteristics: ground-glass chromatin pattern, grooves, indented membrane, and lobulation.
Results:
The patients included four females and one male, with a median age of 70 years. Calcitonin-doubling times for patients 1 and 3 were 0.8 and 0.34 years, respectively. Cytologically, patients 4 and 5 displayed a Ki-67 labeling index of 5.1% and necrotic cells, respectively. All three histologically evaluated patients exhibited papillary-like nuclear features and a Ki-67 labeling index of >5.0%. Patients 1 and 3 had mitotic counts of ≥5 per 2 mm2 . The MTC in all five patients was classified as high-grade. Moreover, patient 1 harbored a RET mutation (M918T), while RET (R912W), BRAF (V600E), and CTNNB1 (S33F, T41I) mutations were present in patient 2.
Conclusion:
Our work suggests that papillary-like nuclear features in MTC may be associated with high-grade tumors. These findings may be cytologically indicative of high-grade tumors other than necrosis or mitosis.
... The Ki67 proliferation index was shown to be a prognostic factor to predict overall survival, diseasespecific survival, distant metastasis-free survival and locoregional recurrence-free survival in MTC. 2,19,20 Similarly, we confirmed that high (≥ 5%) Ki67 was associated with decreased disease-specific survival and distant metastasis-free survival, regardless of the scoring methods used. ...
Aims
The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time‐consuming task.
Methods and results
We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning‐based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near‐perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease‐specific survival and distant metastasis‐free survival.
Conclusions
We herein validate a machine learning‐based deep‐learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3–7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.
... ,38 MTC grade was classified according to The International Medullary Thyroid Cancer Grading System, with high-grade defined as a tumor demonstrating one of: tumor necrosis, mitotic rate ≥5 per 2 mm 3 , or Ki67 proliferation index ≥5%. Other pathological features included tumor size, vascular invasion, extrathyroidal extension (ETE), nodal status, and the presence of extranodal extension. ...
Background:
There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center.
Patients and methods:
A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data.
Results:
In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018).
Conclusion:
Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control.
... While MTC represents < 10% (2%) of all thyroid malignancies, it represents 8% of thyroid cancer-related deaths [2,3]. Investigations into this disproportionately high mortality rate have yielded three histologic features conferring worse survival: elevated Ki67 proliferative index (Ki67PI), elevated mitotic index, and presence of necrosis [4,5]. These findings culminated into the International Medullary Thyroid Carcinoma Grading System (IMTCGS), a two-tiered grading system separating MTC into low-grade and high-grade [6]. ...
Background
Although uncommon, medullary thyroid carcinoma (MTC) accounts for a significant proportion of thyroid cancer deaths. Recent studies have validated the two-tier International Medullary Thyroid Carcinoma Grading System (IMTCGS) to predict clinical outcomes. A 5% Ki67 proliferative index (Ki67PI) cut-off separates low-grade from high-grade MTC. In this study, we compared digital image analysis (DIA) to manual counting (MC) for determining the Ki67PI in a MTC cohort, and explored the challenges encountered.
Methods
Available slides from 85 MTCs were reviewed by two pathologists. The Ki67PI was documented by immunohistochemistry for each case, scanned with the Aperio® slide scanner at 40× magnification, and quantified using the QuPath® DIA platform. The same hotspots were screenshot, printed in color, and blindly counted. For each case, over 500 MTC cells were counted. Each MTC was graded using IMTCGS criteria.
Results
In our MTC cohort (n = 85), 84.7 and 15.3% were low- and high-grade with the IMTCGS. In the entire cohort, QuPath® DIA performed well (R² = 0.9891) but appeared to undercall compared to MC. QuPath® performed better in high-grade cases (R² = 0.99) compared to low-grade cases (R² = 0.7071). Overall, Ki67PI determined with either MC or DIA did not affect IMTCGS grade. Encountered DIA challenges include optimizing cell detection, overlapping nuclei, and tissue artifacts. Encountered MC challenges include background staining, morphologic overlap with normal elements, and counting time.
Conclusion
Our study highlights the utility of DIA in quantifying Ki67PI for MTC and can serve as an adjunct for grading in conjunction with the other criteria of mitotic activity and necrosis.
