163
Cancer Biomarkers 14 (2014) 163–167 DOI 10.3233/CBM-130353 IOS Press
New horizons in diagnosis and management of endocrine tumors George Kontogeorgos Department of Pathology, G. Gennimatas Athens General Hospital, Bldg. #1, 1st Floor 154, Messogion Avenue GR-115 27 Athens, Greece Tel.: +11 30 210 778 4302; Fax: +11 30 201 778 4302; E-mail: [email protected]
Abstract. Endocrine tumors were considered relatively infrequent neoplasms. However, during the last decades, their frequency gradually increased. The use of imaging techniques, guided FNA biopsy, an endoscope camera in the investigation of endocrine lesions, permits early diagnosis. At the histological level, new applications such as non-biotin containing immunohistochemical detection systems, tyramide amplification method, in situ hybridization, FISH, CGH, and other molecular techniques have provided better knowledge on the protein and molecular background. The investigation of somatostatin and dopamine receptors assists targeted therapy of endocrine tumors. Novel treatment modalities have emerged for the management of pituitary and gastroenteropancreatic tumors respectively. Despite this progress, in some instances, the morphological diagnosis remains questionable. Similarities among normal elements, hyperplastic conditions and benign or malignant lesions can make separation difficult. The “gray zones” representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. Furthermore, in most endocrine tumors, the diagnosis of carcinoma is justified only in the presence of local or distant metastases. More precise guidelines are needed, by improving the currently available criteria, to minimize the “gray zones,” leading to a more accurate separation of such endocrine lesions. Keywords: Classification, endocrine, imaging, pathology, therapy
1. Introduction In the past, endocrine tumors were considered as relatively infrequent neoplasms, with malignant tumors accounting for < 1% of all malignancies in humans. During the last three decades, the impact of technology and its applications to the clinical and morphological investigation resulted in their increased frequency.
2. Imaging techniques Ultrasound has become a powerful tool for investigation of thyroid lesions and for the detection of nonpalpable nodules. Guided FNA biopsies provide rapid and accurate diagnosis [1]. Color dopler ultrasound, which is used in the exploration of the neck to investigate thyroid carcinoma can differentiate malignant lymph nodes showing peripheral vascularity, in
contrast to hilar vascularity that is typical of reactive lymph nodes [2]. CT scans and guided FNA biopsy under ultrasound also facilitates diagnosis of pancreatic tumors. Also, MRI and PET scans not only demonstrate endocrine tumors, but also provide information of their functional activity. PET images can demonstrate local relapse of adrenocortical carcinomas [3]. Detection of parathyroid lesions was poor in the past, but now, imaging by sestamibi increases sensitivity in the detection of parathyroid adenomas [4]. Treatment with oral biphosphonates further enhances the sensitivity of sestamibi in patients with primary hyperparathyroidism [5]. Accumulation of sestamibi may reveal ectopic parathyroid adenomas, even if they are hidden in very unusual sites (e.g., posterolateral to the trachea) [6]. During the last two decades, significant progress was achieved in the investigation and diagnosis of gastroenteropancreatic tumors (GEP-NETs). In addition to the evolution of flexible endoscopes and the abil-
c 2014 – IOS Press and the authors. All rights reserved ISSN 1574-0153/14/$27.50
164
G. Kontogeorgos / New horizons in endocrine tumors
ity to take biopsies, the endoscope camera permits early diagnosis of intestinal neuroendocrine tumors. Using the latter device, the patient swallows a capsule equipped with a wireless camera. The pill travels through the esophagus and the intestines, where it can capture up to 870,000 images. The images uploaded from the endoscope capsule camera may be examined but biopsies cannot be taken during this procedure [7]. For pituitary adenomas, gamma knife radiosurgery can be used for the treatment of residual tumors. A computer assisted dose plan illustrates the contour of pituitary adenoma before treatment [8].
3. Morphology methods Regarding the application of morphology methods to histological diagnosis, great progress has been made with the introduction of new, more sensitive immunohistochemical (IHC) systems and antigen retrieval protocols. Non-biotin containing one-step unique detection systems have facilitated the IHC methods; with the tyramide signal amplification method, the sensitivity of IHC has reached that of in situ hybridization. For example, null cell adenomas of the pituitary were considered as non-secreting tumors in the past [9]. However, recent studies have proved that those previously negative tumors by conventional IHC turned positive for pituitary gonadotropin hormones after tyramide signal amplification. Thus, novel ICH protocols have contributed to a better understanding of the functional activity and to the optimal classification of endocrine tumors [10]. Tumor markers and cell proliferation markers are extensively used in current diagnostic routine. They offer useful information for the prognosis and prediction of endocrine tumors. Tissue microarrays, constructed of hundreds of tiny tissue samples, can be screened by antibodies to collect massive data on protein level. In situ hybridization can detect tumor RNAs providing information concerning the functional activity. Fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) represent very important morphologic techniques, integrating molecular genetics and classic cytogenetics and bringing them together to form a single framework for morphologic evaluation [11]. Using DNA-microarrays, thousands of cDNA clones are arrayed in a single experiment. Experimental and reference RNAs are competitively hybridized; thus, gene expression on a global level provides massive novel information. Two major pa-
pers on DNA-microarrays of adrenal cortical tumors illustrate the potential power of molecular profiling approaches based on gene expression for classification [12,13]. Many molecular techniques are currently used for investigating benign and malignant endocrine tumors. All applications mentioned above provide a better knowledge of the protein and molecular background, as well as tumor growth rate.
4. Novel therapies Targeted therapy has introduced novel modalities to treat endocrine tumors. Employment of mTOR inhibitors and Tritium or Lutetium results in prolonged survival in patients with gastroenteropancreatic carcinomas (GEP-NECs) [14]. In addition, the inhibition of cell growth rate of adrenocortical carcinoma by nanoparticle albumin-bound preparations of the antimicrotubular drug Paclitaxel opens new horizons in treating adrenocortical cancer [15]. The contribution of IHC in tumors from patients who are candidates to receive targeted therapy is of utmost importance. Somatostatin analogs currently are being used to treat growth hormone producing pituitary adenomas and GEP-NETs [16]. Investigation of somatostatin receptors (sst) with IHC in pituitary adenomas may predict and also validate the effectiveness of targeted therapy with somatostatin analogs [17]. PET scans can evaluate the effectiveness of octreotide therapy in pituitary adenomas, as this technology demonstrates tumor functional activity. PET images with 11C-methionine from patients with acromegaly demonstrate high metabolism in the pituitary adenoma before treatment and a considerable decrease in metabolism after treatment with somatostatin analogs [18]. Octreotide scan and PET scan images are also useful for detection of GEP-NETs [19,20]. Octreotide is a somatostatin analog that preferentially binds to sst2A, sst2B and sst5, although new analogs binding other sst receptor types recently have been introduced to treat thyroid-stimulating hormone producing pituitary adenomas [21]. In addition, the presence of both sst and dopamine type 2 receptors (D2r) helped to improve the outcome of patients with GEPNETs [22]. New treatment modalities have emerged with the introduction of temozolomide in the management of pituitary adenomas. MGMT (0–6 methylguanine DNA methyltransferase) marker is a DNA repair enzyme. Patients with adenomas showing low MGMT expres-
G. Kontogeorgos / New horizons in endocrine tumors
sion respond to temozolomide, while those with strong expression are resistant. Specific antibodies are currently available to localize MGMT. Therefore, detection of MGMT by IHC is strongly recommended before the administration of temozolomide [23].
5. Classification of endocrine tumors Despite the progress made, in some instances, the accuracy of morphological diagnosis in endocrine lesions remains questionable. Similarities among normal elements, hyperplastic conditions, and benign or malignant lesions make separation difficult. Unfortunately, in such cases, the diagnostic contribution of IHC and even of molecular techniques remains limited. The “gray zones” representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. The pathologist’s role is to make the correct diagnosis by differentiating malignant lesions from benign lesions and further proceeding to accurate classification. In cases in which this cannot be achieved, the pathologist has to approach tumor malignant potential. According to the classifications of endocrine tumors in the WHO books, specific guidelines using morphology and IHC markers have been proposed for each endocrine organ [24]. Adenomas comprise the substantial majority of pituitary tumors. The WHO classifies adenohypophysial tumors into three categories: adenomas when the Ki-67 labeling index (LI) is less than 3%, atypical adenomas suggesting aggressive potential and malignant transformation, which show increased (> 3%) Ki-67 LI and p53 immunoreactivity. As a rule, carcinomas show Ki67 LI more than 10% and extensive immunoreactivity for p53. However, the term pituitary carcinoma can be used only when metastases are well documented [25]. The WHO classification of GEP-NETs includes well-differentiated NETs grade 1 with Ki-67 less than 2%, well-differentiated NECs grade 2 with Ki-67 between 2–20%, and poorly differentiated NECs grade 3 with Ki-67 more than 20% [26]. Parathyroid lesions are divided into adenomas that occur as a single lesion representing 80% of primary hyperthyroidism, hyperplasia that affects multiple glands including patients with MEN-1 syndrome and carcinomas that are very rare, occurring in less than 1% of primary hyperthyroidism. The modern diagnostic approach includes: careful localization or
165
at least lateralization by preoperative radiologic tests (sestamibi scan), surgical neck exploration, and removal of the abnormal gland. A decrease by more than 50% of parathormone levels by intraoperative rapid assay confirms the excision of adenoma. Fat stain is accurate in 85% of cases and the histologic diagnostic accuracy 99.2% [27]. By IHC, parafibromin shows nuclear staining in patathyroids, whereas it is usually absent in carcinomas [28]. Thyroid cancer is a rare oncological entity, representing no more than 1% of all human malignant neoplasms. However, it is the most common malignant endocrine neoplasia whose incidence has progressively increased over the past two decades [29]. Histological separation of hyperplasia from neoplasia is of great importance for thyroid lesions. In hyperplasia, there are multiple nodules, poorly encapsulated, with architectural and cytological heterogeneity. There is no compression of the surrounding parenchyma, which also shows comparable areas. In contrast, neoplasia represents a solitary, encapsulated nodule with uniform architecture and cytology. The space-occupying neoplastic nodule compresses the surrounding parenchyma, which exhibits different histology than that of the nodule. The distinction between follicular adenoma and follicular carcinoma is based on the absence of nuclear features of papillary carcinoma and the invasive features of the tumor [30]. Papillary thyroid carcinoma is defined by the presence of a unique set of nuclear features. They include pale, enlarged and vacuolated overlapping nuclei, with peripheral distribution of chromatin, irregular nuclear membrane and presence of pseudoinclusions, which refer to as “orphan Annie eye” [31]. A study using three-dimensional reconstruction of papillary thyroid carcinoma has shown that nuclei appear to bear either grooves or holes, due to profound remodeling of the nuclear shape with invaginations and tunnels [32]. By IHC, emerin identifies nuclear features of papillary thyroid carcinoma, which represents an effective tool for the detection of nuclear irregularities, allowing identification of such cases [33]. Primary adrenal cortical tumors include adenomas and carcinomas, which are rare in general clinical practice. They may present clinically with hypersecretion of steroid hormones or with general signs of malignancy. Incidental adrenal tumors measuring < 1 cm in autopsy series range from 1.4% to 8.7% (mean 2.33%). They are more commonly identified by imaging techniques, with their incidence reaching up to 4.2% when the abdomen is scanned in the investigation of other
166
G. Kontogeorgos / New horizons in endocrine tumors
intra-abdominal disease [34]. Distinction between a benign adrenal lesion and carcinoma is very important. Carcinoma is a rare, but highly aggressive tumor, accounting for 0.05 to 2% of all malignancies. Many carcinomas are easy to diagnose, as they are infiltrative or have distant metastases at the time of presentation. Histologically, marginal adrenal cases are impossible to differentiate, particularly lesions that have not yet developed invasion or metastasis. It should be noted that there is no single histological feature that defines malignancy. For this reason, several multifactorial systems have been proposed for a diagnostic approach. However, not all systems assess the same morphological features. Some of these combine biochemical, clinical, and histology findings. Unfortunately, as a rule, in routine practice, clinical information is not available or is not considered. The most important system to approach the malignant potential is that proposed by Weiss and modified by Aubert. It uses several histologic criteria. The presence of more than three criteria favors malignancy [35]. The proliferation marker Ki-67 (clone MIB-1) represents an alternative feature to mitotic counting. However, relevant studies have shown an increased labeling index in carcinomas of more than 3% [36]. Pheochromocytomas represent the most important tumors of the adrenal medulla. Approximately 10% occurs in the settings of various familial syndromes. Sporadic tumors are solitary, whereas in familial disease, tumors are mostly bilateral and often coexist with extra-adrenal paragangliomas. Familial tumors tend to occur in younger individuals [37]. The pheochromocytoma of the adrenal gland scaled score (PASS) is the most important multifactorial system that utilizes various histologic criteria to approach the malignant potential of pheochromocytomas. A score equal to or more than four suggests potential malignant behavior [38]. For histologically marginal cases, more precise guidelines are needed, by improving the currently available criteria, to minimize the “gray zones”, leading to a more accurate separation of such endocrine lesions.
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N.A. Johnson, M.E. Tublin, J.B. Ogilvie, Parathyroid Imaging, Radiology 188 (2007), 1706-1715. P. Makras, G. Kaltsas, D. Papadogias, I. Athanasoulis, G. Zografos, G. Kontogeorgos, N. Borboli, S. Livadas, G. Piaditis, Int J Clin Paharm Res 25 (2005), 19-28. H.K Eslamy, H.A. Ziessman, Radiographics 28 (2008), 14611476. J.P. Galmiche, E. Coron, S. Sacher-Huvelin, Gut 57 (2008), 695-703. A. Tooze, C.L. Hiles, J.P. Sheehan, World Neurosurg 78 (2012), 122-128. K. Kovacs, E. Horvath, N. Ryan, C. Ezrin, Virchows Arch A Pathol Anat Histol 387 (1980), 165-174. G. Kontogeorgos, E. Thodou, M. Pateraki, Endocr Pathol 18 (2007), 113-114. G. Kontogeorgos, N. Kapranos, E. Thodou, Applications of FISH in Pathology. in: Morphologic Methods. Lloyd RV (ed), Humana Press, Totowa, New Jersey, 2001, pp. 91-111. T.J. Giordano, Endocr Pathol 14 (2003), 107-116. F. de Fraipont, M. El Atifi, N. Cherradi, G. Le Moigne, G. Defaye, R. Houlgatte, J. Bertherat, X. Bertagna, P.F. Plouin, E. Baudin, F. Berger, C. Gicquel, O. Chabre, J.J. Feige, J Clin Endocrinol Metab 90 (2005), 1819-1829. D. Hörsch, S. Ezziddin, A. Haug, K.F. Gratz, S. Dunkelmann, B.J. Krause, C. Schümichen, F.M. Bengel, W.H. Knapp, P. Bartenstein, H.J. Biersack, U. Plöckinger, S. Schwartz-Fuchs, R.P. Baum, Recent Results Cancer Res 194 (2012), 457-465. M.J. Demeure, E. Stephan, S. Sinari, D. Mount, S. Gately, P. Gonzales, G. Hostetter, R. Komorowski, J. Kiefer, C.S. Grant, H. Han, D.D. Von Hoff, K.J Bussey, Ann Surg. 255 (2012), 140-146. L. Sidéris, P. Dubé, A. Rinke, Oncologist 17 (2012), 747-755. E. Thodou, G. Kontogeorgos, D. Theodosiou, M. Pateraki, J Clin Pathol 59 (2006), 274-279. C. Muhr, Neuroendocrinology 83 (2006), 205-210. G. Piaditis, A. Angellou, G. Kontogeorgos, N. Mazarakis, T. Kounadi, G. Kaltsas, K. Vamvakidis, R.V. Lloyd, E. Horvath, K. Kovacs, J Clin Endocrinol Metab 90 (2005), 2097-2103. R.P. Baum, V. Prasad, M. Hommann, D. Hörsch, Recent Results Cancer Res 170 (2008), 225-242. F. Gatto, F. Barbieri, M. Gatti, R. Wurth, S. Schulz, J.L. Ravetti, G. Zona, M.D. Culler, A. Saveanu, M. Giusti, F. Minuto, L.J. Hofland, D. Ferone, T. Florio, Clin Endocrinol (Oxf) 76 (2012), 407-14. E. Diakatou, G. Kaltsas M. Tzivras, G. Kanakis, E. Papaliodi, G. Kontogeorgos, Endocr Pathol 22 (2011), 24-30. L.D. Ortiz, L.V. Syro, B.W. Scheithauer, F. Rotondo, H. Uribe, C.E. Fadul, E. Horvath, K. Kovacs, Clinics (Sao Paulo) 67(Suppl 1) (2012), 119-123. R.A. DeLellis, P. Heitz, R.V. Lloyd, C. Eng, WHO Classification of Tumours: Pathology and Genetics. Tumours of Endocrine Organs. IARC Press, Lyon, 2004. R.V. Lloyd, K. Kovacs, W.F. Young, Jr, W.E. Farrell, S.L. Asa, J. Trouillas, G. Kontogeorgos, T. Sano, B.W. Scheithauer, E. Horvath, Pituitary Tumours: Introduction in: WHO Classification of Tumours: Pathology and Genetics. Tumours of Endocrine Organs, R.A. DeLellis, P. Heitz, R.V. Lloyd, C. Eng, eds, IARC Press, Lyon, 2004, pp. 10-13. G. Kloppel, A. Perren, P.U. Heitz, Ann NY Acad Sci 1014 (2004), 13-27. A.G. Bondeson, L. Bondeson, O. Ljungberg, S. Tibblin, Hum Pathol 16 (1985), 1255-1263. M.A. Hahn, V.M. Howell, A.J. Gill, A. Clarkson, G. WeaireBuchanan, B.G. Robinson, L. Delbridge, O. Gimm, W.D.
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Cancer Biomarkers 14 (2014) 163–167 DOI 10.3233/CBM-130353 IOS Press
New horizons in diagnosis and management of endocrine tumors George Kontogeorgos Department of Pathology, G. Gennimatas Athens General Hospital, Bldg. #1, 1st Floor 154, Messogion Avenue GR-115 27 Athens, Greece Tel.: +11 30 210 778 4302; Fax: +11 30 201 778 4302; E-mail: [email protected]
Abstract. Endocrine tumors were considered relatively infrequent neoplasms. However, during the last decades, their frequency gradually increased. The use of imaging techniques, guided FNA biopsy, an endoscope camera in the investigation of endocrine lesions, permits early diagnosis. At the histological level, new applications such as non-biotin containing immunohistochemical detection systems, tyramide amplification method, in situ hybridization, FISH, CGH, and other molecular techniques have provided better knowledge on the protein and molecular background. The investigation of somatostatin and dopamine receptors assists targeted therapy of endocrine tumors. Novel treatment modalities have emerged for the management of pituitary and gastroenteropancreatic tumors respectively. Despite this progress, in some instances, the morphological diagnosis remains questionable. Similarities among normal elements, hyperplastic conditions and benign or malignant lesions can make separation difficult. The “gray zones” representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. Furthermore, in most endocrine tumors, the diagnosis of carcinoma is justified only in the presence of local or distant metastases. More precise guidelines are needed, by improving the currently available criteria, to minimize the “gray zones,” leading to a more accurate separation of such endocrine lesions. Keywords: Classification, endocrine, imaging, pathology, therapy
1. Introduction In the past, endocrine tumors were considered as relatively infrequent neoplasms, with malignant tumors accounting for < 1% of all malignancies in humans. During the last three decades, the impact of technology and its applications to the clinical and morphological investigation resulted in their increased frequency.
2. Imaging techniques Ultrasound has become a powerful tool for investigation of thyroid lesions and for the detection of nonpalpable nodules. Guided FNA biopsies provide rapid and accurate diagnosis [1]. Color dopler ultrasound, which is used in the exploration of the neck to investigate thyroid carcinoma can differentiate malignant lymph nodes showing peripheral vascularity, in
contrast to hilar vascularity that is typical of reactive lymph nodes [2]. CT scans and guided FNA biopsy under ultrasound also facilitates diagnosis of pancreatic tumors. Also, MRI and PET scans not only demonstrate endocrine tumors, but also provide information of their functional activity. PET images can demonstrate local relapse of adrenocortical carcinomas [3]. Detection of parathyroid lesions was poor in the past, but now, imaging by sestamibi increases sensitivity in the detection of parathyroid adenomas [4]. Treatment with oral biphosphonates further enhances the sensitivity of sestamibi in patients with primary hyperparathyroidism [5]. Accumulation of sestamibi may reveal ectopic parathyroid adenomas, even if they are hidden in very unusual sites (e.g., posterolateral to the trachea) [6]. During the last two decades, significant progress was achieved in the investigation and diagnosis of gastroenteropancreatic tumors (GEP-NETs). In addition to the evolution of flexible endoscopes and the abil-
c 2014 – IOS Press and the authors. All rights reserved ISSN 1574-0153/14/$27.50
164
G. Kontogeorgos / New horizons in endocrine tumors
ity to take biopsies, the endoscope camera permits early diagnosis of intestinal neuroendocrine tumors. Using the latter device, the patient swallows a capsule equipped with a wireless camera. The pill travels through the esophagus and the intestines, where it can capture up to 870,000 images. The images uploaded from the endoscope capsule camera may be examined but biopsies cannot be taken during this procedure [7]. For pituitary adenomas, gamma knife radiosurgery can be used for the treatment of residual tumors. A computer assisted dose plan illustrates the contour of pituitary adenoma before treatment [8].
3. Morphology methods Regarding the application of morphology methods to histological diagnosis, great progress has been made with the introduction of new, more sensitive immunohistochemical (IHC) systems and antigen retrieval protocols. Non-biotin containing one-step unique detection systems have facilitated the IHC methods; with the tyramide signal amplification method, the sensitivity of IHC has reached that of in situ hybridization. For example, null cell adenomas of the pituitary were considered as non-secreting tumors in the past [9]. However, recent studies have proved that those previously negative tumors by conventional IHC turned positive for pituitary gonadotropin hormones after tyramide signal amplification. Thus, novel ICH protocols have contributed to a better understanding of the functional activity and to the optimal classification of endocrine tumors [10]. Tumor markers and cell proliferation markers are extensively used in current diagnostic routine. They offer useful information for the prognosis and prediction of endocrine tumors. Tissue microarrays, constructed of hundreds of tiny tissue samples, can be screened by antibodies to collect massive data on protein level. In situ hybridization can detect tumor RNAs providing information concerning the functional activity. Fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) represent very important morphologic techniques, integrating molecular genetics and classic cytogenetics and bringing them together to form a single framework for morphologic evaluation [11]. Using DNA-microarrays, thousands of cDNA clones are arrayed in a single experiment. Experimental and reference RNAs are competitively hybridized; thus, gene expression on a global level provides massive novel information. Two major pa-
pers on DNA-microarrays of adrenal cortical tumors illustrate the potential power of molecular profiling approaches based on gene expression for classification [12,13]. Many molecular techniques are currently used for investigating benign and malignant endocrine tumors. All applications mentioned above provide a better knowledge of the protein and molecular background, as well as tumor growth rate.
4. Novel therapies Targeted therapy has introduced novel modalities to treat endocrine tumors. Employment of mTOR inhibitors and Tritium or Lutetium results in prolonged survival in patients with gastroenteropancreatic carcinomas (GEP-NECs) [14]. In addition, the inhibition of cell growth rate of adrenocortical carcinoma by nanoparticle albumin-bound preparations of the antimicrotubular drug Paclitaxel opens new horizons in treating adrenocortical cancer [15]. The contribution of IHC in tumors from patients who are candidates to receive targeted therapy is of utmost importance. Somatostatin analogs currently are being used to treat growth hormone producing pituitary adenomas and GEP-NETs [16]. Investigation of somatostatin receptors (sst) with IHC in pituitary adenomas may predict and also validate the effectiveness of targeted therapy with somatostatin analogs [17]. PET scans can evaluate the effectiveness of octreotide therapy in pituitary adenomas, as this technology demonstrates tumor functional activity. PET images with 11C-methionine from patients with acromegaly demonstrate high metabolism in the pituitary adenoma before treatment and a considerable decrease in metabolism after treatment with somatostatin analogs [18]. Octreotide scan and PET scan images are also useful for detection of GEP-NETs [19,20]. Octreotide is a somatostatin analog that preferentially binds to sst2A, sst2B and sst5, although new analogs binding other sst receptor types recently have been introduced to treat thyroid-stimulating hormone producing pituitary adenomas [21]. In addition, the presence of both sst and dopamine type 2 receptors (D2r) helped to improve the outcome of patients with GEPNETs [22]. New treatment modalities have emerged with the introduction of temozolomide in the management of pituitary adenomas. MGMT (0–6 methylguanine DNA methyltransferase) marker is a DNA repair enzyme. Patients with adenomas showing low MGMT expres-
G. Kontogeorgos / New horizons in endocrine tumors
sion respond to temozolomide, while those with strong expression are resistant. Specific antibodies are currently available to localize MGMT. Therefore, detection of MGMT by IHC is strongly recommended before the administration of temozolomide [23].
5. Classification of endocrine tumors Despite the progress made, in some instances, the accuracy of morphological diagnosis in endocrine lesions remains questionable. Similarities among normal elements, hyperplastic conditions, and benign or malignant lesions make separation difficult. Unfortunately, in such cases, the diagnostic contribution of IHC and even of molecular techniques remains limited. The “gray zones” representing the overlapping in the sequence of normal parenchyma/ hyperplasia/ adenoma/ carcinoma signify a difficult and controversial diagnostic task, which merits special attention. The pathologist’s role is to make the correct diagnosis by differentiating malignant lesions from benign lesions and further proceeding to accurate classification. In cases in which this cannot be achieved, the pathologist has to approach tumor malignant potential. According to the classifications of endocrine tumors in the WHO books, specific guidelines using morphology and IHC markers have been proposed for each endocrine organ [24]. Adenomas comprise the substantial majority of pituitary tumors. The WHO classifies adenohypophysial tumors into three categories: adenomas when the Ki-67 labeling index (LI) is less than 3%, atypical adenomas suggesting aggressive potential and malignant transformation, which show increased (> 3%) Ki-67 LI and p53 immunoreactivity. As a rule, carcinomas show Ki67 LI more than 10% and extensive immunoreactivity for p53. However, the term pituitary carcinoma can be used only when metastases are well documented [25]. The WHO classification of GEP-NETs includes well-differentiated NETs grade 1 with Ki-67 less than 2%, well-differentiated NECs grade 2 with Ki-67 between 2–20%, and poorly differentiated NECs grade 3 with Ki-67 more than 20% [26]. Parathyroid lesions are divided into adenomas that occur as a single lesion representing 80% of primary hyperthyroidism, hyperplasia that affects multiple glands including patients with MEN-1 syndrome and carcinomas that are very rare, occurring in less than 1% of primary hyperthyroidism. The modern diagnostic approach includes: careful localization or
165
at least lateralization by preoperative radiologic tests (sestamibi scan), surgical neck exploration, and removal of the abnormal gland. A decrease by more than 50% of parathormone levels by intraoperative rapid assay confirms the excision of adenoma. Fat stain is accurate in 85% of cases and the histologic diagnostic accuracy 99.2% [27]. By IHC, parafibromin shows nuclear staining in patathyroids, whereas it is usually absent in carcinomas [28]. Thyroid cancer is a rare oncological entity, representing no more than 1% of all human malignant neoplasms. However, it is the most common malignant endocrine neoplasia whose incidence has progressively increased over the past two decades [29]. Histological separation of hyperplasia from neoplasia is of great importance for thyroid lesions. In hyperplasia, there are multiple nodules, poorly encapsulated, with architectural and cytological heterogeneity. There is no compression of the surrounding parenchyma, which also shows comparable areas. In contrast, neoplasia represents a solitary, encapsulated nodule with uniform architecture and cytology. The space-occupying neoplastic nodule compresses the surrounding parenchyma, which exhibits different histology than that of the nodule. The distinction between follicular adenoma and follicular carcinoma is based on the absence of nuclear features of papillary carcinoma and the invasive features of the tumor [30]. Papillary thyroid carcinoma is defined by the presence of a unique set of nuclear features. They include pale, enlarged and vacuolated overlapping nuclei, with peripheral distribution of chromatin, irregular nuclear membrane and presence of pseudoinclusions, which refer to as “orphan Annie eye” [31]. A study using three-dimensional reconstruction of papillary thyroid carcinoma has shown that nuclei appear to bear either grooves or holes, due to profound remodeling of the nuclear shape with invaginations and tunnels [32]. By IHC, emerin identifies nuclear features of papillary thyroid carcinoma, which represents an effective tool for the detection of nuclear irregularities, allowing identification of such cases [33]. Primary adrenal cortical tumors include adenomas and carcinomas, which are rare in general clinical practice. They may present clinically with hypersecretion of steroid hormones or with general signs of malignancy. Incidental adrenal tumors measuring < 1 cm in autopsy series range from 1.4% to 8.7% (mean 2.33%). They are more commonly identified by imaging techniques, with their incidence reaching up to 4.2% when the abdomen is scanned in the investigation of other
166
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intra-abdominal disease [34]. Distinction between a benign adrenal lesion and carcinoma is very important. Carcinoma is a rare, but highly aggressive tumor, accounting for 0.05 to 2% of all malignancies. Many carcinomas are easy to diagnose, as they are infiltrative or have distant metastases at the time of presentation. Histologically, marginal adrenal cases are impossible to differentiate, particularly lesions that have not yet developed invasion or metastasis. It should be noted that there is no single histological feature that defines malignancy. For this reason, several multifactorial systems have been proposed for a diagnostic approach. However, not all systems assess the same morphological features. Some of these combine biochemical, clinical, and histology findings. Unfortunately, as a rule, in routine practice, clinical information is not available or is not considered. The most important system to approach the malignant potential is that proposed by Weiss and modified by Aubert. It uses several histologic criteria. The presence of more than three criteria favors malignancy [35]. The proliferation marker Ki-67 (clone MIB-1) represents an alternative feature to mitotic counting. However, relevant studies have shown an increased labeling index in carcinomas of more than 3% [36]. Pheochromocytomas represent the most important tumors of the adrenal medulla. Approximately 10% occurs in the settings of various familial syndromes. Sporadic tumors are solitary, whereas in familial disease, tumors are mostly bilateral and often coexist with extra-adrenal paragangliomas. Familial tumors tend to occur in younger individuals [37]. The pheochromocytoma of the adrenal gland scaled score (PASS) is the most important multifactorial system that utilizes various histologic criteria to approach the malignant potential of pheochromocytomas. A score equal to or more than four suggests potential malignant behavior [38]. For histologically marginal cases, more precise guidelines are needed, by improving the currently available criteria, to minimize the “gray zones”, leading to a more accurate separation of such endocrine lesions.
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