Sampling of the Adrenal Glands by Endoscopic Ultrasound- Guided Fine-Needle Aspiration
Edward B. Stelow, M.D.,1* Steven M. Debol M.D., Ph.D., 2 Michael W. Stanley, M.D., Shawn Mallery, M.D.,4 Rebecca Lai, M.D., 4 and Ricardo H. Bardales M.D.5
Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has proven to be a valuable modality for the primary diagnosis and staging of gastrointestinal, and perigastrointesti- nal malignancy. Aside from assessing thoracic and abdominal lymph nodes and the liver for metastases, EUS can assess and sample the adrenal glands, which are frequently involved by metastatic disease, but can also harbor benign primary neo- plasms. The cytology files at our institution were reviewed for all cases of EUS-guided FNA of the adrenal glands. Clinical histories, sonographic findings, and cytologic findings of all cases were reviewed. Results were compared with overall EUS- guided FNA performance and the performance of non-EUS- guided FNA of the adrenal. The utility of cell block immuno- histochemistry (IHC) in these cases was reviewed. Between 1/1/ 00 and 5/15/04 there were 24 cases of EUS-guided FNA of the adrenal gland from 22 different patients (13 men; 9 women) at our institution. This represented 1.4% of overall EUS-guided FNA and 77% of adrenal gland FNA. Patient ages ranged from 37 to 86 yr (mean 69 ± 11 yr). Most patients had other cancers or mass lesions and were being staged at the time of the procedure (19 of 22). Almost all FNAs were of the left adrenal gland (23 of 24). Lesion size ranged from 0.9 to 7.9 cm (mean 2.5 ± 1.6 cm). Diagnostic material was present in all cases when compared with an overall EUS-guided FNA diag- nostic rate of 88%. Material for cell block was present in 21 cases, and IHC was used in 3 cases. Final diagnoses were as follows: cortical tissue consistent with cortical adenoma (19), metastatic adenocarcinoma (3), pheochromocytoma (1), and
“Department of Pathology and Laboratory Medicine, University of Virginia, Charlottesville, Virginia
2Department of Pathology and Laboratory Medicine, VA Health Sys- tem, Minneapolis, Minnesota
3Department of Pathology and Laboratory Medicine, Abbott North- western Hospital, Minneapolis, Minnesota
4Department of Medicine, Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota
5Department of Pathology and Laboratory Medicine, Hennepin County Medical Center, Minneapolis, Minnesota
Data from this study were presented in abstract form at the fall meet- ing of the American Society of Cytopathology in Chicago, IL on Nov 15, 2004.
*Correspondence to: Edward B. Stelow, M.D., University of Virginia Health Sciences, Box 800214, Charlottesville, VA 22908.
E-mail: es7yj@virginia.edu
Received 4 November 2004; Accepted 28 January 2005 DOI 10.1002/dc.20273
Published online in Wiley InterScience (www.interscience.wiley.com).
adrenal cortical carcinoma (1). EUS-guided FNA of the adre- nal gland is primarily used in the staging of other malignan- cies when lesions of the left adrenal are recognized sonograph- ically. Diagnostic tissue is easily obtained, including material for cell block IHC, which allows definitive diagnosis in cases that present difficult differential diagnoses. Diagn. Cytopathol. 2005;33:26-30. @ 2005 Wiley-Liss, Inc.
Key Words: adrenal gland; carcinoma; cortical adenoma; endo- scopic ultrasound; fine-needle aspiration; metastases; pheochro- mocytoma
Endoscopic ultrasound (EUS) has proven to be a powerful modality for the diagnosis of pancreatic, gastrointestinal, and perigastrointestinal lesions.16 This is especially true when the procedure is paired with fine-needle aspiration (FNA), which improves both the sensitivity and specificity of the procedure. Aside from the diagnosis of primary lesions, the combined procedure can also be used to stage malignancy, and lymph nodes and other sites can be sampled either during or after the diagnosis of a primary malignancy.7-9
The adrenal glands are commonly involved both by metastases and primary benign neoplasms (e.g. cortical adenoma). This often creates a diagnostic dilemma during the workup of patients with diagnosed malignancies, who are also noted by imaging or other studies to have con- comitant adrenal lesions. EUS-guided FNA can provide information in these cases as the adrenal glands, espe- cially the left adrenal gland, can be sampled by the proce- dure.10-12 We report our experience with 24 consecutive cases of EUS-guided FNA of the adrenal gland.
Methods
The cytology files between 12/1/00 and 5/15/04 at Henne- pin County Medical Center were reviewed for all cases of EUS-guided FNA of the adrenal gland. Clinical histories, sonographic findings, and cytologic findings of all these .- cases were reviewed. Results were compared with overall performance of EUS-guided FNA and non-EUS-guided FNA of the adrenal. The utility of cell block immunohis- tochemistry (IHC) in these cases was reviewed.
All aspirations were performed by gastroenterologists with specialty training in EUS-guided FNA (SM and RL). 22- and 25-gauge needles were used at the discretion of the gastroenterologists. On-site interpretation was per- formed by a cytopathologist (EBS, SMD, MWS, and RHB). Cell blocks were made in the following manner. Aspirated material was sprayed onto a single slide, by the gastroenterologist. The cytopathologist then made air- dried smears for immediate interpretation and ethanol- fixed slides for later processing at his own discretion. Any remaining material was allowed to clot on the slide and scraped into a container of 10% neutral-buffered for- malin. This material was then processed as per routine histologic procedures. Special stainings were then per- formed at the discretion of the cytopathologist.
Results
Between 1/1/00 and 5/15/04 there were 24 cases of EUS- guided FNA of the adrenal gland from 22 different patients at Hennepin County Medical Center. This repre- sented 1.4% of overall EUS-guided FNA and 77% of adrenal gland FNA. Patient ages ranged from 37 to 86 yr (mean 69 ± 11 yr). Samples were from 13 men and 9 women.
Nineteen of 22 (86%) patients had other cancers or mass lesions and were being staged or potentially staged at the time of the procedure (3 esophageal lesions, 2 gas- tric lesions, 2 duodenal/ampullary masses, 3 lung lesions, 6 pancreatic lesions, 2 renal lesions, and 1 case with dif- fuse lymphadenopathy). Three patients had adrenal lesions as the primary reason for the procedure. Almost all cases were of the left adrenal gland (23 of 24). Lesion size ranged from 0.9 to 7.9 cm (mean 2.5 ± 1.6 cm). Diag- nostic material was present in all cases compared to an overall EUS-guided FNA diagnostic rate of 88%. All seven computed tomography-guided FNAs of the adrenal glands also yielded diagnostic tissue. Material for cell block was present in 21 cases and IHC was used in 3 cases. Final diagnoses were as follows: cortical tissue consistent with cortical adenoma (19), metastatic adeno- carcinoma (3), pheochromocytoma (1), and adrenal corti- cal carcinoma (1).
Discussion
The preoperative staging of malignancy has become important for triaging patients to different treatment modalities. Not uncommonly, non-specific lesions are identified concomitantly with primary malignancies. As these lesions may represent either metastases or other unrelated lesions, they are often sampled before treatment in an attempt to accurately stage the patient’s malig- nancy.
EUS-guided FNA has become a helpful method for the staging of malignancy.16 The method can sample possi-
ble metastases in lymph nodes or other sites at the time of primary diagnosis or later. Studies have shown that the method is especially helpful in the sampling of both pos- sible nodal disease and possible liver metastases. The method also appears valuable for assessing possible adre- nal gland involvement. 10-12
The adrenal glands are commonly involved both with metastases and primary benign neoplasms (e.g. adrenal cortical adenoma). Although radiographic features can be helpful for distinguishing the two, some overlap exists and certainty can rarely be established by radiology alone.13 Tissue sampling of the adrenal gland can then be helpful, as cortical tissue or neoplasms can generally be distinguished from metastatic tumors.
The adrenal glands can be sampled in several ways. Recently, EUS-guided FNA of the left adrenal has been shown to be a relatively effective and safe method.10-12 Although sampling of the right adrenal is more difficult and much less common, occasional lesions have been sampled, especially when they are large. (Our single aspi- rate of the right adrenal gland was the largest mass in our series and extended to abut the wall of the duode- num.) Our data suggests that when sampling of the adre- nal glands is attempted by EUS-guided FNA, material is always procured.
The cytologic features of non-neoplastic adrenal corti- cal tissue and adenomas are indistinguishable and have been well-described.14-19 Aspirates show numerous loose clusters of large cells with abundant foamy cytoplasm with round to oval nuclei that have smooth contours. As the case with most endocrine cytology, anisopoikilonu- cleosis can be focally prominent and has little meaning in and of itself. The background can show single cells with numerous stripped nuclei and is often quite foamy (Fig. C-1). Occasionally, stripped nuclei can clump and rarely raise the question of a metastatic small cell carci- noma.
Distinguishing cortical cells from most metastases is generally not difficult; however, some overlap may be seen, especially with certain metastases such as renal cell carcinoma or hepatocellular carcinoma (HCC). 14,15,17,19-22 Furthermore, although primary malignant lesions of the adrenal gland are rare, both pheochromocytomas and adrenal cortical carcinomas can present with cytologic features that may overlap with those of metastatic carci- nomas. In such cases, ancillary testing, especially cell block IHC, may be helpful.20,2 20,22,23
In our experience, cell block IHC was generally not needed as most of our aspirates showed features of either benign cortical cells or obvious metastatic carcinoma (MC) from a malignancy of which we also possessed tissue for comparison. However, cell block IHC was help- ful in cases of suspected metastatic renal cell carcinoma, adrenal cortical carcinoma, and pheochromocytoma (Fig. C-2).
Fig. C-1
Fig. C-2
Fig. C-3
Fig. C-4
Adrenal cortical cells and cortical cell neoplasms have recently been shown to react with antibodies directed against inhibin and A103, antigens that are not generally expressed in most epithelial neoplasms.20,22 Staining for these two markers will generally allow for a clear distinc- tion of cortical tissue or neoplasms from possible metasta- ses, including renal cell carcinoma and HCC. These markers are also not expressed by pheochromocytomas and may be used in conjunction with chromogranin and S-100 stains to help differentiate cortical neoplasms from medullary neoplasms. Pheochromocytomas will generally react with antibodies directed against chromogranin and synaptophysin and can show S-100 reactivity of the sus- tentacular cells.23 Epithelial differentiation markers such as TTF-1 and CDX-2 may also be helpful in some cases as primary adrenal lesions should not react with either of these two markers.
Differentiating cortical adenomas and carcinomas can be difficult even with the resected specimen and probably
should not be attempted with aspiration cytology of large tumors, since many criteria (e.g. tumor weight) require the actual gross and histologic assessment of the resected specimen.24-26 We were able to diagnose our single case of adrenal cortical carcinoma, as a concomitant liver lesion showing metastatic cortical carcinoma was also sampled (Fig. C-3). In general, cytologic features of malignancy are more common in cortical carcinomas, including increased nuclear to cytoplasmic ratios, increased nuclear and cytoplasmic pleomorphism, increased mitotic figures, and background necrosis.
Pheochromocytomas can also present difficulty cytolog- ically (Fig. C-4). Although the cytology of paraganglio- mas has been well described, significant cytologic overlap can exist between non-neoplastic adrenal medulla and pheochromocytomas, cortical tumors and pheochromocy- tomas, and metastases and pheochromocytomas.23,27-30 Cell block IHC can obviously sort out some of these diffi- culties. Separating malignant and benign pheochromocyto-
mas is not something that should be attempted with cytol- ogy, as it can rarely be accomplished even with histol- ogy. 31
Differentiating non-neoplastic tissue from neoplastic adrenal cortical tissue and medullary tissue will not be assisted by cell block IHC. In such cases, the clinical his- tory and the clinical laboratory may be especially helpful, as both types of neoplasms can have specific chemical findings. Furthermore, paying attention to the EUS-guided FNA with visualization of needle placement within the mass may also be helpful much as assessment of needle placement is helpful for the diagnosis of a soft-tissue lip- oma by aspiration. With direct visualization it seems doubtful that such aspirates should be considered either non-diagnostic or even very non-specific.
Because of the overall make-up of adrenal tissue it may be especially easy to obtain tissue by FNA. In our series, diagnostic tissue was obtained in all cases that biopsy was attempted, and we were able to produce good cell blocks in most cases. We cannot underestimate the assistance a good cell block can have with such cases even when IHC is not judged to be necessary. Routine H&E histology should only be understood as one more tool in a cytopathologist’s kit to be used for the correct diagnosis of a case.
In summary, EUS-guided FNA appears to obtain tissue easily with attempted sampling of the left adrenal gland. The cytology of most lesions is apparent; however, material for cell block can be gathered when needed. The true sensitivity and specificity of this procedure, aside from occasional primary tumors, may be difficult to measure, as most patients will not undergo additional sampling of their lesions. It has been shown, however, that interpretations of cytology samples from adrenal masses sampled with computed tomography guidance as being benign are accurate, suggesting that the radio- graphic or sonographic appreciation of a mass lesion and needle localization with cytologically benign-appearing adrenal cortical cells on FNA are sufficient for the diag- nosis of adenoma.32
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