Differential Diagnosis Of Adrenal Tumors Research Articles

Computed tomography in the differential diagnosis of adrenal tumors

Background. Modern methods of topical diagnostics have high accuracy and can determine the morphological structure of the adrenal tumor with high probability before surgery, but none of them has 100% sensitivity and specificity. Contrast-enhanced computed tomography is most commonly used by clinicians. The criteria for the malignancy of an adrenal tumor determined by this method continue to be discussed.The aim is to evaluate the effectiveness of contrast-enhanced computed tomography in the preoperative diagnosis of adrenal tumors and to analyze errors.Materials and methods. Contrast-enhanced computed tomography was performed in 69 patients with adrenal tumors. After morphological examination of the removed tumors, the effectiveness of preoperative diagnostics was evaluated with the determination of sensitivity and specificity of the method. If the pre- and postoperative diagnosis did not match, the causes of errors were analyzed.Results. The attenuation on unenhanced CT in adenomas ranged from 5 to 36 HU, in adrenocortical cancer — from 26 to 80 HU, in pheochromocytomas — from 25 to 99 HU. The attenuation of adenomas on unenhanced CT was significantly less than with pheochromocytomas (p=0.005) and adrenocortical cancer (p=0.012). In the venous phase, no significant differences were found, and in the delayed phase, the attenuation of adenomas was also significantly less than in malignant tumors (p=0.008, p=0.008). The median of absolute percent contrast washout in adenomas was 85%, in pheochromocytes — 59%, in adrenocortical cancer — 57%. When comparing the diagnosis before and after surgery, its non-coincidence was found in 8 cases (10.39%). Two patients (2.59%) with small tumors (diameter of 15 mm) were diagnosed with adenoma in ­combination with pheochromocytoma and adenoma before surgery. After morphological examination, the diagnosis was changed to adrenocortical cancer in combination with adenoma and «mute» pheochromocytoma.Conclusion. The sensitivity and specificity of contrast-enhanced CT in the diagnosis of adenomas was 95.61% and 94.82%, pheochromocytomas — 95% and 95.08%, adrenocortical cancer — 92.31 and 98.48%. Diagnostic errors of «mute» pheochromocytoma and adrenocortical cancer occurred with small sizes (15 mm) of adrenal tumors.

Adrenal Hemangioma Presenting as an Incidentaloma Clinically Suspicious for Malignancy

Abstract Introduction/Objective Adrenal hemangiomas are rare, benign and non-functioning tumors. Clinical diagnosis can be challenging given that the presentation is usually vague and lesions are often found incidentally during diagnostic imaging performed for other reasons. Methods/Case Report We report a case of a 67-year-old man with history of hypertension, hyperlipidemia, and anemia, arthralgia and joint swelling with unexplained weight loss, which prompted imaging studies. Computed tomography (CT) scan revealed a 5.4 cm mass involving the left adrenal gland. The patient had no clinical manifestations of adrenal medullary or cortical hyperfunction. Biochemical testing performed included urine and plasma metanephrines and aldosterone/renin ratio, which yielded results within normal range. The patient was taking prednisone for hand and ankle swelling, precluding assessment for Cushing’s syndrome. Given the size of the lesion, the possibility of malignancy was considered. The patient elected for a left adrenalectomy. Gross examination revealed a 4.9 cm mass, weighing 54 grams, with a tan-brown, congested cut surface and a thin rim of residual normal appearing adrenal gland parenchyma. Histologic examination of the surgical specimen showed an enlarged adrenal gland predominantly replaced by hemorrhage with foci of thick and thin walled vessels with areas of intermingled adrenocortical elements at the periphery. A diagnosis of adrenal hemangioma was made. Results (if a Case Study enter NA) NA. Conclusion Adrenal hemangioma should be considered in the differential diagnosis of adrenal tumors. Surgical resection is the mainstay of treatment for a large, isolated adrenal mass to exclude malignancy and prevent retroperitoneal hemorrhage.

The First Experience of Using Magnetic Resonance Spectroscopy in the Differential Diagnosis of Adrenal Tumors

Purpose: To improve the differential diagnosis of various adrenal tumors using a two-dimensional (2D) multivoxel 1 H-magnetic resonance spectroscopy (MRS) protocol. Material and methods: The study included 32 patients who underwent examination and treatment from February 2021 to February 2022, who, according to various radiation methods of research, had tumor formations in the adrenal glands. In total, 36 neoplasms were found in the adrenal glands, of which: 10 adenomas in 10 patients (27.8 %), 5 adrenocortical carcinomas in 5 patients (13.9 %), 5 pheochromocytomas in 5 patients (13.9 %), 6 metastatic nodes in 5 patients (16.7 %, 1 patient had 2 metastatic nodes in both adrenal glands), 4 affected adrenal glands with lymphoproliferative diseases with bilateral adrenal involvement in 2 patients (11.1 %), 2 myelolipomas in 2 patients (5.6 %). We evaluated the age and sex of patients, the location of the tumor and its size, as well as the amplitude of metabolites obtained by multivoxel MRS: choline (Cho), creatine (Cr), glutamine/glutamate (Glx), N-acetylaspartate (NAA), lactate (Lac) and their Cho/Cr ratios, Lac/Cr, Cho/NAA, Glx/Cr. Results: Malignant formations of the adrenal glands were larger in size compared to benign ones (p = 0.0265). The size of benign formations ranged from 1.4 cm to 8.5 cm (median 3.2 cm), malignant from 2 to 12 cm (median 5.8 cm). Statistically significant differences in the groups of malignant and benign adrenal neoplasms were determined by the creatine content detected by MRS (p = 0.0323). Creatine content in benign formations was higher and ranged from 0.415 units to 52 units. (median 4.013 units), in malignant — from 0.221 units to 16.6 units (median 2 units). With a threshold value of creatine content less than 3.42 units, the sensitivity of the trait in the differential diagnosis of malignant neoplasms was 73.3 %, specificity 66.7 %, accuracy 79.3 %. The area under the ROC curve (AUC) was 0.703, which corresponds to the good quality of the predictive model on the scale of expert assessments. There was a moderate inverse correlation between the size of the adrenal gland formations and the creatine content in it according to MRS (correlation coefficient –0.432). If the size of adrenal neoplasm increase, the creatine content in it is proportionally decrease. There were no statistically significant differences in the content of other metabolites and their ratios between malignant and benign adrenal neoplasms, also there were no statistically significant differences in the size of neoplasms, gender and age of patients.

Diagnostic Value of Unenhanced CT Attenuation and CT Histogram Analysis in Differential Diagnosis of Adrenal Tumors.

Background and Objectives: Our aim was to verify the optimal cut-off value for unenhanced CT attenuation and the percentage of negative voxels in the volume CT histogram analysis of adrenal masses. Materials and Methods: We retrospectively analyzed the CT data of patients who underwent an adrenalectomy in the period 2002–2019. In total, 413 adrenalectomies were performed. Out of these, 233 histologically verified masses (123 adenomas, 58 pheochromocytomas, 18 carcinomas, and 34 metastases) fulfilled the inclusion criteria and were selected for analysis. The mean unenhanced attenuation in Hounsfield units (HU) and the percentage of voxels with attenuation less than 0 HU (negative voxels) were measured in each mass. Results: The mean unenhanced attenuation with a cut-off value of 10 HU reached a sensitivity of 59.4% and a specificity of 99.1% for benign adenomas. The mean unenhanced attenuation with a cut-off value of 15 HU reached a sensitivity of 69.1% and a specificity of 98.2%. For the histogram analysis, a cut-off value of 10% of negative pixels reached a sensitivity of 82.9% and a specificity of 98.2%, whereas a cut-off value of 5% of negative pixels reached a sensitivity of 87.8% and a specificity of 75.5%. The percentage of negative voxels reached a slightly better area under the curve (0.919) than unenhanced attenuation (0.908). Conclusion: Mean unenhanced attenuation with a cut-off value of 10 HU represents a simple tool, and the most specific one, to distinguish adrenal adenomas from non-adenomas. CT histogram analysis with cut-off values of 10% of negative voxels improves sensitivity without any loss of specificity.

AQP2 as a diagnostic immunohistochemical marker for pheochromocytoma and/or paraganglioma.

Aquaporin2 (AQP2) is water channel protein that is widely distributed among mammalian tissues and plays a major role in water homeostasis. However, little is known about the expression and significance of AQP2 in human adrenal tumors. Thus, we performed an immunohistochemical investigation of AQP2 in normal and neoplastic adrenal tissues. AQP2 protein expression was investigated in 190 adrenal tumor patients using immunohistochemistry. Correlation between protein expression and clinicopathological features was statistically analyzed. We demonstrated immunopositivity for AQP2 in all adrenal medulla-originating tumors, including 96 pheochromocytomas (PCC), 7 metastatic pheochromocytomas (MPCC), and 10 neuroblastic tumors (NT) and 13 extra-adrenal paragangliomas (EAPGL). Whereas, APQ2 was absent from the 52 adrenal cortical adenomas and 2 adrenal cortical carcinomas examined. The 10 metastatic carcinomas examined in adrenal tissue were also negative for AQP2. In 82 (85%) of the 96 samples from patients with PCC, we studied the relationship between clinicopathologic factors and AQP2 expression and our findings suggested that the tumors that exhibited diffuse expression pattern of AQP2 were larger in diameter than those exhibiting focal (P=0.007) or mediate expression pattern (P=0.001). AQP2 protein is significantly expressed in normal adrenal medullary tissues and medullary tumors (including PCC, MPCC and NT) as well as EAPGL. AQP2 expression may indicate the origin of normal adrenal tissues, and its expression in cancer tissue may reflect the maintenance of water metabolism via AQP2 during tumorigenesis. AQP2 may serve as a valuable marker for the differential diagnosis of adrenal tumors.

Utility of contrast-enhanced ultrasound in differential diagnosis of adrenal tumors in dogs.

This prospective case study aimed to clarify the clinical significance of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of canine adrenal tumors. Forty-three client-owned dogs with adrenal tumors were included. All dogs underwent CEUS, which was evaluated qualitatively and quantitatively. The peak signal intensity (PI), time to peak signal intensity (TPI), mean transit time (MTT), upslope, and downslope were calculated for each time-intensity curve. The histopathological diagnosis of each resected mass was compared with the CEUS findings and parameters. Enhancement distribution, vascularity, tortuous nourishing vessels, enhancement pattern, and late-phase enhancement did not differ significantly between adrenal cortical adenoma (CA), adenocarcinoma (CAC), and pheochromocytoma (PHEO) in qualitative assessment. In PHEO, the TPI was significantly more rapid compared with that in CA (P=0.0287) and CAC (P=0.0404). The MTT in PHEO was significantly shorter than that in CA (P=0.0016) and CAC (P=0.0003). Upslope in PHEO was larger than that in CAC (P=0.0406). Downslope in PHEO was significantly larger than that in CA (P=0.0048) and CAC (P=0.0018). A receiver operating characteristic curve analysis demonstrated that the area under the MTT curve yielded 0.91 for distinguishing PHEO from adrenocortical tumors in dogs; an MTT cut-off value less than 6,225 msec yielded a sensitivity of 69%, specificity of 94%, and likelihood ratio of 12.46. CEUS appears to be clinically applicable for the differential diagnosis between cortical and medullary origins of primary adrenal tumors in dogs.

Adrenal cavernous hemangioma: a case report

BackgroundAdrenal cavernous hemangiomas are very rare benign tumors that usually present as incidental findings on abdominal imaging. Preoperative differential diagnosis from other benign or malignant adrenal neoplasms may be challenging.Case presentationA 70-year old man was referred for an 8-cm abdominal mass incidentally discovered on a contrast-enhanced computed tomography (CT) performed to investigate a pulmonary nodule. Biochemical tests ruled out any endocrine dysfunction and iodine 123 metaiodobenzylguanidine whole body scintiscan single-photon emission CT excluded a pheocromocitoma. Findings on magnetic resonance imaging were non-specific and the patient was elected for a left adrenalectomy. Histopathological diagnosis revealed a cavernous hemangioma. A portion of the resected tissue was tested for drug sensitivity to mitotane, doxorubicin, and sunitinib.ConclusionsAdrenal hemangioma is a rare disease but should be included in the differential diagnosis of adrenal tumors. The surgical resection is generally required to exclude malignant disease, resolve pressure-related symptoms, and prevent retroperitoneal hemorrhage. Although specific features in diagnostic imaging are often lacking, if the diagnosis is established preoperatively a laparoscopic adrenalectomy can be performed due to the benign nature of the lesion. Doxorubicin and sunitinib were both capable of reducing primary culture cell viability, this suggest that similar drugs may be useful in the medical treatment of adrenal hemangiomas.

Adrenal myelolipoma: a comprehensive review.

Adrenal myelolipoma is an invariably benign neoplasm of the adrenal gland that is the second most common primary adrenal incidentaloma following adrenocortical adenomas. It is composed of elements of adipose tissue and extramedullary hematopoiesis. Hypotheses on stem cells and hormonal factors have been formulated regarding its pathogenesis that is still obscure. Despite its benign behavior, adrenal myelolipoma is clinically relevant as it might cause significant difficulties in the differential diagnosis of adrenal tumors. We have reviewed 420 cases reported between 1957 and 2017 on adrenal myelolipoma retrieved from PubMed and Scopus databases and also 20 of our case series to provide a comprehensive analysis of their pathology, epidemiological and clinical features. The average age for its diagnosis was 51 years, and no gender difference was observed. The average size of tumors was 10.2 cm. Congenital adrenal hyperplasia was associated to 10% of all cases analyzed, while other adrenal hypersecretory disorders (cortisol, aldosterone) were found in 7.5% of cases. Computed tomography and magnetic resonance imaging can be reliably used for its differential diagnosis. If the diagnosis of an adrenal myelolipoma is unambiguous, and no associated symptoms or hormonal activity are established, surgical intervention is usually not necessary.

Possibilities of radiological methods in diagnostics of adrenal tumors

The aim - to assess the possibilities of ultrasound and computed tomography in the diagnosis and differential diagnosis of adrenal tumors. Results of the study. The paper analyzes the possibilities of ultrasound (US) and computed tomography (CT) in the diagnosis of various nosological forms of adrenal tumors in 54 patients. As according to US and CT the large size of tumors were characterized to pheochromocytoma (PCHC) (78,5 ± 5,3 - 75,6 ± 6,3 mm), small and medium - to corticosteroma (CS) (45,2 ± 2 6 - 45,6 ± 4,3 mm) and aldosteroma (AS) (46,2 ± 7,1 - 45,9 ± 5,4 mm). Adrenocortical tumors were characterized mostly by round or oval shape, to pheochromocytoma in most cases - wrong rounded shape. These morphometric parameters like irregular contours, heterogeneity of structure and presence of inclusions in the structure of tumor was characterized mainly for pheochromocytoma, whereas tumors of the adrenal cortex these signs were absent. Statistically significant differences in density of PCHC (+ 24,2 ± 2,3 UH), CS (+ 13,4 ± 0,3 UH) and the AS (+ 5,1 ± 0,2 UH) in native mode and contrasting (PCHS - + 41,5 ± 6,1 UH; CS - 18,6 ± 0,9 UH; AS - + 12,1 ± 0,4 UH), as well as the time difference of contrast washout (in pheochromocytoma 14,7 ± 0 5 min. at corticosteroma 8,7 ± 0.4 min., and at aldosteroma 6,2 ± 0,4 min.). Due to the small size of the tumor, obesity and meteorism ultrasound was not informative in 3 cases. In all cases, CT permit to determine the location of the tumor definitely and to differentiate their various nosological forms significantly. Conclusion. Ultrasound and CT in the detection and differentiation of adrenal tumors showed high sensitivity and specificity, and the comparison of different clinical signs of adrenal tumors with the revealed CT signs can more accurately suggest adrenal tumor morphology and to be clinically significant in the choice of further treatment approach.

Comparative of dynamic enhanced CT, MRI differential diagnosis of adrenal tumors

Objective To compare the clinical value of dynamic enhanced CT, MRI in differential diagnosis of adrenal tumors. Methods 62 patients with adrenal tumor by pathologically confirmed in our hospital were selected.All patients underwent unenhanced and dynamic enhanced CT, MRI examination.The qualitative and adrenal tumor localization diagnostic accuracy, the adrenal adenomas and non adenoma tumor clearance rate of the two methods were compared. Results The accuracy of enhanced CT positioning, qualitative examination were 96.77%, 90.57%, respectively, which were slightly higher than those of the MRI enhancement(91.94%, 86.79%), but the differences were not statistically significant (χ2=0.479, 0.376, all P>0.05).53 adrenal adenomas and 9 cases non-adenomas absolute and relative clearance rate clearance rate in enhanced CT 5 min delay time, the differences were statistically significant (t=2.962, 2.018, all P<0.05).53 cases adrenal adenomas and 9 cases non adenoma clearance of correction in the enhanced MRI delay 5min, respectively (33.41±20.17)%, (14.74±12.16)%, the difference was statistically significant (t=2.684, P<0.05). Conclusion Dynamic enhanced CT, MRI are good methods for differential diagnosis of adrenal tumors, two methods have location and qualitative diagnosis correct rate.So dynamic enhanced CT, MRI are reliable means of diagnosis of adrenal tumors. Key words: Tomography, computer; Magnetic resonance imaging; Image enhancement; Adrenal gland neoplasms

Use of Contrast-Enhanced Ultrasound in the Differential Diagnosis of Adrenal Tumors in Dogs

We evaluated the diagnostic accuracy of the contrast-enhanced ultrasonography (CEUS), using a second-generation microbubble contrast agent, in differentiating the different types of adrenal mass lesions in 24 dogs. At B-mode ultrasound, 9 lesions involved the right adrenal gland, 14 the left, and 1 was bilateral. Each dog received a bolus of the contrast agent into the cephalic vein, immediately followed by a 5-mL saline flush. The first contrast enhancement of each adrenal lesion was evaluated qualitatively to assess the degree of enhancement and its distribution during the wash-in and wash-out phases, as well as the presence of non-vascularized areas and specific vascular patterns. Pathological diagnoses were determined in all dogs by histopathology or by cytology. Combining enhancement degree and vascularity resulted in the best predictive model, allowing CEUS to differentiate adrenocortical adenoma (n=10), adenocarcinoma (n=7), and pheochromocytoma (n=7) with an accuracy of 91.7% (P < 0.001). Combining enhancement degree and vascularity, CEUS can discriminate malignant versus benign adrenal lesions with a sensitivity of 100.0%, a specificity of 80.0%, and an accuracy of 91.7% (P < 0.001). In conclusion, results of this study confirm that CEUS is useful for differentiating between the different types of adrenal tumors in dogs.

Возможности компьютерной томографии в дифференциальной диагностике опухолей надпочечников

Возможности компьютерной томографии в дифференциальной диагностике опухолей надпочечников

5th International ACC Symposium: Imaging for Diagnosis and Surveillance of Adrenal Tumors--New Advances and Reviews of Old Concepts.

Adrenocortical carcinoma (ACC) is often diagnosed incidentally. However, significant difficulties persist in diagnosing the rare ACC among the very common benign adrenal tumors, which are present in up to 5% of the population. Due to the very low prevalence of ACC, prospective studies are impossible to conduct. Two recent studies took the approach of reviewing preexisting adrenal tumors prior to the diagnosis of ACC. These data challenge current concepts of diagnosis and surveillance of incidentally discovered masses. Oncocytomas (benign and malignant) represent an entity that can be difficult to be diagnosed by radiographic characteristics and even histologically. However, some recent data provides insight into their appearance in imaging procedures. With regards to ACC specific imaging, which could be applied for differential diagnosis of adrenal tumors, surgery planning and surveillance several radionucleotides have been evaluated over the last decades showing promising results. Of particular interest, these substances can potentially be used for therapy as well.

Giant Adrenal Myelolipoma : A rare case report

Summary Background: Regarding differential diagnosis of adrenal tumors, Myelolipoma must be kept in mind (as a cautionary tale) to avoid surgical exploration or extensive surgeries due to its non-functioning and benign nature. Case Report: A 45-year-old male was referred for pain in the right lumber region. The patient had a history of hypertension since 7 years. On systemic examination, a mass was palpable in the right lumber region. Imaging studies, including computerized tomography (CT) and magnetic resonance imaging (MRI), revealed a well-defined mass with predominantly fatty content, likely a benign neoplastic lesion. Routine hematological and biochemical test results were within normal limits. The clinical diagnosis was pheochromocytoma, in view of the patient being known to have hypertension. To avoid rupture and retroperitoneal hemorrhage, right adrenalectomy was performed. Final histopathological diagnosis was made as giant adrenal myelolipoma. Conclusions: Adrenal myelolipoma should be considered in the differential diagnosis of fat-containing tumors in the retroperitoneum. The uncommon presentation of this benign tumor sometimes causes confusion with other, aggressive neoplasms. CT and MRI are sensitive modalities of diagnosis, but confirmation of myelolipoma is based on histology; therefore care must be taken for accurate diagno sis to avoid extensive surgeries.

Avaliação por ressonância magnética dos tumores de adrenal com correlação histológica

A ressonância magnética é ferramenta importante para a detecção e caracterização dos tumores adrenais. O conhecimento das diferentes apresentações dos tumores primários e secundários à ressonância magnética e sua correlação com dados da histologia são essenciais para o correto raciocínio diagnóstico. Este artigo revisa os aspectos que podem estreitar o diagnóstico diferencial dos tumores adrenais, dando ênfase à correlação histológica daqueles mais comuns.

Adrenal tumors with late enhancement on CT and MRI

To identify adrenal masses showing gradual persistent enhancement on delayed contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Computed tomography or magnetic resonance images of pathologically proven 400 adrenal tumors were retrospectively reviewed over a 10-year period. We included only adrenal tumors showing gradual persistent enhancement on CT and MRI performed at 15 and 5 min, respectively, after contrast material injection. Four tumors in four patients (three men and one woman; mean age, 51 years) met the inclusion criteria. These lesions were as follows: two ganglioneuromas, one myelolipoma with infarction, and one angiomyolipoma with minimal fat. All of these tumors showed gradual persistent enhancement, and highest attenuation during delayed contrast-enhanced CT or strongest enhancement during delayed contrast-enhanced MRI. The differential diagnosis of adrenal tumors showing gradual persistent enhancement on delayed contrast-enhanced CT and MRI should include ganglioneuroma, myelolipoma with infarction, and angiomyolipoma with minimal fat.

Fine-needle aspiration cytology of primary granulosa cell tumor of the adrenal gland: A case report

Extraovarian granulosa cell tumors are extremely rare. We report on a primary granulosa cell tumor of the adrenal gland. A 69-yr-old African-American female presented with a 1-yr history of irregular uterine bleeding and a palpable right abdominal mass. CT scan showed a 9.0-cm suprarenal mass as well as an enlarged uterus. CT-guided fine-needle aspiration (FNA) cytology of the adrenal mass was interpreted as a malignant neoplasm. She underwent exploratory laparotomy, right nephrectomy, and hysterectomy with bilateral salpingo-oophorectomy. The gross, histologic, and immunohistochemical findings of the adrenal mass were characteristic of a granulosa cell tumor. The uterus contained multiple leiomyomas. The endometrium showed simple hyperplasia. Both fallopian tubes and ovaries showed no pathologic abnormality. There was no evidence of tumor elsewhere. Although rare, extraovarian granulosa cell tumor should be considered in the differential diagnosis of adrenal tumors in women showing the FNA features described herein, especially when there is evidence of excessive estrogen production. Diagn. Cytopathol. 2000;22:107-109.

Class III beta-tubulin isotype (beta III) in the adrenal medulla: II. Localization in primary human pheochromocytomas.

The Class III beta-tubulin isotype (beta III) is expressed specifically in central and peripheral nervous system neurons at various stages of neuronal differentiation. We have shown previously that beta III is expressed in a differentiation-dependent manner in human neuroblastomas arising in the adrenal medulla and sympathetic chains (Katsetos et al., Clin Neuropathol 13:241-255, 1994). The neuronal distribution of beta III in the developing and mature human adrenal medullae is detailed in the companion article (Katsetos et al., 1998A). We have compared the localization of the neuronal beta III to S-100 protein, a sustentacular cell marker, in 14 formalin-fixed, paraffin-embedded primary human pheochromocytomas of the adrenal medulla and 14 adrenocortical tumors (adenomas and carcinomas). In pheochromocytomas, beta III staining was present in all tumors, but the number of stained cells varied in the two neural neoplastic phenotypes. Although the majority of chromaffin-like cells were beta III-positive, there was a lack of beta III in one-third of the tumor cells. Compared to chromaffin-like phenotypes, neuronal (ganglion-like cells) were invariably beta III-positive. Stromal sustentacular cells, stromal fibroblasts, and tumor blood vessels were beta III-negative. Sustentacular cells in pheochromocytomas were S-100 protein-positive, but beta III-negative. Primary adrenocortical tumors were beta III-negative with the exception of rare beta III-positive cells demonstrated in one case. The distribution of beta III in human pheochromocytomas of the adrenal gland is differentiation-dependent, closely recapitulating chromaffin cell and neuronal phenotypes of the normal adrenal medulla. Our findings indicate that beta III may be used as one of the adjuvant neural markers in the differential diagnosis of adrenal tumors, i.e., pheochromocytoma versus adrenocortical carcinoma. The occurrence of rare beta III-positive cells in cortical carcinomas is exceptional and probably represents the acquisition of a divergent neuroendocrine phenotype. The significance of the latter is unclear, although it may constitute a marker for malignancy.