Handling and Pathology Reporting of Adrenal Gland Specimens $

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1 European Urology European Urology 45 (2004) Review Handling and Pathology Reporting of Adrenal Gland Specimens $ M. Scarpelli a,*, F. Algaba b, Z. Kirkali c, H. Van Poppel d a Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), Umberto I8 Hospital, Via Conca, snc, I Torrette, Ancona, Italy b Section Pathology, Fundació Puigvert, Autonomous University of Barcelona, Barcelona, Spain c Department of Urology, School of Medicine, Dokuz Eyül University Izmir, Turkey d Department of Urology, University Hospital, KU Leuven, Leuven, Belgium Accepted 18 December 2003 Available online 11 January 2004 Abstract Proper treatment of resection specimens by the urologist and pathologist is critical in accurately reporting tumors and tumor-like nodules of the adrenal gland. Clinically inapparent adrenal masses are discovered, with increasing frequency, in the course of diagnostic testing or treatment for conditions that are not related to adrenal diseases. As a consequence an increasing number of relatively small tumors lacking the characteristic gross features of malignancy is detected. There is a need for identification of pathological findings that can improve the diagnostic accuracy and predict patient outcome. The aim of this paper is to review the handling and pathology reporting of adrenal gland specimens in the light of recent advances in this field of pathology. # 2004 Elsevier B.V. All rights reserved. Keywords: Adrenal gland tumors; Sampling; Pathology reporting 1. Introduction With increasing frequency clinically inapparent adrenal masses are discovered in the course of diagnostic testing or treatment for clinical conditions that are not related to adrenal diseases. As a consequence an increasing number of relatively small tumors lacking the characteristic gross features of malignancy is detected. On the other hand, adrenal tumors present, traditionally, the pathologist with a number of problems including differentiation of benign cortical nodules and other hyperplastic conditions from adenomas and identification of malignant cortical tumors. There is also a need of finding new features that can $ This publication is made under the auspices of the European Society of Uropathology (a full section office member of the European Association of Urology, EAU) and the Uropathology Working Group (European Society of Pathology, ESP). * Corresponding author. Tel. þ ; Fax: þ address: m.scarpelli@univpm.it (M. Scarpelli). accurately predict patient outcome either in cortical or medullary tumors. The aim of this paper is to review the handling and pathology reporting of adrenal gland surgical specimens in the light of recent advances in this field of pathology. 2. The role of the urologist Either open or laparoscopic adrenalectomy is an acceptable procedure for the resection of adrenal masses. Relative contraindications to laparoscopic adrenalectomy have been considered a definitive or presumed diagnosis of invasive adrenal cortical carcinoma or large tumors. Accurate preoperative adrenal imaging by using computerized tomography (CT) scans, magnetic resonance imaging (MRI), scintigraphy with I-m-iodobenzylguanidine (MIBG) and dynamic gadolinium-enhanced MRI with chemical shift is very helpful in the identification of pheochromocytomas and /$ see front matter # 2004 Elsevier B.V. All rights reserved. doi: /j.eururo

2 M. Scarpelli et al. / European Urology 45 (2004) potentially malignant cortical tumors. For this reason, laparoscopic adrenalectomy is increasingly used as a standard treatment for pheochromocytomas and cortical tumors preoperatively classified as benign [1]. Very rarely, for larger lesions, the specimen is morcellated in laparoscopic retrieval bags thus rendering the appropriate macroscopic definition of surgical margins impossible. Cytology obtained through CT scan or Ultrasound guided Fine Needle Aspiration biopsy or cytology (FNAB-FNAC) is helpful in the diagnostic evaluation of patients with a history of cancer. A few data are available regarding the utility of FNA in patients without a history of malignancy due to extreme overlap in cytologic features between benign and malignant adrenal cortical lesions and the risk of precipitating hypertensive crisis in pheochromocytomas [1,2]. Whenever possible, immediately after the resection, the intact specimen should be sent unfixed to the pathology laboratory accompanied by an accurate and complete description of relevant clinical findings. That should include, in adjunct to patient identification, the clinical history, results of hormonal and imaging studies and clinical diagnosis. If, for any reason, the specimen cannot be sent to the laboratory immediately it should be put in adequate 10% formalin saline to fix. It is advisable to put the whole specimen in the fixation fluid avoiding any cutting. 3. The role of the pathologist 3.1. Handling of specimen The following steps should be followed when dealing with adrenalectomy specimens: The specimen is oriented (if possible). A careful dissection of fat tissue is carried out. The whole specimen is accurately weighted. The dimensions on the three axes are recorded. The gland is cut into slices 3 5 mm thick perpendicular to the long axis. The dimensions of the tumor(s) are accurately assessed. The macroscopic appearance of the tumor is described, in particular the color and the presence of necrosis and hemorrhage. The appearance of the adrenal remnant is also described, in particular the presence of nodules or cortical atrophy. At this stage, pictures can be taken as well as fresh tissue to be frozen for research purposes or other ancillary procedures. For neuroblastic tumors a slightly different approach is used following guidelines given by the Localized Neuroblastoma European Study Group [3]. In particular: (a) The specimen should be transferred unfixed to the pathology laboratory under sterile conditions. (b) At least 2 pieces, each measuring 1 1 1cm should be taken from viable-appearing areas of the tumor. If there are macroscopic differences on the cut surface, pieces should be taken from all these areas. Each piece is identified with capitals (A, B etc.) and divided in fourths identified by numbers (1 4). Samples A1, B1, etc. should be used to make touch preparations (at least 10) and than put in formalin for histopathologic examination. Samples A2, B2, etc should be put in sterile tissue-culture medium. Pieces 3 and 4 should be snap frozen in liquid nitrogen. (c) The remaining tumor specimen should be fixed in formalin for further examination. The orientation of the specimen is especially useful when hyperplasia of the medulla is suspected since the chromaffin tissue is found mainly in the head and body of the gland. No definite guidelines are available as what should be considered adequate sampling for adrenal tumors. General rules can be followed such as one block of tumor per cm diameter from central and peripheral areas of the tumor including surgical margins. Adequate assessment of the margins is mandatory since it is part of a number of features used to discriminate between benign and malignant cortical tumors. As a consequence every area macroscopically suspect for capsular invasion should be microscopically examined. The adrenal remnant should also be sampled with special attention to nodular areas. Lymphadenectomy is not usually performed for adrenal gland tumors while is mandatory for staging of neuroblastomas. Macroscopic examination is helpful since a series of macroscopic features strongly support a diagnosis of malignancy. Tumor weight was the most useful criterion to distinguish benign (<50 g) from malignant tumors (>100 g) in the series from Tang and Gray [4]. Also the diameter is important since most malignant tumors are larger than 5 cm. Nevertheless those macroscopic features are not absolute indicators of biological behavior since malignant tumors smaller than 4 cm have been described [5]. Hemorrhage and necrosis are also frequent but not constant findings in malignant tumors and since an increasing number of small tumors are discovered by imaging, the probability

3 724 M. Scarpelli et al. / European Urology 45 (2004) Table 1 Classification of adrenal gland tumors a Adrenal cortical tumors Adenoma Carcinoma Myelolipoma Tumor-like adrenal cortical nodule(s) Adrenal medullary tumors Pheochromocytoma Neuroblastoma, Ganglioneuroblastoma Ganglioneuroma Miscellaneous neoplasms and tumor-like lesions Adrenal cyst Primary mesenchimal and neural tumors Metastatic tumors Other a From reference [6] with minor changes. of finding these macroscopic features is proportionally decreasing. 4. Pathology reporting 4.1. Microscopic description Cortical tumors Should include type or subtype of tumor and margins of surgical resection. Descriptive features are also appropriate since a number of histologic features are predictive of malignant biologic behavior in cortical tumors. The histologic classification of adrenal tumors is shown in Table 1 [6]. There are a number of problems in correctly classifying tumors of the adrenal cortex. One of the most common problems arises in the discrimination between nonfunctioning adenomas and hyperplastic nodules. Different features have been used to make this distinction [7,8]. A few authors believe that a differential diagnosis is possible based on a number of histologic features [9]. In general, considerable overlapping exists for most of the features and the morphologic distinction remains difficult and even arbitrary [10]. The problem of differentiating adenomas from hyperplastic nodules arises specifically with patients having primary hyperaldosteronism. In fact Conn s adenomas usually lack definite encapsulation and the non-tumorous cortex often shows hyperplasia of the zona glomerulosa with formation of a broad zone focally or a continuous thickened zone at the periphery of the entire cortex. A high incidence of associated small cortical nodules has been noted by some investigators and described as incidental non-hyperfunctioning cortical nodules possibly related to the underlying hypertension [11]. Recent advances in molecular biology have not clarified this field since a number of nodules diagnosed as hyperplastic have in fact shown a monoclonal pattern. Also the potential sequence hyperplasia to adenoma has not been completely proved [12]. At present a pathologic diagnosis of adenoma should not be made independently from the radiologic and clinical findings. The diagnosis of cortical carcinomas is based on a series of macroscopic as well as histologic criteria. A combination of histologic features has been proposed by different authors to discriminate between benign and malignant tumors [13 15]. The most commonly used system has been proposed by Weiss [13].It takes in consideration 9 histologic features that are reported in Table 2. Benign tumors have always less than 3 features [16]. This system has been widely tested and found very efficient in discriminating malignant from benign tumors. The features taken in consideration are easily identified by pathologists even though for some of them a certain subjectivity and interobserver variation seems to be present. In a recent study the Weiss system has been tested on 49 benign and 50 malignant tumors [17]. It was found that the most reliable criteria were mitotic rate and necrosis followed by abnormal mitoses, eosinophilic cytoplasm and capsular invasion. Nuclear grade and venous invasion Table 2 Histologic criteria for malignancy in adrenal cortical tumors a (1) High nuclear grade (grade III and IV according to the criteria of Führnam) (2) Mitotic rate >5 per 50 HPF (10 HPF in each of the five areas that are most suspect to be malignant) (3) Atypical mitotic figures (abnormal distribution of chromosomes or an excessive number of mitotic spindles) (4) Eosinophilic tumor cell cytoplasm (>75% of tumor cells or <25% clear vacuolated cells resembling the normal fasciculata) (5) Diffuse architecture (>33% of the tumor forming patternless sheets of cells) (6) Necrosis (occurring in confluent nests of cells) (7) Venous invasion (endothelial-lined vessel with smooth muscle as a component of the wall) (8) Sinusoidal invasion (endothelial lined vessel in the adrenal with little supportive tissue) (9) Capsular invasion (nests or cords of tumor extended into or through the capsule with corresponding stromal reaction) a From reference [17] with minor changes.

4 M. Scarpelli et al. / European Urology 45 (2004) Table 3 Staging of adrenal cortical carcinoma a Percentage Stage Staging criteria 2.8 I T1N0M0 T1 Tumor <5 cm, no invasion T2 Tumor >5 cm, no invasion 29.0 II T2N0M0 T3 Tumor any size, locally invasive but not involving adjacent organs T4 Tumor of any size with invasion of adjacent organs 19.3 III T1N1M0 N0 Negative regional node(s) T2N1M0 N1 Positive regional node(s) T3N0M0 M0 No distant metastases M1 Distant metastases 48.9 IV Any T any N, M1 T3N1 T4 a From reference [26]. showed lesser reliability which was even lower when architecture and sinusoid invasion were taken into account. Immunohistochemistry can be helpful for the differential diagnosis of adrenal cortical tumors. In particular Inhibin, A103 and Calretinin have been used to distinguish adrenal cortical tumors from medullary tumors, hepatocellular carcinomas and renal tumors [18 20]. Adrenal cortical tumors are usually not graded on histologic grounds. Grading has been applied to adrenal cortical tumors in adults on the basis of mitotic activity. Medeiros and Weiss [21] found that patients having less than 20 mitoses per 10 HPF had significantly longer diseasefree survival. However, other authors were not able to confirm this result [22,23]. There is no TNM staging system published for adrenal gland tumors by the American Joint Committee on Cancer/International Union Against Cancer. The more commonly used staging system for adrenal cortical carcinoma was proposed by MacFarlane [24] and modified by Sullivan et al. [25]. Wooten and King have, relatively recently, reviewed the proportion of patients in each stage at diagnosis as reported in Table 3 [26] Medullary tumors Pheochromocytomas. Pheochromocytomas, the most common adrenal medullary tumors in adults, do not usually pose specific diagnostic problems. In fact the architecture and the morphology of the cells are quite distinctive. Much more difficult it is to identify features that can predict the biologic behavior. Even though increased size and weight are suggestive or worrisome for malignancy a separation between benign and malignant tumors on this basis is not feasible [27,28]. Other macroscopic features such as hemorrhages, degenerative changes and cysts are common either in benign or malignant tumors. Recently, a Pheochromocytoma of the Adrenal gland Scaled Score (PASS) has been proposed [29]. It takes into account 12 histologic features that are weighed according to their suggested sensitivity to detect malignant tumors as shown in Table 4. This scoring system has been tested on 100 adrenal pheochromocytomas that were followed up for a sufficient period of time and it has been shown that tumors with a PASS value 4 have a potential for a biologically aggressive behavior. Due to the extreme uncertainty in predicting biological behavior in pheochromocytomas, a number of potential markers have been studied in recent years. Among them, telomerase activity [30], immunohistochemical expression of Tenascin [31] and angiogenesis and vascular architecture [32] have given encouraging Table 4 Pheochromocytoma of the Adrenal gland Scoring Scale (PASS) a Feature Large nests or diffuse growth 2 (>10% of or volume) Central (middle of large nests) or confluent 2 tumor necrosis (not degenerative change) High cellularity 2 Cellular monotony 2 Tumor cel spindling (even if local) 2 Mitolic figures >3/10 HPF 2 Atypical mitolic figure(s) 2 Extension into adipose tissue 2 Vascular invasion 1 Capsular invasion 1 Profound nuclear pleomorphism 1 Nuclear hyperchromasia 1 Total 20 a From reference [29]. Score if present (no. of points assigned)

5 726 M. Scarpelli et al. / European Urology 45 (2004) Table 5 Classification of neuroblastic tumors a International neuroblastoma pathology classification Schwannian development Category and subtype Shimada classification Neuroblastoma Stroma-poor (Schwannian stroma-poor) None or minimal Undifferentiated Undifferentiated Poorly Differentiated None to minimal to <50% of the tumor tissue Differentiating Differentiating >50% of the tumor tissue Ganglioneuroblastoma, intermixed Stroma-rich (Schwannian stroma-rich) Intermixed Ganglioneuroma (Schwannian stroma-dominant) Dominant Maturing Stroma-rich Well-differentated Mature Ganglioneuroma Proportion of Schwannian stroma-rich/stroma-dominant Ganglioneuroblastoma, nodular Stroma-rich and stroma-poor (nodular) areas, variable (composite Schwannian stroma-rich/stroma-dominant and stroma-poor Nodular a From reference [35]. results that should be tested on more cases before being accepted on clinical practice. The most promising feature seems to be the evaluation of the proliferative activity by means of MIB-1 antibody. The proliferative activity has been studied by different groups of investigators. (for a summary see reference [33]). As promising as it can be this feature has not yet been included among the information to be given in the histologic reporting due to incongruencies in numerically evaluating this feature. Staging is not done for pheochromocytoma. Protocols for handling and reporting adrenal gland specimens are available through the College of the American Pathologists [34]. Also guidelines have been given recently for the handling of incidentally discovered adrenal masses (incidentalomas) through the NIH [35] Neuroblastic tumors Accurately reporting of neuroblastic tumors is mandatory since differences in clinical behavior and responsiveness to current therapeutic schemes are highly dependent on the diagnosis and the evaluation of biologic variables. At present, neuroblastomas are classified, as proposed by the International Neuroblastoma Pathology Committee according to the scheme by Table 6 International Neuroblastoma Staging System a Stage 1 Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymphnodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive). Stage 2A Localized tumor with incomplete gross excision; representative ipsilateral nonhaderent lymphnodes negative for tumor microscopically. Stage 2B Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically. Stage 3 Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement or localized unilateral tumor with contralateral regional lymph node involvement or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. Stage 4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined by stage 4S) Stage 4S Localized primary tumor (as defined for stage 1, 2A or 2B) with dissemination limited to skin, liver, and/or bone marrow. Limited to infants <1 year of age. a From reference [39].

6 M. Scarpelli et al. / European Urology 45 (2004) Fig. 1. (A) Cortisol producing adenoma. Female, 57-year-old. Bright yellow nodule, 6:5 5 4:3 cm, gm, with small areas of adipose tissue suggestive for myelolipoma. (B) Adrenal cortical carcinoma. Male, 64-year-old. This tumor measured 9.5 cm and weighted 300 g. The capsule is infiltrated and the cut surface has a variegated pattern. (C) Pheochromocytoma of the adrenal gland. Female, 45-year-old. Well circumscribed nodule, 6:5 5:5 cm, g, the cut surface is gray-tan, homogeneous. (D) Adrenal cortical adenoma. The tumor cells are arranged in small nests and have clear cytoplasm; there are also small areas in which the cells have eosinophilic cytoplasm. (E) Adrenal cortical carcinoma. The growth pattern is solid, there is nuclear pleomorphism and the cytoplasms are eosinophilic. Mitoses are easily found. (F) Pheochromocytoma. The tumor cells are arranged in the characteristic zellballen architecture. Nuclear pleomorphism is mild and mitotic figures are absent. Shimada et al. [36] with minor modifications [37]. The classification distinguishes favorable and unfavorable histology groups and is reported in Table 5. The following additional histologic features are evaluated in each of the subtypes of neuroblastoma: mitosiskaryorrhexis index, mitotic rate and calcification since they are correlated with clinical behavior. Details for the evaluation of each feature are available [38].

7 728 M. Scarpelli et al. / European Urology 45 (2004) The International Neuroblastoma Staging System (INSS) has been revised in 1993 [39] and implemented worldwide. It is reported in Table 6. Fig. 1A F, illustrate the macroscopic and histologic aspect of the most common adrenal tumors. 5. Conclusions Correct handling of adrenal specimens allows for accurate diagnosis which is based on the identification of multiple histological features. Immunohistochemistry can help in distinguishing adrenal cortical neoplasms from pheochromocytoma and other carcinomas. MIB-1 immunostaining is a promising feature to predict malignant behavior. Acknowledgements This paper is one of the seven dedicated to standardization of handling and pathology reporting in uropathology. The additional six deal with kidney, bladder, prostate biopsies, radical prostatectomies, testis and penis. 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