Analysis of changes in WHO pituitary tumor classification in 2017

Analysis of changes in WHO pituitary tumor classification in 2017.  The incidence of tumors around the pituitary gland and sellar area accounts for about 15% of all intracranial tumors. Pituitary adenomas are the most common intracranial benign tumors.

For a long time, the classification criteria for pituitary adenomas are based on different criteria: including tumor cell morphology, hormone secretion and ultrastructure. The Classification Criteria for Endocrine Tumors published by WHO in 2017 emphasizes more precise classification based on the differentiation lineage of tumor cells. This article focuses on the new changes and significance in the publication standards.

1. The background of the new classification

The latest edition of “Classification Standards for Endocrine Tumors” (4th edition) was revised in 2017. In 2004, WHO published the third edition of “Endocrine Organ Pathology and Genetic Tumor Classification” according to the types of hormones secreted by pituitary adenoma cells, and classified by immunohistochemical staining and observing the ultrastructural characteristics of tumor cells. Most pituitary adenomas are defined as benign tumors, but there are still some tumors that invade the dura, periosteum and even bone and important surrounding structures, including sella, cavernous sinus, intracranial, slope, and paranasal sinuses. Therefore, it is necessary to establish a classification method based on the clinical manifestations of individual tumors, focusing on predicting those tumors with aggressive tendency and identifying their biological characteristics such as aggressiveness, aggressiveness, and early recurrence.

The 4th edition of the WHO “Classification Standards for Endocrine Tumors” establishes a sound and reliable classification mechanism for pituitary tumors. In the new version of the classification of pituitary adenomas, in addition to identifying the types of hormones secreted by tumor cells, it also emphasizes that pituitary transcription factors are in determining the differentiation direction of tumor cell lineages, regulating the secretion of different types of hormones by the pituitary gland and in the development and progression of pituitary adenomas. Play a role that cannot be ignored.

2. The application of immunohistochemical detection and the redefinition of “zero-cell adenoma”

The cell development process is an organized and complex process that is coordinated by specific transcription factors. Pituitary transcription factors also play a similar role in determining the cell differentiation and hormone production of pituitary adenomas. Therefore, they can be used as diagnostic markers. The 4th edition of 2017 “Classification Criteria for Endocrine Tumors” proposes immunohistochemical detection of pituitary transcription factors for adeno-pituitary cell lines, which provides an accurate basis for reclassification of pituitary adenomas according to cell lineage. Pituitary adenomas are tumors originated from endocrine pituitary cells in the anterior pituitary gland, and can be divided into three cell lineages: eosinophils, gonadotropin cells and ACTH.

According to different transcription factors and their combination forms, each lineage is finally manifested as growth hormone cell adenoma, prolactin cell adenoma, thyroid stimulating hormone cell adenoma, corticotropin cell adenoma, gonadotropin cell adenoma, zero Cell adenoma, dual hormone cell adenoma and multihormone cell adenoma.

During the development and differentiation of pituitary adenoma cells, pituitary transcription factors determine the differentiation direction of adeno-pituitary stem cells: ①pituitary specific POU-class homoe domain transcription factor-1 (pituitary specific POU-class homoe domain transcription factor-1) , PIT-1) participate in and induce the differentiation of eosinophil lineage into growth hormone cells, prolactin cells, lacto-growth hormone cells and thyroid-stimulating hormone cells. ② Steroidogenic factor-1 (SF-1) mainly regulates the differentiation of gonadotropin cells. ③T-BOX family member TBX19 (T-PIT) is mainly involved in regulating the differentiation and maturation of ACTH cells. Therefore, the immunohistochemical staining of pituitary transcription factors can accurately identify and classify the subtypes of pituitary adenomas, and it is not necessary to rely on electron microscopy for routine ultrastructural analysis.

In addition, the concept of this new classification is also reflected in the naming of pituitary adenomas: according to the different lineage sources of adeno-pituitary cells, they are named in combination with different types of secreted hormones and specific pituitary cell transcription factors and their combinations. For example: growth hormone cell adenoma (formerly known as “growth hormone secreting adenoma”), its diagnosis must have positive expression of pituitary specific transcription factor PIT-1 in addition to immunohistochemical staining showing positive growth hormone staining.

In clinical pathological diagnosis, routine immunohistochemical staining of GH, PRL, ACTH and other pituitary hormones and α subunits can accurately classify most adenomas. Therefore, referring to the 4th edition of the “Criteria for the Classification of Endocrine Tumors”, it is not necessary to stain all pituitary adenomas with pituitary transcription factors, and for certain subtypes of adenomas, pituitary transcription factors and related cofactors are required for immune tissue Chemical dyeing is reclassified. For example, in the third edition of “Endocrine Organ Pathology and Genetic Tumor Classification” in 2004, “zero-cell adenoma” was defined as a pituitary adenoma with negative immunohistochemical staining for pituitary hormones. Only conventional hormone immunohistochemistry and other methods were used. Pituitary adenomas are distinguished from each other. However, in fact, a negative hormone staining cannot be diagnosed as a zero-cell adenoma.

According to the third edition classification criteria, zero-cell adenomas account for about 10% of all pituitary adenomas. In fact, some gonadotropin cell adenomas that are negative for pituitary hormone immunohistochemistry are included in the category, traced back to the pathological sections diagnosed as “zero cell adenoma” in the past, and re-stained the pituitary transcription factor SF-1 by immunohistochemical staining. , The gonadotropin cell adenoma with negative hormone staining and positive SF-1 transcription factor can be distinguished from true zero-cell adenoma with negative hormone and transcription factor. The re-testing of pituitary transcription factors by immunohistochemistry statistics shows that zero-cell adenomas account for less than 1% of all pituitary adenomas.

Therefore, in the 4th edition of “Classification Standards for Endocrine Tumors”, zero-cell adenomas are precisely defined as: pituitary adenomas that are negative in immunohistochemical staining of pituitary secreting hormones and pituitary cell transcription factors. In addition, multi-hormonal adenomas are defined as tumor cells derived from one or more adeno-pituitary cell lines within the same tumor, which are divided into PIT-1-positive multi-hormonal cell adenomas (previously called static type III pituitary Adenoma) and a rare combination of immunohistochemical adenoma. It can be seen that there are limitations to using hormone immunohistochemistry to achieve accurate classification. The correct use of pituitary transcription factor immunohistochemical detection can play an important supplementary role in the accurate diagnosis of hormone expression-negative or only focal-positive pituitary adenomas.

3. The abandonment of the term “atypical adenoma” and the proposal of “high-risk pituitary adenoma”

In the third edition of 2004 “Classification of Endocrine Organ Pathology and Genetic Tumors”, in order to reflect the malignant potential of pituitary adenomas and assess the prognosis of patients, pituitary adenomas are divided into typical adenomas, atypical adenomas and pituitary carcinomas. Typical adenomas include most of the pituitary neuroendocrine tumors. Atypical adenomas are those with elevated mitotic index of tumor cells, Ki-67 marker index> 3%, and p53 immunoreactive staining. However, it has been found in clinical work that some typical adenomas have invaded the sphenoid sinus and/or cavernous sinus, grew around the carotid artery or optic canal in preoperative MRI imaging, and the residual tumor tissue recurred rapidly after surgery. Chemotherapy and other adjuvant treatments have poor results and poor prognosis; preoperative MRI and related imaging examinations of some atypical adenomas showed limited space occupation, clear boundaries with surrounding tissues, no obvious abnormalities in hormone levels, and good postoperative prognosis .

The results of different reports showed that there was no significant correlation between the aggressive growth of tumors and the pathological diagnosis of atypical adenomas. The results of KIM and other studies showed that the postoperative recurrence rate of pituitary adenomas was not significantly correlated with mitotic counts. The results of HASANOV and other studies showed that: p53 immunoreactive staining was not significantly related to postoperative recurrence. The segmentation value of Ki-67 was greater than 2.5% and the MRI imaging showed that the sphenoid sinus, cavernous sinus and other surrounding tissues were invaded and the adenoma recurred. Highly correlated. The diagnosis of atypical adenoma cannot effectively help assess the prognosis of the prognosis of the prognosis of the pituitary adenoma.

In the fourth edition of the 2017 classification criteria, the diagnosis of “atypical adenoma” is no longer recommended, but other parameters such as mitotic count, Ki-67 marker index, and p53 staining are still reserved to assess whether pituitary adenomas are aggressive Growth of tumor behavior and prediction of patient prognosis, and the question of whether tumor aggressiveness should be included in the clinicopathological classification of neuroendocrine tumors is another important discussion point. Some scholars advocate that aggressiveness should be included in the classification of pituitary neuroendocrine tumors. However, it is generally believed that aggressiveness should not be included in the pathological classification and classification.

This is mainly due to the fact that clinicians use imaging criteria and evidence of gross tumor invasion during surgery to assess the invasive ability. The subjective bias is strong and the deviation is large; while pathological smear observations usually lack imaging data or surgeon evaluations. With regard to clinical data on invasion, pathological results alone cannot assess its aggressive behavior. Therefore, WHO does not include the aggressiveness of tumors in the pathological classification of pituitary adenomas, but uses invasion as an important reference index for predicting the prognosis of pituitary adenomas. It appears as an aggressive growth of adenoma, which deviates from the benign histological characteristics of a typical adenoma.

The definition is different in the relevant literature, such as: “huge and fast-growing tumors that are invasive and enveloping with surrounding tissues”, “tumors that will recur early even if they are completely removed”, and “resistance to conventional treatments.” Drug tumors”. These subtypes of pituitary adenomas with aggressive growth, high potential for value-added and prone to recurrence are defined as “high-risk pituitary adenomas” in the 4th edition of 2017 “Classification Standards for Endocrine Tumors”, including: sparse granular type Growth hormone cell adenoma, PIT-1 positive multihormone cell adenoma, quiescent corticotropin cell adenoma, Crooke cell adenoma, and male prolactin cell adenoma.

These five types of adenomas usually grow in an invasive and enveloping manner with the surrounding tissue structures, and have a high tendency to relapse and are more difficult to control. Therefore, in clinical work, formulate and standardize individualized diagnosis and treatment plans for patients whose case diagnosis results are high-risk pituitary adenomas, adopt relevant indications for adjuvant therapy after total resection/subtotal resection, and review the density of management after follow-up. Time and duration, as well as the best time node and treatment methods for early intervention for signs of recurrence, are issues that need to be resolved and standardized in the future.

4. Non-neuroendocrine tumors of the pituitary-pituitary blastoma

In the fourth edition of 2017, “The Classification Standards for Endocrine Tumors”, the pituitary non-neuroendocrine tumors are also elaborated in detail. Compared with the previous version, many types are improved, including craniopharyngiomas, neuronal and paraneuronal tumors originating in the sella area. , Posterior pituitary tumors, mesenchymal tissue tumors, germ cell tumors, lymphohematopoietic system tumors and secondary tumors. The improved classification is basically consistent with the 2016 version of the central nervous system tumor classification. In addition, a solid tumor-pituitary blastoma, which is a rare malignant pituitary non-neuroendocrine tumor, is introduced for the first time in infants under 24 months (median age of onset is 8 months), female The incidence rate is higher than that of men. Most of the sick children have Cushing syndrome and have a poor prognosis.

5. Summary

The pathological evolution of pituitary adenoma is developed through multi-step and multi-organ factors, among which genetic configuration, specific somatic mutations and endocrine factors are important inducing factors. From the early evaluation of chromaffin cells, eosinophils, and basophils to the new classification of immunohistochemical studies based on transcription factors in 2017, the ability to qualitatively diagnose pituitary adenomas has been greatly improved.

The new classification standard emphasizes that immunohistochemistry is the main auxiliary diagnostic tool for the classification of pituitary neuroendocrine tumors. Immunohistochemical staining of immune markers such as pituitary hormones, pituitary transcription factors and cytokeratins is the basis of the classification standard. Under the guidance of the new classification, it has guiding significance for accurately diagnosing the pathological subtypes of pituitary adenomas, identifying pituitary adenomas with high invasiveness and high risk of recurrence, as well as clinical treatment, prognosis prediction and follow-up management; this time is at the molecular level Explaining the mechanism and classification of pituitary tumors is not only the ultimate goal of pituitary tumor classification, but also a new beginning for the transformation of pituitary tumors.

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