Category Archives: Adrenal

Thompson LD.

Am J Surg Pathol. 2002 May;26(5):551-66.

No comprehensive series has evaluated the histologic features of pheochromocytoma to separate benign from malignant pheochromocytoma by histomorphologic parameters only. Fifty histologically malignant and 50 histologically benign pheochromocytomas of the adrenal gland were retrieved from the files of the Armed Forces Institute of Pathology. The patients included 43 females and 57 males, with an age range of 3-81 years (mean 46.7 years). Patients usually experienced hypertension (n = 79 patients). The mean tumor size was 7.2 cm (weight was 222 g). Histologically, the cases of malignant pheochromocytomas of the adrenal gland more frequently demonstrated invasion (vascular [score = 1], capsular [score = 1], periadrenal adipose tissue [score = 2]), large nests or diffuse growth (score = 2), focal or confluent necrosis (score = 2), high cellularity (score = 2), tumor cell spindling (score = 2), cellular monotony (score = 2), increased mitotic figures (>3/10 high power fields; score = 2), atypical mitotic figures (score = 2), profound nuclear pleomorphism (score = 1), and hyperchromasia (score = 1) than the benign tumors. A Pheochromocytoma of the Adrenal gland Scaled Score (PASS) weighted for these specific histologic features can be used to separate tumors with a potential for a biologically aggressive behavior (PASS > or =4) from tumors that behave in a benign fashion (PASS <4). The pathologic features that are incorporated into the PASS correctly identified tumors with a more aggressive biologic behavior. Application of these criteria to a large cohort of cases will help to elucidate the accuracy of this grading system in clinical practice.

PubMed ID: 11979086

Article Size: 3 MB

 

Riedmeier M, Thompson LDR, Molina CAF, Decarolis B, Härtel C, Schlegel PG, Fassnacht M, Wiegering V.

Endocr Relat Cancer. 2023 Mar 8;30(4):e220259. doi: 10.1530/ERC-22-0259. Print 2023 Apr 1.

Histopathological differentiation in pediatric adrenocortical carcinoma (pACC) is difficult and clinical prediction and stratification scores are not evaluated yet. Therefore, this review aims to summarize current evidence on the value and accuracy of the two commonly used scoring systems (Weiss/Armed Forces Institute of Pathology (AFIP)) pACC. On this base, one might be able to evaluate if patients may benefit from a unique scoring system. For this, we performed a systematic review of the published literature and included 128 patients in our analysis. The majority (72%) of the pACCs had a good clinical course. The follow-up time ranged from 0 to 420 months with a mean age of 5.6 years at diagnosis. Patients with a good clinical course were younger (mean 4.8 years) than patients with a poor outcome (mean 7.6 years). Comparing the two scoring systems, the specificity of the Weiss score was very low (25%), whereas the sensitivity was 100%. According to the AFIP score, specificity (77%) was higher than the Weiss score, whereas the sensitivity of the AFIP score was minimal lower with 92%. Age differences were recognizable as the specificity was lower in infants <4 years (20%) than in older children (32%). In contrast, the specificity of the AFIP score was higher in infants <4 years (82%) than in older age groups (76%). Summarizing our results, we could show that the Weiss score is not a suitable tool for the prediction of malignancy in pACC in comparison with the AFIP score, but further efforts may seek to ensure early and accurate stratification through augmented scoring.

PubMed ID: 3675331

Article Size: <1 MB

Wieneke JA, Thompson LD, Heffess CS.

Am J Surg Pathol. 2003 Jul;27(7):867-81.

Adrenal cortical neoplasms in pediatric patients (<20 years) are rare. The clinical manifestations and biologic behavior of these lesions can be quite distinct from their histologically similar counterparts in the adult population, making pathologic criteria for distinguishing benign from malignant tumors equivocal. We undertook a study of 83 adrenal cortical neoplasms to determine if adult clinical and histologic features can be applied to pediatric patients in an outcome-based analysis. Most of the patients (50 girls and 33 boys) presented with hormone-related symptoms present for a mean of 6.8 months. The tumors ranged in size from 2 to 20 cm (mean 8.8 cm). Histologic parameters examined included capsular and/or vascular invasion, extraadrenal soft tissue extension, growth pattern, cellularity, necrosis, cytoplasmic eosinophilia, nuclear pleomorphism, nuclear-to-cytoplasmic ratio, prominent nucleoli, mitotic figures, atypical mitotic figures, bands of fibrosis, and calcifications. Immunophenotypically, there was reactivity with inhibin, vimentin, CK5, and focally with p53 and Ki-67. All patients underwent adrenalectomy, and 20 patients received adjuvant therapy. All patients with tumors classified as adenomas (n = 9) were alive, without evidence of disease (mean 14.7 years), whereas 21 patients with carcinomas had died with disease (mean 2.4 years). Only 31% of histologically malignant tumors behaved in a clinically malignant fashion. Features associated with an increased probability of a malignant clinical behavior included tumor weight (>400 g), tumor size (>10.5 cm), vena cava invasion, capsular and/or vascular invasion, extension into periadrenal soft tissue, confluent necrosis, severe nuclear atypia, >15 mitotic figures/20 high power fields, and the presence of atypical mitotic figures. Vena cava invasion, necrosis, and increased mitotic activity (>15 mitotic figures/20 high power fields) independently suggest malignant clinical behavior in multivariate analysis.

PubMed ID: 12826878

Article Size: 2 MB

 

Wiegering V, Riedmeier M, Thompson LDR, Virgone C, Redlich A, Kuhlen M, Gultekin M, Yalcin B, Decarolis B, Härtel C, Schlegel PG, Fassnacht M, Timmermann B.

BACKGROUND AND PURPOSE: Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting.

MATERIALS AND METHODS: We searched the PubMed and Embase database for manuscripts regarding RT for pACC.

RESULTS: We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient.

CONCLUSIONS: Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.

PubMed ID: 35601796

Article Size: <1 MB

Wieneke JA, Thompson LD, Heffess CS.

Ann Diagn Pathol. 2001 Oct;5(5):304-8.

Corticomedullary mixed tumors of the adrenal gland are quite rare, with only five well-documented cases reported in the literature.(1-4) Herein, we report the light microscopic and immunohistochemical features of two cases of this rare tumor. Patient 1 is a 34-year-old woman who presented with hypertension, hair loss, and amenorrhea of 1-year duration. Patient 2 is a 52-year-old woman who presented with flank pain and what appeared to be a renal mass on arteriogram with no history of hypertension, Cushing’s syndrome, or other endocrine abnormalities. At surgery, the tumor was noted to arise from the adrenal gland rather than the kidney and adrenalectomy was performed. In both cases, the surgically resected specimens consisted of a well-circumscribed, single adrenal mass surrounded by a rim of uninvolved adrenal cortical tissue. The tumors were composed of adrenal cortical cells intimately admixed with pheochromocytes. Immunohistochemical studies highlighted these two cellular components. The pheochromocytes were strongly reactive with chromogranin and the sustentacular cells with S-100 protein, whereas the adrenal cortical cells reacted specifically with inhibin. Thus, we report two additional cases of mixed corticomedullary tumor of the adrenal gland. Ann Diagn Pathol 5:304-308, 2001. This is a US government work. There are no restrictions on its use.

PubMed ID: 11598859

Article Size: <1 MB

 

Nanba K, Omata K, Gomez-Sanchez CE, Stratakis CA, Demidowich AP, Suzuki M, Thompson LDR, Cohen DL, Luther JM, Gellert L, Vaidya A, Barletta JA, Else T, Giordano TJ, Tomlins SA, Rainey WE.

Hypertension. 2019 Apr;73(4):885-892. doi: 10.1161/HYPERTENSIONAHA.118.12070.

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.

PubMed ID: 30739536

Article Size: <1 MB

Thompson LDR.

Pathol Case Rev 2005;10 (5): 243-25.

Pheochromocytomas are tumors arising from the chromaffin cells of the adrenal medulla. They are equivalent to paragangliomas in other anatomic sites. They are uncommon neoplasms and most are sporadic, although 10% are described in syndromes, another 10% are bilateral (usually syndrome associated), and about 10% are malignant. They develop in both genders and peak in the fourth to fifth decades, although familial tumors occur at a younger age. Patients present clinically with the pharmacologic effects of excess catecholamines, manifested by episodic, postural, paroxysmal and/or labile hypertension, headaches, diaphoresis, palpitations, chest pain, and anxiety. Radiographic studies with nucleotide scans are often diagnostic. Malignant pheochromocytomas have historically required the presence of metastatic tumor to confirm the diagnosis of a malignant neoplasm. However, a series of histologic features, when used in conjunction with laboratory findings, radiographic findings, macroscopic features, and immunohistochemical results, can help to prospectively diagnose malignant heochromocytoma. These features include invasion, large nests or diffuse growth (loss of Zellballen architecture), focal or confluent necrosis, high cellularity, tumor cell spindling, cellular monotony, increased mitotic figures, atypical mitotic figures, profound nuclear pleomorphism, and hyperchromasia. Overall, the patient prognosis for benign pheochromocytoma is excellent, although that for malignant pheochromocytoma is intermediate, with surgery achieving the best clinical result of about 75% 5-year survival. Separation from benign pheochromocytoma and adrenal cortical neoplasms is important as the management is different.

PubMed ID: n/a

Article Size: 4 MB

Giordano TJ, Berney D, de Krijger RR, Erickson L, Fassnacht M, Mete O, Papathomas T, Papotti M, Sasano H, Thompson LDR, Volante M, Gill AJ.

Hum Pathol. 2021 Apr;110:50-61. doi: 10.1016/j.humpath.2020.10.001. Epub 2020 Oct 12.

Complete resection of adrenal cortical carcinoma (ACC) with or without adjuvant therapy offers the best outcome. Recurrence is common and in individual cases the long term outcome is difficult to predict, making it challenging to personalize treatment options. Current risk stratification approaches are based on clinical and conventional surgical pathology assessment. Rigorous and uniform pathological assessment may improve care for individual patients and facilitate multi-institutional collaborative studies. The International Collaboration on Cancer Reporting (ICCR) convened an expert panel to review ACC pathology reporting. Consensus recommendations were made based on the most recent literature and expert opinion. The data set comprises 23 core (required) items. The core pathological features include: diagnosis according to the current World Health Organization (WHO) classification, specimen integrity, greatest dimension, weight, extent of invasion, architecture, percentage of lipid rich cells, capsular invasion, lymphatic invasion, vascular invasion, atypical mitotic figures, coagulative necrosis, nuclear grade, mitotic count, Ki-67 proliferative index, margin status, lymph node status and pathological stage. Tumors were dichotomized into low grade (<20 mitoses per 10 mm2) and high grade (>20 mitoses per 10 mm2). Additional noncore elements that may be useful in individual cases included several multifactorial risk assessment systems (Weiss, modified Weiss, Lin-Weiss-Bisceglia, reticulin, Helsinki, and AFIP scores/algorithms). This data set is now available through the ICCR website with the hope of better standardizing pathological assessment of these relatively rare but important malignancies.

PubMed ID: 33058949

Article Size: 5.4 MB

Riedmeier M, Antonini SRR, Brandalise S, Costa TEJB, Daiggi CM, de Figueiredo BC, de Krijger RR, De Sá Rodrigues KE, Deal C, Del Rivero J, Engstler G, Fassnacht M, Fernandes Luiz Canali GC, Molina CAF, Gonc EN, Gültekin M, Haak HR, Guran T, Hendriks A EJ, Idkowiak J, Kuhlen M, Malkin D, Meena JP, Pamporaki C, Pinto E, Puglisi S, Ribeiro RC, Thompson LDR, Yalcin B, Van Noesel M, Wiegering V.

Eur J Endocrinol. 2024 Mar 30;190(4):G15-G24. doi: 10.1093/ejendo/lvae038.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects.

METHODS: A Delphi method with three rounds of questionnaires within the pACC expert consortium of the international network groups ENSAT-PACT and ICPACT was used to create 21 final consensus statements.

RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stage III and IV and with incomplete resection/tumor spillage. For stage II patients mitotane is not generally indicated.The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14-20 mg/L Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2 to 4 weeks), along with evaluation and assessment of laboratory values are required.

CONCLUSIONS: Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

PubMed ID: 38552173

Article Size: <1 MB

Riedmeier M, Antonini SRR, Benoit C, Deal C, Martin F, de Figueiredo BC, Gonc EN, Hartel C, Idkowiak J, Kurlbaum M, de Krijger RR, Ribeiro RC, Del Rivero J, Schlegel PG, Thompson LDR, Yalcin B, Wiegering V.

Pediatric Hematology Oncology Journal, Volume 9, Issue 2, June 2024, Pages 74-77, ISSN 2468-1245, https://doi.org/10.1016/j.phoj.2024.03.005.

BACKGROUND: Mitotane is employed as adjuvant therapy in managing adrenocortical carcinoma in pediatric patients. While various adverse effects, such as estrogen-like manifestations, are well-documented in adults, there is limited knowledge regarding pediatric-specific toxicity. This report details an uncommon case of isosexual precocious pseudopuberty induced during childhood due to the estrogen-like effects of mitotane.

CASE REPORT: A 2.8-year-old female diagnosed with adrenocortical carcinoma (pT4 pN0 M0) underwent adjuvant treatment with mitotane and cytotoxic chemotherapy following incomplete resection (tumor stage III). Approximately eight months into mitotane treatment, she exhibited signs of puberty (Tanner stage 2), including progressive breast development, uterine enlargement, vaginal discharge, and an advancement of bone age by nearly two years. Gonadotrophin-dependent puberty and endogenous estrogen production were ruled out. The precocious pseudopuberty was attributed to previously reported estrogen-like effects of mitotane therapy. Subsequent administration of the aromatase inhibitor anastrozole in combination with mitotane led to a reduction in clinical signs of puberty.

CONCLUSIONS: Monitoring for estrogen-like effects of mitotane is crucial, particularly in pre-pubertal children, to avert potentially irreversible changes associated with precocious pseudopuberty.

PubMed ID: tbd

Article Size: <1 MB