Fine Needle Aspiration Biopsy of the Adrenal Gland: Cytological Features and Clinical Applications
Kenneth C. Suen, M.D., FRCP(C), and Norman H. Chan, M.D., FRCP(C)
Abstract
The ability to visualize the adrenal glands with modern imaging techniques has improved our detection of small adrenal masses. In cancer patients, metastatic tumors to the adrenal glands are common, but not all adrenal masses are metastases. Percutaneous fine needle aspiration biopsy can be used in distinguishing metastatic malignancies to the adrenal glands from pri- mary adrenal lesions. In our series we achieved a success rate of 86% in obtaining cellular ma- terial for diagnosis. A diagnosis of metastatic malignancy obviates the need for surgical inter- vention and is essential for staging and therapeutic planning. Primary adrenal cortical masses with benign cytology and under 5 cm in size can be managed conservatively with follow-up scans; those with atypical cytology or greater than 5 cm in size warrant surgical exploration. Adrenalectomy is the treatment of choice for any adrenal tumor associated with endocrine abnormality, irrespective of tumor size and cytology. Endocr Pathol 3:173-181, 1992.
Departments of Pathology, Vancourver General Hospi- tal (KCS) and St. Paul’s Hospital (NHC), University of British Columbia, Van- couver, B.C., Canada.
Address correspondence to Dr. Kenneth Suen, Depart- ment of Pathology, Vancou- ver General Hospital, 855 West 12th Avenue, Vancou- ver, BC V5Z 1M9, Canada.
@ 1992 Blackwell Scientific Publications, Inc.
Before the advent of modern imaging tech- niques, one often had to resort to technically difficult procedures, such as venography or arteriography, to visualize the adrenal glands. With the advent of ultrasound, computed tomography (CT), and magnetic resonance imaging, small masses in the adrenal glands are readily visualized and aspirated, resulting in an increased demand for the cytopathology laboratory to interpret these specimens [12, 16, 34]. Interpretive difficulties will arise if the pathologist does not have sufficient training in this area. Unfortunately, the literature contains few detailed cytological descriptions of adrenal lesions. The purpose of this review is twofold: to familiarize pathologists with the cytological features of adrenal gland lesions and to suggest a practical approach to the investigation of adrenal lesions, with particular reference to the application of fine needle aspiration biopsy (FNAB).
Aspiration Technique
Fine needle aspiration biopsy of abdominal organs, performed by interventional radiolo- gists using a 15 or 20 cm long, 22 gauge spinal or Chiba needle under ultrasound or CT guidance, has been described in detail in the radiological literature [4, 9, 22]. Adrenal masses can be aspirated through the anterior abdominal wall with patients supine or via a lumbar approach with patients in a prone position. The posterior approach is more likely to cause pneumothorax because of the proximity of the posterior costophrenic lung region to the upper poles of the kidneys. Some investigators prefer to aspirate the right adrenal gland, using the right transhepatic approach in the supine position [3, 4]. Two needle passes are performed routinely for
each lesion, and more are required when special studies, such as immunocytochemis- try or electron microscopy, are deemed necessary. A cytotechnologist is in attendance
to ensure optimal preparation of slides. For routine light microscopical examination, mul- tiple ethanol-fixed smears and cytospin prep- arations are made and stained with hematoxy- lin and eosin or with the Papanicolaou stain. In addition, cell blocks are made if tissue fragments are visible and can be retrieved from the aspirates.
Diagnostic Accuracy
In a study of 22 patients who had undergone adrenal FNAB, Katz and co-workers [12] reported an overall sensitivity of 85% in detecting malignancy. The number of cases correctly classified for all adrenal masses was 90%. The specificity was 100% for malignant lesions. Heaston and associates [9] performed percutaneous FNAB of adrenal masses in 14 patients. Diagnostic material was recovered in 13 of the 14 cases (93%). One false-negative diagnosis was attributed to inadequate sam- pling. There were no false-positive diagnoses. In a study by Berkman and associates [3], the success rate in obtaining diagnostic material was 94% (15 of 16 cases) and the diagnostic accuracy rate was 100%. There were no false-positive or false-negative examinations. The largest series has been reported by Saboorian and colleagues [24], who per- formed 157 adrenal FNABs and achieved an overall diagnostic accuracy rate of 85% (133 cases).
We recently analyzed our experience consisting of 57 cases of adrenal FNAB performed in a 3-year period from 1987 through 1989. Our experience prior to 1987 had been reported elsewhere [31]. In the present series, an adequate cellular sample for interpretation was obtained in 49 of the 57 cases (86% success rate). The 8 unsatisfactory aspirations included 2 metastatic malignan- cies and 6 benign adrenal masses; the 49 cases of satisfactory FNAB included 27 (55%) metastatic tumors and 22 (45%) primary adrenal lesions. In the group of metastatic tumors diagnosed by FNAB, there were no false-positive results: all the diagnoses of metastatic malignancy were confirmed by clinical follow-up or autopsies. The sensitiv- ity of FNAB in detecting metastatic tumors was 93% and the specificity was 100%. The 22 primary adrenal lesions evaluated by FNAB included 13 cases of benign cortical nodules
or adenomas, 3 adrenocortical carcinomas, 3 adrenal cysts, and 2 pheochromocytomas. A fourth case of cytologically diagnosed adreno- cortical carcinoma proved to be renal cell carcinoma on laparotomy. In addition, an aspirate of a retroperitoneal mass interpreted on FNAB as epitheloid leiomyosarcoma subsequently proved to be a pheochromocy- toma. All the cortical nodules/adenomas were asymptomatic masses discovered in the investigations of patients who had nonadrenal malignancies or diseases unrelated to the adrenal gland. The size of the lesions varied from 1.5 to 4 cm. The adrenocortical carcinomas ranged from 6 to 14 cm in diameter and were associated with loin pain or discomfort.
Clinical Applications of FNAB
O’Leary and Ooi [25] reviewed 95 cases of incidentally discovered adrenal masses (inci- dentalomas) reported in the literature up to 1986. Seventy-one of these incidentalomas were managed surgically. A variety of condi- tions were identified: adrenocortical adeno- mas (30 cases), metastases (17 cases), pheo- chromocytomas (4 cases), cysts (9 cases), and myelolipomas (5 cases). But no cases of adrenocortical carcinoma (ACC) presenting as an incidentaloma were diagnosed. On the basis of this extensive review, the authors recommended a conservative approach, using percutaneous needle biopsy and hormonal evaluation, to the management of these lesions. Our study and studies of others (see above) have confirmed the practicality of this approach. FNAB is an appropriate initial diagnostic procedure, providing morphologi- cal diagnoses without necessitating open surgical biopsy.
Patients with a Known Nonadrenal Malignancy
Metastases to the adrenal glands are common, especially those from the lung, breast, and melanoma [1, 5, 29]. However, not all adrenal masses represent metastases. In a series reported by Belldegrun and associates [2], 73% of the adrenal masses were metasta- ses and the other 27% had an unrelated benign adrenal lesion. In this clinical setting, differentiation between metastatic carcinoma
A
B
and intrinsic adrenal tumor by FNAB is not difficult because the number of likely diag- noses is limited (metastasis vs. adrenal nod- ule) and metastases generally have a morpho- logical appearance different from the normal cortical cells or cortical tumors [3, 4, 9, 13, 22].
Patients with No Nonadrenal Malignancy
When an adrenal mass is detected incidentally by abdominal imaging in a patient who has no evidence of an extraadrenal malignancy, the differential diagnosis in this clinical setting is between benign and malignant primary adre- nal lesions. Screening for excessive hormone production should be performed to rule out a functioning adrenocortical neoplasm, pheo- chromocytoma, or neuroblastoma. Adrenalec- tomy is the treatment of choice for any adrenal tumor associated with endocrine abnormality, irrespective of whether it is benign or malignant. As for the nonfunction- ing adrenal incidentalomas, the great majority will be benign adenomas or nodular hyperpla- sia, as ACC is very rare, afflicting 1 in 1,500,000 population [28]. We as well as others [14, 21, 25, 28] have shown that cortical adenomas are small tumors seldom more than 4 cm in size. On the other hand, ACCs are large tumors (>5 cm), although small ACCs have rarely been reported [7].
Weiss [35] observed that the median size of cortical carcinoma was 14 cm, while that of nonrecurring, nonmetastasizing cortical tu- mors was 2 cm. On the basis of our experience and literature review [9, 13, 21, 25], we believe that the great majority of incidentally discovered adrenal masses can be safely managed conservatively, provided that the lesion is under 5 cm in size and shows benign cytology on FNAB, and subsequent scans do not indicate unabated growth. Lesions that are more than 5 cm in size or show atypical cytology should be surgically excised.
Cytological Interpretation
The following descriptions of adrenal cytol- ogy are not limited to the cases analyzed in the 3-year period outlined above, but are based on the authors’ overall experience accumulated since 1978 and on literature review.
Normal Adrenal Cytology
On an aspirate smear, the cells of normal adrenal cortex are arranged in small aggre- gates or thin cords of uniform polygonal cells. Two types of cortical cells are generally seen. The dominant cells are the clear cells (Fig. 1A), which have vacuolated cytoplasm owing to the accumulation of cytoplasmic fat drop- lets. The nuclei are small, round, and centrally located, with fine chromatin and small or inconspicuous nucleoli. The nuclear- cytoplasmic (N/C) ratio is low. These clear cells are derived mostly from the zona fasciculata. The second cell type consists of smaller polygonal cells, characterized by eosinophilic cytoplasm and absence of cyto- plasmic vacuolation (Fig. 1B). These cells correspond to the compact cells of the zona reticularis. The cells of the adrenal medulla are usually scant or absent on aspiration specimens. If present, they are polygonal cells (Fig. 2) that show large slightly eccentric nuclei, distinct nucleoli, with salt-and-pepper- type nuclear chromatin pattern. The moder- ately abundant cytoplasm is cyanophilic and finely granular.
Diagnostic Pitfalls Mitchell et al. [20] re- ported a case in which the cells of a metastatic
adenocarcinoma from the lung were mis- taken for normal adrenal cortical cells. In our experience, metastatic malignancies to the adrenal glands generally show obvious cyto- logical features of malignancy. False-negative diagnoses are due mostly to sampling rather than interpretative errors. Misinterpretation of metastatic malignant cells as normal adrenal cells is caused usually by inexperience.
Adrenocortical Nodule/Adenoma
Aspiration Cytology The cytological fea- tures of cortical nodule and adenoma are similar and are described together here. On an aspirate smear, the cells of cortical nodule/adenoma are arranged in small cords or in a vague nesting pattern. Both lipid-rich, vacuolated cells and compact cells can be seen, either in combination or alone. The morphological appearance of these cells is similar to the normal cortical cells, although
enlarged hyperchromatic nuclei may at times be present. In some adenomas, there may be cellular atypia and giant cells (Fig. 3). However, atypia alone, especially when it is minimal, is not indicative of malignancy. The process of aspiration and smearing may disrupt the cell membranes of many lipid- rich cells, releasing fat droplets onto the background and many naked nuclei that closely mimic small lymphocytes.
Diagnostic Pitfalls and Comments Since ade- noma cells and normal cortical cells may be indistinguishable from one another on FNAB, it is imperative to verify the location of the biopsy needle by CT to ensure its correct placement within the suspected mass. Hence, the performance of adrenal FNAB requires a skilled and experienced operator. Without this placement verification, the pathologist can confuse the recovered normal cortical cells for neoplastic cells of an adenoma, when in fact the normal part of the cortex has been aspirated.
In some cases of adenoma, cellular pleomorphism may be seen. This is usually focal and associated with a background population of bland monomorphic cells, unlike the diffuse pleomorphism seen in many of the adrenal cortical carcinomas.
The naked round nuclei of the cortical cells may mimic lymphocytes. On occasion, these naked nuclei are present in such large numbers that they may be mistaken for lymphoma cells. The presence of fat droplets admixed with the naked nuclei and their resemblance to the nuclei of the other cortical cells aid in identifying the true nature of these cells.
The naked nuclei of the adrenal cortical cells have been mistaken for small-cell anaplastic carcinoma [19, 32]. This mistake can be avoided if one looks for the uniform chromatin distribution and staining character- istics of the adrenal cortical cells. Common features of small-cell anaplastic carcinoma, such as smudging, nuclear molding, and cell necrosis, are conspicuously absent in an aspirate consisting only of these benign naked nuclei.
Adrenocortical Carcinoma
Aspiration Cytology On FNAB, cells of adrenocortical carcinoma occur singly or in
loosely cohesive aggregates. Scattered lipid droplets may be seen in the background in some of the cases. Although the proportions of vacuolated clear cells and eosinophilic cells vary from case to case, the eosinophilic cells are generally the predominant cell type. The nuclear changes vary also from case to case. Some tumors show markedly atypical nuclei with irregular chromatin distribution and prominent nucleoli (Fig. 4); others show uniform small nuclei resembling adenoma (Fig. 5). There is no single absolute cytologi- cal criterion indicative of malignancy in adrenal cortical tumors. The sole criterion, as in other malignant endocrine neoplasms, is the presence of metastasis. However, the presence of necrosis, mitotic figures, marked cytological atypia, and large tumor size are strong indicators of malignancy.
Diagnostic Pitfalls and Comments Well- differentiated adrenocortical carcinomas need
to be differentiated from cortical adenomas. In addition to the distinguishing cytological features discussed above, the size of the tumors should be carefully noted. Cortical carcinomas are generally large (>6 cm), small carcinomas being extremely rare [14, 15, 35].
The usefulness of various immunostains in differentiating adrenocortical adenomas from adrenocortical carcinomas is controver- sial at present. Normal cortical tissue and adenomas stain positively for low molecular weight cytokeratin [6], whereas cortical carci- nomas have lost the ability to express cytokeratin when these tumors are formalin fixed, paraffin embedded, and processed as cell blocks [8]. Unfixed adrenocortical carci- nomas may retain cytokeratin expression. The presence of the intermediate filament protein vimentin has been suggested as a useful marker for adrenocortical carcinoma [18] as adenoma rarely expresses vimentin. However, the role of vimentin has been challenged recently by Suzuki et al. [33], who demonstrated vimentin reactivity in all carci- nomas but also in 3 of 6 cases of adenoma. Flow cytometry studies have shown that alterations in DNA content of the tumor cells correlate well with malignant behavior in adrenocortical tumors. This methodology is easily applicable to FNAB specimens and seems to be more promising than immunocy- tochemistry in predicting the behavior of cortical tumors [33].
At the other end of the morphological spectrum, a poorly differentiated adrenocorti- cal carcinoma may be confused with poorly differentiated metastatic tumor on light mi- croscopy. Electron microscopy, immunocyto- chemistry, and attention to clinical history and radiological and hormonal data are helpful in resolving this problem (see below, Neoplasms Metastatic to the Adrenal Gland).
Adrenal Cysts
Adrenal cysts are usually discovered inciden- tally at autopsy but may present as a space-occupying suprarenal mass. The wide- spread use of sophisticated imaging tech- niques will likely disclose more cases that are clinically unsuspected. Most of the adrenal cysts are in fact pseudocysts [10]. The wall is composed of collagenized tissue with few
inflammatory cells. Occasionally, there may be focal calcification in the cyst wall. FNAB provides cloudy, watery, red-brown fluid, which on microscopical examination shows many macrophages, some lymphocytes, and some benign adrenocortical cells.
Myelolipoma
Adrenal myelolipoma is a rare benign lesion. They are generally small and clinically silent, but large tumors producing symptoms of abdominal discomfort have been described. CT scan often demonstrates low-density fatty tissue in the lesion. FNAB, consisting of hematopoietic cells and mature fat cells resembling bone marrow specimens in appear- ance, easily establishes the diagnosis [11, 31].
Pheochromocytoma
Aspiration Cytology Aspirates are moder- ately to markedly cellular, with the cells arranged in dyshesive clusters, syncytia, and single naked nuclei. Tumor cells (Fig. 6) vary considerably in size and shape and have abundant, finely granular, eosinophilic or basophilic cytoplasm with indistinct cellular borders. Single central or eccentric nuclei are noted, with anisonucleosis and nuclear pleo- morphism. Nuclear chromatin pattern ranges from reticular with a single prominent nucleolus to diffuse hyperchromasia with a coarsely granular chromatin pattern and
inconspicuous nucleoli. Three principal types of tumor cells have been described. The predominant cells are the small to medium- sized, uniform, polygonal cells containing moderately abundant granular cytoplasm and oval nuclei with fine reticular chromatin. These are the prototypic cells of neuroendo- crine neoplasm. The second type are the large multinucleated cells with bizarre hyperchro- matic nuclei and voluminous, eosinophilic, foamy or granular cytoplasm. Frequently, one recognizes gradations between these two types. The third type consists of spindle- shaped cells with elongated nuclei and indistinct cytoplasmic borders.
Diagnostic Pitfalls FNAB of catecholamine- producing tumors is not without risk-a case of fatality following fine needle aspiration has been reported [17]. If a biochemical diagnosis of pheochromocytoma has already been established, FNAB is not indicated. Most FNAB have been performed on clinically unsuspected adrenal pheochromocytomas or extraadrenal paragangliomas.
Owing to the variable cytological appear- ance of pheochromocytoma and its rarity, FNAB diagnosis may present a problem to the unwary. The bizarre giant cells and the spindle cells of the neoplasm have led us [31] and many others [23, 24, 26] to misdiagnose pheochromocytomas as a sarcoma or other unclassifiable malignancy. Diagnostic errors can be prevented by identifying the uniform polygonal cells with slight eccentric nuclei and granular cytoplasm, which are character- istic of cells of neuroendocrine lineage. If the diagnosis of pheochromocytoma is suspected, confirmation by a positive argyrophil stain or an immunostain for chromogranin can be performed.
Neuroblastoma
Aspiration Cytology The aspirates (Fig. 7) are generally cellular and consist of small round cells with hyperchromatic nuclei, coarsely stippled chromatin, and scanty cyto- plasm. Each nucleus contains one or two small nucleoli. The nuclear membranes may occasionally show lobulation. The tumor cells are arranged singly or in loosely cohesive clusters. Rosette formations are seen in about 50% of the cases and are formed by radial arrangement of cells around a space contain-
2
ing eosinophilic neurofibrils. Similar fibril- lary material may be seen in the smear background. Maturation of neuroblastoma is indicated by an admixture of small neuro- blasts and variably mature ganglion cells. Ganglion cells are characterized by large cell size, eccentric nuclei, prominent nucleoli, and abundant cytoplasm.
Diagnostic Pitfalls and Comments The cyto- logical features alone may not be sufficient to make a diagnosis of neuroblastoma, because on FNAB it may be confused with other small round cell tumors, such as small-cell anaplastic carcinoma, malignant lymphoma, Ewing’s sarcoma, and embryonal rhabdomyo- sarcoma [30]. However, when FNAB cytol- ogy is combined with a complete clinical history, physical examination, radiological findings, and laboratory studies, a diagnosis of neuroblastoma can often be rendered.
Neoplasms Metastatic to the Adrenal Gland
The cytological diagnosis of metastases to the adrenal gland is usually straightforward. Squamous cell carcinoma, anaplastic small- cell carcinoma, adenocarcinoma, and malig- nant lymphoma should present no interpre- tive difficulties because of the different appearance of these tumor cells from the
adrenal cells. However, adrenocortical carci- nomas may be difficult to distinguish from metastatic carcinomas that are composed of large polygonal cells with eosinophilic or clear cytoplasm, such as renal cell carcinoma, hepatocellular carcinoma, malignant mela- noma, and poorly differentiated adenocarci- noma. A history of previous extraadrenal malignancy, laboratory evaluation of plasma and urinary steroid profiles, and special studies (e.g., cytochemistry, immunocyto- chemistry, and electron microscopy) are additional aids to an accurate diagnosis. Evidence of mucin production demonstrated by a mucicarmine stain or a periodic acid- Schiff (PAS) stain with diastase digestion is a simple way to identify metastatic adenocarci- noma. Renal cell carcinoma is particularly difficult to distinguish from ACC due to their close topographic relationship and their cyto- logical similarities (both show clear cells and eosinophilic cells). Ultrastructurally, cells of ACC show features typical of steroid- secreting cells, such as abundant smooth endoplasmic reticulum and characteristic mi- tochondria with tubulovesicular cristae, which serve to distinguish adrenocortical cells from those of metastatic tumors. Moreover, renal cell carcinoma and ACC have different immunocytochemical profiles: the former expresses cytokeratin, vimentin, as well as Lewis blood cell isoantigens [6], whereas the latter expresses vimentin but has lost the ability to express low molecular weight cytokeratin in fixed tissue. A similar diagnos- tic problem exists between hepatocellular carcinoma and adrenal cortical tumor. Cells of hepatocellular carcinoma, in general, resem- ble liver cells. Evidence of bile production, the presence of PAS-positive cytoplasmic hyaline globules, immunostaining of bile canaliculi by carcinoembryonic antigen, the ability to express cytokeratin in fixed tissue, and a high serum level of a-fetoprotein are all useful markers for hepatocellular carcinoma. Metastatic melanoma can be identified by the uniformly prominent nucleoli, eccentric nu- clei imparting a plasmacytoid appearance, granular cytoplasm with or without melanin pigment, and strong immunoreactivity for S-100 protein. Malignant melanoma must always be considered in the differential diagnosis of any poorly differentiated epithe- lial malignancy; otherwise, melanoma will often be missed.
Conclusion
We have described in detail the cytological features of various adrenal lesions commonly encountered in fine needle aspirates. We believe that imaging-guided FNAB of adre- nal masses should be performed as a prefera- ble alternative to an open surgical biopsy. In an appropriate clinical setting, a diagnosis of metastatic disease would eliminate the need for surgical intervention. It is possible to follow incidentally found adrenal masses without surgery in patients with no endocrine abnormalities, if the lesions are less than 5 cm in size and the FNABs are consistent with the various described benign lesions.
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