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Background
This is a highly malignant tumor derived from the adrenal cortical cells. It is extremely rare but may present with a variety of symptoms mimicking other conditions. The most common presenting symptoms include an abdominal mass in 30% of patients. Endocrine syptoms may occur.
OUTLINE
CHARACTERIZATION INCIDENCE 1-2/1,000,000
0.02% of all malignanciesAGE RANGE-MEDIAN Bimodal with one peak in first 2 decades and larger peak in 5th decade
Adrenocortical tumors in Brazilian children: immunohistochemical markers and prognostic factors.
Sbragia L, Oliveira-Filho AG, Vassallo J, Pinto GA, Guerra-Junior G, Bustorff-Silva J.
Division of Pediatric Surgery, Department of Surgery, School of Medical Sciences, State University of Campinas, UNICAMP, Campinas, Sao Paulo, Brazil.
Arch Pathol Lab Med. 2005 Sep;129(9):1127-31. Abstract quote
CONTEXT: The behavior of adrenocortical tumors (ACTs) is usually difficult to establish in childhood, and the role of immunomarkers in predicting outcome has not yet been elucidated.
OBJECTIVE: To investigate the relationship between clinical, pathologic, and immunohistochemical findings and prognosis in a series of children with ACTs.
PATIENTS AND METHODS: Clinical data were evaluated retrospectively in 33 children with ACTs, including age at diagnosis, sex, time between first symptoms and diagnosis, clinical signs and symptoms, tumor position, and follow-up. Histologic sections were reviewed, each tumor was classified, and staging was performed according to previously published criteria. Immunohistochemical analysis of p53, Ki-67, c-Erb-B2, and Bcl-2 was performed according to previously published techniques.
RESULTS: Sixty-four percent (n = 21) of the patients were female, and the age at diagnosis in the cohort ranged from 2 to 96 months. Virilization alone affected 70% (n = 23) of the patients, and 18 patients had stage 1 disease, 9 had stage 2 disease, and 3 each had stage 3 and stage 4 disease. Female sex and stage 1 and stage 2 disease were associated with good outcome. None of the histopathologic criteria evaluated correctly predicted outcome. Only tumors with a volume exceeding 200 mL were associated with malignant behavior. Because only a small number of tumors expressed the antigens, results of these immunohistochemical tests were considered inconclusive.
CONCLUSION: In this sample of pediatric ACTs, the clinical and surgical parameters are the most important prognostic factors, while the immunohistochemical markers evaluated were not predictive of outcome.F slight predominance but some studies show slight M predominance
PATHOGENESIS CHARACTERIZATION An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.
Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R.
Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Proc Natl Acad Sci U S A 2001 Jul 31;98(16):9330-5 Abstract quote
The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10-15 times higher than that of pediatric ACC worldwide.
Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members.
Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.
LABORATORY/
RADIOLOGIC/
OTHERCHARACTERIZATION RADIOLOGIC Imaging findings in pediatric adrenocortical carcinoma.
Ribeiro J, Ribeiro RC, Fletcher BD.
International Outreach Program, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Pediatr Radiol 2000 Jan;30(1):45-51 Abstract quote
BACKGROUND: Adrenocortical carcinoma (ACC), a tumor that is rare among children, causes clinically evident hormonal disturbances. Imaging methods are used to stage disease and to plan surgical resection.
OBJECTIVE: To describe the findings of the various imaging methods used to evaluate ACC.
MATERIALS AND METHODS: We reviewed the records of ten consecutive patients (mean age, 8.1 years) who presented from 1987 to 1998 with ACC. All patients underwent computed tomography (CT) scanning; five underwent magnetic resonance (MR) imaging; four underwent ultrasonography (US); and eight underwent radionuclide bone scans.
RESULTS: Seven patients presented with signs of hormonally functional tumors. Typical imaging findings consisted of a large, well-defined suprarenal tumor, containing calcifications (seven patients) with a thin capsule and central necrosis or hemorrhage (six patients). The inferior vena cava (IVC) was compressed by tumor in three patients, and ultrasonography demonstrated invasion of the IVC wall in one of these. Three patients' bone scans showed that the primary tumor took up radioactive tracer. Spread to lungs or liver or both was demonstrated in six patients.
CONCLUSIONS: CT, US and MR imaging are effective methods of imaging the primary tumor. Chest CT and bone scintigraphy should be performed to detect metastases. The presence of a thin tumor capsule, a stellate central zone of necrosis, and evidence of hormonal function help distinguish ACC from neuroblastoma.
LABORATORY Erythropoietin-producing adrenocortical carcinoma.
Oka T, Onoe K, Nishimura K, Tsujimura A, Sugao H, Takaha M, Kurata A.
Department of Urology, Osaka National Hospital, Japan.
Urol Int 1996;56(4):246-9 Abstract quote
A 62-year-old Japanese male with an erythropoietin-producing adrenocortical carcinoma is presented.
The elevated erythropoietin level and erythrocytosis returned to normal after surgical removal of a huge left adrenal tumor weighing 1,580 g. A histopathological diagnosis of adrenocortical carcinoma was made. Despite adjuvant combined chemotherapy, the patient died of lung and liver metastases 3.5 months after operation.
Although the possibility that the elevated plasma erythropoietin level and erythrocytosis resulted from local kidney hypoxia, caused by pressure from the huge adrenal tumor, cannot be completely neglected, the positive cytoplasmatic evidence of immunoreactive erythropoietin in the carcinoma cells and the detection of a high erythropoietin level in the tumor extract on radioimmunoassay confirmed that this is a very rare case of erythropoietin-producing adrenocortical carcinoma.
Adrenocortical carcinoma: clinical and laboratory observations.
Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Ferreira Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA.
Endocrine Service, Hospital Das Clinicas, Sao Paulo, Brazil.
Cancer 2000 Feb 15;88(4):711-36 Abstract quote
BACKGROUND: The clinical features and natural history of adrenocortical carcinoma are highly dependent on the type of center reporting their experience. Observations from oncology services suggest a high incidence of nonfunctioning tumors, whereas reports from endocrine clinics emphasize excessive corticoid and androgen production in the majority of tumors. The incidence rate and natural history of childhood adrenal carcinoma generally has been under emphasized.
METHODS: Over the past 17 years, the authors have evaluated and treated 47 patients with adrenocortical carcinoma referred to the University of Sao Paulo, 22 of whom were children.
RESULTS: There is a bimodal age incidence of adrenal carcinoma, with the disease peaking in the first and fourth decades of life. Childhood adrenal carcinoma is characterized by a high rate of incidence of virilization, marked overproduction of androgens, and a less aggressive clinical course, and appears to be more amenable to surgical and other therapeutic modalities. By contrast, adrenocortical carcinoma occurring in adults presents more commonly as a mixed Cushing and virilizing syndrome, with overproduction of corticoids and androgens and a far more aggressive clinical course, leading to rapid death within months or years. Nonfunctioning adrenocortical carcinoma is less common; it generally occurs in older adults and exhibits a rapid downhill course. Modern day imaging methods have improved the diagnosis and staging of adrenal carcinoma greatly. In the authors' experience, the histologic criteria of Weiss appeared to predict tumor prognosis most accurately, whereas immunologic markers, cytoskeletal markers, DNA ploidy, cell phase markers, and oncogenic probes have yielded inconsistent results to date. Surgical removal of a localized tumor remains the best hope for long term survival. Medical therapy with mitotane and its successors in patients with Stage III or IV (MacFarlane system as modified by Sullivan et al.) disease appear to have added little to longevity or quality of life.
CONCLUSIONS: When diagnosed in children, adrenal carcinoma is associated with virilism and a less aggressive natural history; however, when it occurs in adults, the disease presents more commonly as a mixed Cushing-virilizing syndrome and has a virulent course. The Weiss histologic criteria appear to correlate best with disease prognosis, but other histochemical, cell cycle, and genetic markers have not, to date, aided in disease management.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL As a general rule, usually >100 gms
Commonly >740 gmsThere have been occasional cases <50 gms which have metastasized
Nodular tumor with pink to yellow tan cut surface varying upon lipid content
Necrosis and hemorrhage common
May invade continguous structures such as kidney and liverCarcinomas associated with feminization or virilization are red-brown
Tumors associated with Cushing's syndrome usually yellowVARIANTS PEDIATRIC TUMORS Cancer 1986;57:2235-2237
>500 gms = malignant
Only 1 tumor <500 gms was malignant
Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients.Wieneke JA, Thompson LD, Heffess CS.
Am J Surg Pathol. 2003 Jul;27(7):867-81 Abstract quote 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.
HISTOLOGICAL TYPES CHARACTERIZATION General Variety of patterns:
Alveolar
Trabecular
SolidMay have myxoid change, pseudoglandular patterns, spindle cells
Pleomorphic cells with occasional eosinophilic globular inclusions
Numerous mitosesVARIANTS MYXOID Myxoid Neoplasms of the Adrenal Cortex A Rare Histologic Variant
Felix M. Brown, M.D.; Thomas A. Gaffey, M.D.; Lester E. Wold, M.D.; Ricardo V. Lloyd, M.D., Ph.D.
From the Department of Pathology (T.A.G., L.E.W., R.V.L.), Mayo Clinic and Mayo Foundation, Rochester, MN; and the Department of Pathology (F.M.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA, U.S.A.
Am J Surg Pathol 2000;24:396-401 Abstract quote
The myxoid variant of adrenocortical carcinoma is a rare neoplasm described previously in only two case reports. Because of the rarity of these lesions, the presence of myxoid changes in adrenal cortical neoplasms usually raises the possibility of malignancy.
We studied the histopathologic features of 14 cases of myxoid adrenocortical neoplasms, including six adenomas and eight carcinomas. All patients with adenomas with sufficient follow-up (n = 5) were alive with no recurrence of their tumors or evidence of metastatic disease. Four patients with carcinomas died of their disease, two were alive with metastatic disease, and one was alive with no evidence of recurrence or metastatic disease. Histologically, the 14 tumors varied in their myxoid composition, ranging from 10% to 95%. The myxoid foci stained positively with Alcian blue and were usually negative with periodic acid–Schiff and mucicarmine stains. As a group, the immunophenotype of the lesions was typical of other adrenal cortical neoplasms, with positive immunostaining for vimentin, synaptophysin, and -inhibin. One tumor was focally positive for keratin.
Myxoid adrenal cortical neoplasms should be included in the differential diagnosis of myxoid retroperitoneal neoplasms. Myxoid changes in adrenal cortical neoplasms may be present in both adenomas and carcinomas, and the usual clinical and histopathologic features for adrenocortical neoplasms should be used to diagnose these neoplasms.
ONCOCYTIC
Oncocytic adrenocortical carcinoma: a morphologic, immunohistochemical and ultrastructural study of four cases.Hoang MP, Ayala AG, Albores-Saavedra J.
Department of Pathology (MPH, JA-S), University of Texas Southwestern Medical Center, Dallas, Texas.
Mod Pathol 2002 Sep;15(9):973-8 Abstract quote We present the clinical, histologic, immunohistochemical, and ultrastructural findings of four cases of non-functioning oncocytic adrenocortical carcinomas. The patients' ages ranged from 39 to 71 years. There was no sex predilection. Large yellow-tan tumors (8.5 to 17.0 cm), well demarcated from the adjacent kidney, were seen with a thin rim of normal adrenal gland along one edge.
One tumor invaded the inferior vena cava and extended up to the level of the right atrium, and another metastasized to bone. The other two tumors had similar morphologic features and therefore were considered carcinomas. Histologic sections of all four cases showed a diffuse proliferation of polygonal neoplastic cells with large nuclei containing prominent nucleoli and abundant granular and eosinophilic cytoplasm. Occasional mononuclear and binucleated giant cells were noted in one case. There were rare mitotic figures (less than one per 10 high power fields). All tumors were immunoreactive for cytokeratins (AE1/AE3 and CAM5.2). Inhibin was focally expressed by one tumor and its bone metastasis.
Ultrastructurally, the cytoplasm of the neoplastic cells was packed with innumerable mitochondria. Cytologic atypia or mitotic rate cannot reliably predict the biologic behavior of oncocytic adrenocortical neoplasms.
Large tumor size (4/4), extracapsular extension (3/4), blood vessel invasion (2/4), necrosis (4/4), and metastasis (1/4) are features of malignancy for oncocytic adrenocortical carcinomas. The treatment of these tumors is complete surgical excision.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION GENERAL In routine formalin fixed tissue, cytokeratins are absent or nearly absent
Vimentin is positive
The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study.Zhang PJ, Genega EM, Tomaszewski JE, Pasha TL, LiVolsi VA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19147, USA.
Mod Pathol. 2003 Jun;16(6):591-7. Abstract quote Morphologic distinction between adrenal cortical and medullary tumors can be difficult. Previous studies have shown inhibin, melan-A, and BCL-2 to be useful markers for adrenal cortical tumors.
We have recently observed a high level of calretinin expression in normal adrenal cortex but not the medulla and therefore evaluated its diagnostic application for adrenal tumors in comparison with inhibin, melan-A, and BCL-2. C-kit is a transmembrane tyrosine kinase receptor. Immunodetection of c-kit expression has been recently used for tumor diagnosis, and c-kit-positive tumors can potentially benefit from kit kinase inhibitor treatment. Although c-kit expression was reported in adrenal medulla and pheochromocytoma, it has not been evaluated in adrenal cortical tumors.
In this study, 28 adrenal cortical tumors (12 carcinomas, 16 adenomas), 20 pheochromocytomas, and 20 extraadrenal paragangliomas were evaluated for calretinin, inhibin, melan-A, BCL-2, and c-kit expression by standard immunohistochemical assays on paraffin sections. The percentage of immunoreactivity in adrenal cortical tumors was as follows: calretinin, 96%; melan-A, 89%; inhibin, 92%; BCL-2, 20%; and c-kit, 5%. Normal adrenal medulla did not stain for c-kit but was positive for BCL-2. Eighty-six percent of pheochromocytomas stained for BCL-2 and none for calretinin, with the exception of the ganglioneuromatous areas in composite pheochromocytomas (n = 5). Extraadrenal paragangliomas showed reactivity with calretinin in 25%, melan-A in 5%, inhibin in 16%, BCL-2 in 38%, and c-kit in 8% of the cases.
Our results indicate that calretinin is the most sensitive among all the adrenal markers tested. Like melan-A and inhibin, calretinin is also a very specific marker in differentiating cortical from medullary adrenal tumors. In addition, calretinin can be used to confirm a composite pheochromocytoma. BCL-2 does not appear to be useful in differentiating adrenal cortical from medullary tumors. C-kit is not useful in the diagnosis of adrenal tumors, and kit kinase inhibitor might have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.A103 A103 Immunostaining in the Diagnosis of Adrenal Cortical Tumors
An Immunohistochemical Study of 316 Cases
Timothy S. Loy, MD, Roy W. Phillips, MD, and Chadwick L. Linder, MDFrom the Department of Pathology, University of Missouri Medical School, Columbia, Mo
Arch Pathol Lab Med 2002;Vol. 126, No. 2, pp. 170–172. Abstract quote Context.—The monoclonal antibody A103 recognizes an antigen on melanoma cells known as Melan-A or MART-1. Recent studies have shown that A103 also reacts with adrenal cortical cells and may be useful in the diagnosis of adrenal cortical tumors. However, only small numbers of some of the tumors in the differential diagnosis of adrenal cortical neoplasms have been studied.
Objective.—To study the specificity of A103 immunohistochemistry in a large number of tumors in the differential diagnosis of adrenal cortical neoplasms.
Design.—Formalin-fixed, paraffin-embedded tissue from 21 adrenal cortical tumors, 16 cases of metastatic carcinoma to the adrenal, 10 pheochromocytomas, and 269 extra-adrenal carcinomas was evaluated for A103 immunoreactivity using a commercially available antibody (Novocastra, Newcastle, UK).
Results.—Positive staining was seen in all of the adrenal cortical tumors but in none of the adrenal metastases or pheochromocytomas. In the 269 extra-adrenal carcinomas, A103 immunoreactivity was limited to a single ovarian serous carcinoma.
Conclusion.—A103 immunostaining is useful in distinguishing adrenal cortical neoplasms from other carcinomas and pheochromocytoma.
CYTOKERATIN Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases.
Chu P, Wu E, Weiss LM.
Division of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
Mod Pathol 2000 Sep;13(9):962-72 Abstract quote
Cytokeratin 7 (CK 7) and cytokeratin 20 (CK 20) are low molecular weight cytokeratins. Their anatomic distribution is generally restricted to epithelia and their neoplasms.
We surveyed 435 epithelial neoplasms from various organ systems by immunohistochemistry using CK 7 and CK 20 monoclonal antibodies.
Expression of CK 7 was seen in the majority of cases of carcinoma, with the exception of those carcinomas arising from the colon, prostate, kidney, and thymus; carcinoid tumors of the lung and gastrointestinal tract origin; and Merkel cell tumor of the skin. The majority of cases of squamous cell carcinoma of various origins were negative for CK 7, except cervical squamous cell carcinoma, in which 87% of cases were positive. Approximately two thirds of cases of malignant mesothelioma were CK 7-positive. CK 20 positivity was seen in virtually all cases of colorectal carcinomas and Merkel cell tumors. CK 20-positive staining was also observed in cases of pancreatic carcinomas (62%), gastric carcinoma (50%), cholangiocarcinomas (43%), and transitional cell carcinomas (29%).
The expression of CK 20 was virtually absent in carcinomas from other organ systems and in malignant mesothelioma.
CK 7- and CK 20-negative epithelial neoplasms included adrenal cortical carcinoma, germ cell tumor, prostate carcinoma, renal cell carcinoma, and hepatocellular carcinoma.
INHIBIN Immunoexpression of inhibin alpha-subunit in adrenal neoplasms.
Cho EY, Ahn GH.
Department of Diagnostic Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Appl Immunohistochem Mol Morphol 2001 Sep;9(3):222-8 Abstract quote
Inhibin normally is produced by ovarian granulosa cells and testicular Sertoli cells. Extragonadal inhibin expression also has been detected in the placenta, pituitary gland, and liver. It may be difficult to make a distinction between adrenal cortical tumors, pheochromocytoma, and metastatic carcinomas including renal cell and hepatocellular carcinoma.
Immunohistochemical expression of inhibin alpha-subunit was evaluated to determine whether any usefulness of immunostaining could be found for inhibin alpha-subunit in the differential diagnosis of adrenal glandular lesions. The authors performed immunostaining against inhibin alpha-subunit on 5 cases of normal adrenal gland, 1 case of adrenal cortical hyperplasia, 25 cases of adrenal cortical adenoma, 6 cases of adrenal cortical carcinoma, 21 cases of pheochromocytoma, 8 cases of metastatic carcinoma, and 10 cases of primary renal cell carcinoma.
Normal adrenal gland showed a strong immunoreactivity against inhibin alpha-subunit, especially in the inner layer of the adrenal cortex, representing the zona reticularis, but adrenal medulla was negative for inhibin alpha-subunit. Adrenal cortical hyperplasia associated with Cushing's syndrome showed a strong, diffuse immunoreactivity for inhibin alpha-subunit. Immunoreactivity against the inhibin alpha-subunit was identified in all cases of adrenal cortical adenoma and carcinoma, especially in the adrenal cortical neoplasm with Cushing's syndrome, which showed a strong reactivity. However, immunoreactivity was absent in two metastatic carcinomas from the liver and colon and most of the pheochromocytomas, except three cases with weak focal positivity for inhibin alpha-subunit. Four cases of metastatic renal cell carcinoma and 10 cases of primary renal cell carcinoma revealed no immunoreactivity. Metastatic adenocarcinoma from the prostate showed a weak immunoreactivity for inhibin alpha-subunit. Metastatic hepatoblastoma was negative against inhibin alpha-subunit with endogenous biotin blocking.
Immunoexpression for inhibin alpha-subunit is useful for making distinction between adrenal cortical tumors, pheochromocytoma, and metastatic carcinoma. Inhibin alpha-subunit may be valuable as part of a diagnostic immunohistochemical panel in adrenal glandular lesions.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES BENIGN VERSUS MALIGNANT Combination of several histologic parameters as well as weight over 100 gms have helped to distinguish benign from malignant tumors In favor of malignancy:
High nuclear grade
>5 MF/50 hpf
Atypical MF
Diffuse patterns of growth
Invasion of venous, sinusoidal, or capsular structures
Clear cells <25% of tumorClinical and histopathological evaluation of the adrenal incidentaloma.
Sworczak K, Babniska A, Stanek A, Lewczuk A, Siekierska-Hellmann M, Blaut K, Drobinska A, Basinski A, Lachnski AJ, Czaplinska-Kalas H, Gruca Z.
Department of Internal Medicine, Endocrinology and Hemostatic Disorders, Medical University of Gdansk, Poland.
Neoplasma 2001;48(3):221-6 Absract quote
Clinically silent adrenal masses (incidentaloma) are incidentally discovered lesions, when noninvasive imaging methods (USG, CT, MRI) are performed for reasons other than known or suspected adrenal disease. Most studies report on a prevalence of adrenal incidentaloma range between 1% and 10% in radiological series.
Between 1994 and 1999 we observed in our Department 57 patients with incidentalomas of adrenal glands. After endocrinological evaluation silent Cushing's syndrome was found in 2 cases (3.5%).
Fifty two patients were qualified for surgery. Adrenocortical adenoma was diagnosed in 73.1%; adrenocortical carcinoma in 7.7%; pheochromocytoma in 7.7% and less frequent adrenal lesions in 11.5%. All adrenal carcinomas and malignant pheochromocytomas (11.5%) were found in tumors with diameter over 4 cm.
RENAL CELL CARCINOMA Adrenocortical carcinoma. An immunohistochemical comparison with renal cell carcinoma.
Wick MR, Cherwitz DL, McGlennen RC, Dehner LP.
Am J Pathol 1986 Feb;122(2):343-52 Abstract quote
The diagnosis of adrenocortical carcinoma (ACC) is often difficult, because this tumor may present with direct extension into adjacent renal parenchyma or with metastatic disease. Renal cell carcinoma and other histologically similar tumors are potentially confused with ACC by conventional light microscopy, and their separation from the latter is often impossible without the aid of additional studies. Furthermore, the distinction between adrenal cortical adenoma and ACC may also be problematic.
Because of these factors, the authors studied 10 cases each of ACC, adrenocortical adenoma, and renal cell carcinoma (RCC) immunohistochemically, in an attempt to develop objective parameters which may aid in this differential diagnostic dilemma.
Nontrypsinized, formalin-fixed, paraffin-embedded specimens were used in all cases, and tissue from the adrenocortical tumors was also studied for intermediate filament content after protease digestion. All 20 nontrypsinized adrenocortical neoplasms were positive for vimentin, but not for cytokeratin, epithelial membrane antigen, or blood group isoantigens. Conversely, each of 10 cases of RCC expressed epithelial membrane antigen, cytokeratin, and blood group isoantigens, but none was immunoreactive for vimentin. Two adrenocortical carcinomas and three adenomas manifested cytokeratin positivity after trypsin digestion.
There were no significant differences between the immunostaining profiles of ACC and adrenocortical adenoma, which suggest that this distinction must still rely upon clinical and morphologic criteria.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS Median survival slightly longer for functional tumors
Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.Stojadinovic A, Brennan MF, Hoos A, Omeroglu A, Leung DH, Dudas ME, Nissan A, Cordon-Cardo C, Ghossein RA.
Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20037,USA.
Mod Pathol. 2003 Aug;16(8):742-51. Abstract quote We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa).
A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001).
Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index.
Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.Clinical features and prognostic factors associated with adrenocortical carcinoma: Lahey Clinic Medical Center experience.
Tritos NA, Cushing GW, Heatley G, Libertino JA. Section of Endocrinology and Metabolism,
Lahey Clinic Medical Center, Burlington, Massachusetts 01805, USA.
Am Surg 2000 Jan;66(1):73-9 Abstract quote
Adrenocortical carcinoma is a rare tumor associated with a commonly poor prognosis. However, data on the natural history and response to therapy of patients with this malignancy have often been conflicting.
Our objective of this retrospective study was to evaluate the clinical course and survival of patients with adrenocortical carcinoma and to identify relevant prognostic factors. Between 1966 and 1996, 31 patients with histologically documented adrenocortical carcinoma were observed at the Lahey Clinic Medical Center. Patient information was obtained from chart review. At the time of diagnosis, 48 per cent of patients had endocrine symptoms with compatible hormonal studies, 19 per cent had involvement of the inferior vena cava by tumor thrombus, and 32 per cent had metastatic disease. The median survival time was 17 months (range, 1-205 months) for the entire group, and the 5-year survival rate was 26 per cent. Age <54 years, absence of metastatic disease at the time of diagnosis, and completeness of surgical resection were associated with better prognosis. Evaluation of survival with the Cox proportional hazards model suggested that age <54 years, absence of metastatic disease, and nonfunctioning tumor status were independently associated with improved survival.
The prognosis of patients with adrenocortical carcinoma is poor but appears more favorable in patients <54 years, with localized disease, or nonfunctioning tumor status. Complete tumor resection may be associated with improved survival.
Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery.
Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C.
Department of Surgery, Hopital Cochin, Paris, France
Surgery 1992 Dec;112(6):972-9 Abstract quote
BACKGROUND. Because of the rarity of adrenocortical carcinoma, survival rates and prognosis for patients who have undergone operation are not well known. The purpose of the French Association of Endocrine Surgery was to evaluate these factors in all patients treated during a 12-year period by its members.
METHODS. One hundred fifty-six patients (95 women, 61 men) with a mean age of 47 years were included. Functional symptoms were found in 52% of patients, and hormonal studies revealed secreting tumors in 62% of cases. Ninety-four percent of the patients underwent resection of the adrenal tumor, and 20% of them had extensive resection because of invasive cancers. Complete resection was achieved in 127 patients (81%) and incomplete resection in 29 patients. Mean tumor weight was 714 gm (range, 12 to 4750 gm), and the mean diameter was 12 cm (range, 3 to 30 cm). The results of the tumor staging were stage I, eight patients (5%); stage II (local disease), 75 patients (48%); stage III (locoregional disease), 39 patients (25%); and stage IV (metastases), 34 patients (22%).
RESULTS. The 5-year actuarial survival rates were 34% overall, 42% in curative group, 53% in local cancer group, 24% in regional disease group, and 27% in the reoperated group. One-year actuarial survival rate of the palliative group was 9% (median survival, 6 months). Multivariate analysis showed that better prognosis occurred in patients younger than 35 years of age (p = 0.01) and in patients with androgen-secreting tumors, precursor-secreting tumors, or nonsecreting tumors (p = 0.003). Mitotane improved the survival rate only in patients with metastases who received it after operation (vs non-mitotane-treated patients [p < 0.05]).
CONCLUSIONS. In this study age, extent of disease, aspect of the surgical resection, and type of hormonal secretion influenced survival.
Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody.
Tartour E, Caillou B, Tenenbaum F, Schroder S, Luciani S, Talbot M, Schlumberger M.
Department of Nuclear Medicine, Institut Gustave Roussy, Villejuif, France.
Cancer 1993 Dec 1;72(11):3296-303 Abstract quote
BACKGROUND. The diagnosis of adrenocortical carcinoma (ACC) may be difficult with conventional light microscopy, especially when the tumor is nonfunctioning. Until now, no specific adrenocortical tumor marker was available. The current study was undertaken to investigate the interest of the D11 MoAb for the diagnosis and prognosis of ACC.
METHODS. Eighteen adrenocortical carcinomas, 10 primary adrenomedullary tumors, 20 primary hepatocellular carcinomas, 50 primary renal cell carcinomas, 5 primary lung carcinomas, and 18 intraadrenal metastases were analyzed immunohistochemically with the D11 monoclonal antibody. ACC were also evaluated for the expression of other tumor markers, including neuron-specific enolase, chromogranin A, S-100, Leu-7, vimentin, KL1, AE1AE3, and epithelial membrane antigen. Relationships between clinical features and results of immunohistochemistry were also sought.
RESULTS. Nuclear D11 staining appears to be highly specific for normal adrenocortical cells and related tumors. Nuclear D11 positivity was demonstrated in 44% of ACC and was restricted to well-differentiated tumors. No cytoplasmic or nuclear D11 staining was observed in adrenomedullary tumors. D11 reactivity confined to the cytoplasm was found in 5 of 18 adrenal metastases, in all 20 hepatocellular carcinomas tested, in 3 of 5 lung carcinomas, and in 1 of 50 primary renal cell carcinomas. Patients with nuclear D11 immunostaining were initially seen with metastases less often and survived longer than those with no nuclear D11 immunostaining (P < 0.05).
CONCLUSIONS. Nuclear D11 immunoreactivity may help to differentiate ACC from intraadrenal metastases and adrenomedullary tumors. This also selects a group of ACC patients with a more favorable outcome.
Image cytometric DNA analysis of adrenocortical neoplasms as a prognostic parameter: a clinico-pathologic study of 13 patients.
Lu X, Stallmach T, Gebbers JO.
Institute of Pathology, Kantonsspital Luzern, Switzerland.
Anal Cell Pathol 1996 Oct;12(1):1-11 Abstract quote
Formalin-fixed paraffin-embedded material of thirteen adrenocortical neoplasms were examined by conventional microscopy, and by DNA image cytometry in Feulgen-stained tissue sections and cytospin preparations. The subsequent clinical course of each patient was reviewed.
Seven of the neoplasms were classified according to the histologic criteria of Weiss as adenomas and six as carcinomas. The DNA content and indices of all 13 adrenocortical neoplasms were measured by image cytometry. For the internal standard, the DNA values of the adjacent normal adrenal cells in 10 cases and of nuclei of fibrocytes of the tumour stroma were determined. DNA values in all seven adenomas, in normal adrenal cells, and in the nuclei of fibrocytes were unequivocally diploid.
The six carcinomas expressed aneuploid, tetraploid or hypertetraploid DNA values. DNA values of normal adrenal cells seemed to provide a better internal control than those of connective tissue cells. Of the seven adenoma patients with a follow-up between 8 and 124 months (mean 59 months), six were alive without evidence of tumour; one patient died from other causes. Of the six carcinoma patients with a follow-up ranging from 5 days to 36 months, three patients died from the disease; one patient was alive with metastases, and only two patients were alive without evidence of the disease for 25 and 36 months, respectively.
Our results strongly suggest that image cytometric DNA analysis is a valuable method to distinguish between benign and malignant adrenocortical neoplasms.
Am J Surg Pathol 1997;21:556-562
Mean tumor proliferation fraction (TPF) by counting MIB-1 positive cells per 1,000 tumor cells
Adenomas 14.9
Carcinomas 208.1
Recurrent or metastatic tumors 166.10/20 benign tumors had TPF >80
1/20 malignant tumros had TPF <8045% of carcinomas p53 positive
0% adenomas p53 positive
Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors.Aubert S, Wacrenier A, Leroy X, Devos P, Carnaille B, Proye C, Wemeau JL, Lecomte-Houcke M, Leteurtre E.
Am J Surg Pathol 2002 Dec;26(12):1612-9 Abstract quote The definitive diagnostic criteria for malignant adrenocortical tumors are distant metastasis and/or local invasion. The Weiss histopathologic system is the most commonly used method for assessing malignancy because of its simplicity and reliability. Unfortunately, its application remains subjective.
This current retrospective study evaluated the Weiss system and assessed the value of MIB-1 labeling in the diagnosis of adrenocortical malignancy. Twenty-four malignant tumors with distant metastasis, gross local invasion, or recurrence were selected and matched on their functioning status to 25 benign tumors. Two independent observers delineated the Weiss criteria. An MIB-1 labeling index was determined. Presence of three or more Weiss microscopic criteria was related to malignancy (specificity 96%, sensitivity 100%), thus confirming the value of the Weiss system. Interobserver agreement for the Weiss system (total score) was excellent (r = 0.94).
The lack of reliability for some Weiss criteria led us to propose a statistically modified system, based on the most reliable criteria (2.mitotic rate x 2.cytoplasm x abnormal mitoses x necrosis x capsular invasion) with a significant correlation with the Weiss system (r = 0.98). The MIB-1 labeling index was significantly higher in malignant tumors (p <0.0001). MIB1 could also help to differentiate malignant from benign adrenocortical tumors.
FUNCTIONING TUMORS Adrenocortical carcinoma: is prognosis different in nonfunctioning tumors? results of surgical treatment in 31 patients.
Favia G, Lumachi F, D'Amico DF.
Endocrine Surgery Unit, Department of Surgical and Gastroenterological Sciences, University of Padua, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy.
World J Surg 2001 Jun;25(6):735-8 Abstract quote
From 1980 to 1998 a series of 265 patients with adrenal tumors underwent surgery, with an adrenocortical carcinoma found in 31 (11.7%).
Altogether, 17 (54.8%) patients (group A) had Cushing syndrome (n = 15) or virilization (n = 2), and 14 (45.2%) patients (group B) had nonfunctioning adrenal tumors. Tumor staging was as follows: (groups A/B): stage I, n = 5 (3/2), stage II, n = 14 (9/5), stage III, n = 5 (1/4), stage IV, n = 7 (4/3) patients. There were 12 (38.7%) men and 19 (61.3%) women (median age 51 years, range 25-73 years), and the size of the mass ranged from 3.5 to 20.0 cm (median 8.0 cm), with no differences (p = NS) between groups A and B. Two (6.4%) patients (stage IV) did not undergo surgery and received only palliative drug treatment; 6 (19.4%) were treated with debulking surgery; 15 (48.4%) had unilateral adrenalectomy; and 8 (25.8%) had an extended adrenalectomy. Eighteen (58.0%) patients underwent adjuvant postoperative mitotane treatment, and in 8 (25.8%) patients one or more reoperations for recurrence were required. Nine (29.0%) patients are still alive with a mean follow-up of 34 months; 22 (71.0%) died 2 to 60 months (median 20 months) after surgery.
The overall 2- and 5-year survival rates were 62.1% and 10.3%, with no difference (p = NS) between groups A and B. The survival rates at the 1- and 3-year follow-ups were 90.3% and 32.3% (stages I and II) and 71.0% and 6.5% (stages III and IV).
In conclusion, adrenocortical carcinoma remains a highly malignant tumor, and stage III-IV patients still have a poor prognosis; but nonfunctioning tumors do not seem to be more aggressive.
VASCULAR PROLIFERATION Contribution of the microvessel network to the clonal and kinetic profiles of adrenal cortical proliferative lesions
Salvador J. Diaz-Cano, MD, PhD
Manuel De Miguel, PhD
Alfredo Blanes, MD, PhD
Hugo Galera, MD, PhD
Hubert J. Wolfe, MDHum Pathol 2001;32:1232-1239. Abstract quote
Monoclonal adrenocortical lesions have been characterized by an inverse correlation between proliferation and apoptosis, and polyclonal lesions show a direct correlation. Their relationship with the vascular pattern remains unknown in adrenocortical nodular hyperplasias (ACNHs), adenomas (ACAs), and carcinomas (ACCs).
We studied 20 ACNHs, 25 ACAs, and 10 ACCs (World Health Organization classification criteria) from 55 women. The analysis included X-chromosome inactivation assay (on microdissected samples), slide and flow cytometry, and in situ end labeling. Endothelial cells were stained with anti-CD31, and the blood vessel area and density were quantified by image analysis in the same areas. Appropriate tissue controls were run in every case. Regression analyses between kinetic and vascular features were performed in both polyclonal and monoclonal lesions. Polyclonal patterns were observed in 14 of 18 informative ACNHs and 3 of 22 informative ACAs, and monoclonal patterns were seen in 4 of 18 ACNHs, 19 of 22 ACAs, and 9 of 9 ACCs. A progressive increase in microvessel area was observed in the ACNH–ACA–ACC transition but was statistically significant between benign and malignant lesions only (191.36 ± 168.32 v 958.07 ± 1279.86 µm2; P < .0001). In addition, case stratification by clonal pattern showed significant differences between polyclonal and monoclonal benign lesions; 6% of polyclonal and 57% of monoclonal lesions had microvessel area >186 µm2 (P = .0000008). Monoclonal lesions showed parallel trends (but with opposite signs) for microvessel area and density in comparison with proliferation and apoptosis, whereas polyclonal lesions showed inverse trends.
In conclusion, the kinetic advantage of monoclonal adrenal cortical lesions (increased proliferation, decreased apoptosis) is maintained by parallel increases in microvessel area and density.
WEISS SYSTEM
Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors.Weiss LM.
Am J Surg Pathol 1984 Mar;8(3):163-9 Abstract quote A series of 43 adrenocortical tumors was analyzed using nine histologic features. Mitotic activity, especially with atypical forms, and venous invasion correlated best with metastasizing or recurring tumors; however, no single criterion was useful alone.
The combination of the following nine criteria was most useful in distinguishing malignant from benign tumors: nuclear grade III or IV; mitotic rate greater than 5/50 high-power fields; atypical mitoses; clear cells comprising 25% or less of the tumor; a diffuse architecture; microscopic necrosis; and invasion of venous, sinusoidal, and capsular structures.
None of the 24 tumors with two or less of these criteria metastasized or recurred, while all but one of the 19 tumors with four or more of these criteria either recurred or metastasized.
Pathologic features of prognostic significance in adrenocortical carcinoma.Weiss LM, Medeiros LJ, Vickery AL Jr.
Department of Pathology, Stanford University, California.
Am J Surg Pathol 1989 Mar;13(3):202-6 Abstract quote There are currently no well-established pathologic prognostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 pathologic parameters on survival was investigated in 42 cases of adrenocortical carcinoma.
Only one variable, mitotic rate, had a strong statistical association with patient outcome. The 21 patients with carcinomas with greater than 20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with less than or equal to 20 mitoses had a median survival of 58 months (p less than 0.02). The presence of atypical mitoses, capsular invasion, tumor weight greater than 250 g, and size greater than 10 cm each showed a marginal statistical association with poor survival (p less than 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival.
It is proposed that adrenal cortical carcinomas with greater than 20 mitoses be designated high grade, whereas tumors with less than or equal to 20 mitoses be designated low grade.
SURVIVAL Cancer 1981;47:2153-2161
Mean duration of symptoms was 6 months
Mean survival was 14 months
5 year survival was 24%Adrenal adenocarcinoma: a review of 53 cases.
Zografos GC, Driscoll DL, Karakousis CP, Huben RP.
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263.
J Surg Oncol 1994 Mar;55(3):160-4 Abstract quote
PROBLEM: Fifty-three patients (30 men, 23 women) with histologically proven adrenal carcinoma were reviewed. Nineteen (36%) had endocrine manifestations from functioning tumors. Arteriography was positive in 95% (19/20), CT scan in 94% (17/18), and ultrasound in 92% (12/13). Seventy-six percent of the patients, at the time of diagnosis, were stage III and IV. Most common metastatic sites were the liver, lymph nodes, bone, and lungs. Local recurrence developed in 39% of cases (15/38).
METHOD: Forty-one patients underwent an operation. Complete surgical removal of all gross tumor was achieved in 24 patients.
RESULT: The overall median survival time was 8 months, and the estimated 5-year survival rate 19%. There were significant differences in survival between the various stages (P = 0.01) and between the group of patients who underwent complete excision of the tumor and those with incomplete resection (P = 0.002).
CONCLUSIONS: Complete surgical excision offers the best prospect for long-term survival in localized adrenal carcinoma.
Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma.
Bellantone R, Ferrante A, Boscherini M, Lombardi CP, Crucitti P, Crucitti F, Favia G, Borrelli D, Boffi L, Capussotti L, Carbone G, Casaccia M, Cavallaro A, Del Gaudio A, Dettori G, Di Giovanni V, Mazziotti A, Marrano D, Masenti E, Miccoli P, Mosca F, Mussa A, Petronio R, Piat G, Marazano L, et al.
Istituto di Clinica Chirurgica, Policlinico Universitario A Gemelli, Rome, Italy
Surgery 1997 Dec;122(6):1212-8 Abstract quote
BACKGROUND: Recurrence of adrenal cortical carcinoma (ACC) after radical surgery is a common finding. Although successful reoperations have been reported with encouraging results, most published experiences are anecdotal and based on few cases. We report the results of surgical treatment for recurrent ACC in a multiinstitutional series.
METHODS: One hundred eighty-eight cases of ACC were collected in a national registry. A complete follow-up was obtained in 179 cases. At initial diagnosis 92 patients had local disease (stage I or II). One hundred seventy patients underwent surgical treatment, considered radical in 140; in this group, recurrent disease was observed in 52 cases (37%) after a mean disease-free interval of 21.7 months.
RESULTS: Adjuvant chemotherapy was ineffective in ameliorating the prognosis. The mean survival in 20 patients who underwent reoperation was significantly higher (15.85 +/- 14.9 months) than in nonreoperated cases (3.2 +/- 2.9 months). Five-year actuarial survival in reoperated patients is significantly better than in nonreoperated patients (49.7% versus 8.3%, respectively).
CONCLUSIONS: Although the prognosis of this tumor is still poor, surgery is the only effective therapy; reoperation allows survival comparable to that observed in patients without recurrent disease. An aggressive strategy for recurrent ACC is advisable until prospective studies demonstrate a real effectiveness for chemotherapy.
Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma.
Schulick RD, Brennan MF.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Ann Surg Oncol 1999 Dec;6(8):719-26 Abstract quote
BACKGROUND: One of the key issues in the treatment of adrenocortical carcinoma is the efficacy of repeat resection of local recurrence and metastatic disease in affected patients. Options in the treatment of locally recurrent or metastatic disease are limited because chemotherapy and radiotherapy generally do not provide any significant prolongation in survival in treated patients.
METHODS: A series of 113 patients who presented to Memorial Sloan-Kettering Cancer Center for treatment of adrenocortical carcinoma are presented.
RESULTS: The median overall survival for all 113 patients was 38 months (5-year survival, 37%). Patients presenting with early stage I or II disease (n = 57) had a median survival of 101 months (5-year survival, 60%), whereas those with late stage III or IV disease (n = 56) had a median survival of 15 months (5-year survival, 10%). Patients who had complete primary resection (n = 68) had a median survival of 74 months (5-year survival, 55%), whereas those with incomplete primary resection (n = 45) had a median survival of 12 months (5-year survival, 5%). Resection of locally recurrent or distant metastatic disease was performed in 47 of these patients. Patients who had a complete second resection had a median survival of 74 months (5-year survival, 57%), whereas those with incomplete second resection had a median survival of 16 months (5-year survival, 0%).
CONCLUSIONS: Improved survival is seen in patients who present with early stage and have complete primary resection. Patients who undergo complete repeat resection of local recurrence or distant metastasis also have improved survival. Complete repeat resection was more readily accomplished in discrete distant metastatic lesions compared with bulky local recurrences.
METASTASIS 52% had distant metastases at time of diagnosis
41% had locally advanced disease
7% had tumor confined to adrenal glandLung, retroperitoneal lymph nodes, liver, and bone most common sites
Adrenocortical carcinoma with cerebral metastasis in a child: case report and review of the literature.
Romaguera RL, Minagar A, Bruce JH, Jagid JR, Falcone S, Curless RG, Ragheb J, Morrison G.
Department of Pathology, University of Miami, Jackson Memorial Hospital, East Tower Room # 2142, 1611 NW 12th Ave., Miami, FL 33136, USA.
Clin Neurol Neurosurg 2001 Apr;103(1):46-50 Abstract quote
OBJECTIVE AND IMPORTANCE: Adrenocortical carcinoma (ACC) is rare in the pediatric population, and brain metastasis seldom occurs.
CLINICAL PRESENTATION: The authors report a case of metastatic ACC to the brain in a 9-year-old patient who had an adrenal cortex neoplasm removed at 4 years of age, and was free of symptoms for 5 years. Two weeks before admission she complained of blurred vision in both eyes.
INTERVENTION: Examination revealed bilateral papilledema, and a Magnetic Resonance Imaging (MRI) of the brain revealed a mass in the left lateral ventricle with extensive vasogenic edema and hydrocephalus. The tumor was removed, and histopathologic examination demonstrated metastatic ACC.
CONCLUSION: Although ACC is a rare neoplasm it must be considered in the differential diagnosis of cerebral lesions in patients with a history of this tumor. Periodic long-term brain imaging is suggested as part of the follow up in patients with adrenocortical neoplasms.
TREATMENT CHEMOTHERAPY Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study.
Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED.
Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, KS, USA.
Cancer 2000 Mar 1;88(5):1159-65 Abstract quote
BACKGROUND: A previous Southwest Oncology Group study demonstrated a 30% response rate with the combination of cisplatin and mitotane in the treatment of patients with metastatic adrenocortical carcinoma. Several case reports suggested that the combination of etoposide and cisplatin may be an active regimen in this disease. Because of these reports of potential activity, the authors conducted a Phase II trial evaluating the combination of etoposide and cisplatin. Due to the lack of data regarding the objective response rates to mitotane, the authors planned to evaluate the response rate to mitotane after disease progression on etoposide and cisplatin in patients with no prior mitotane therapy.
METHODS: Patients with advanced, unresectable, or metastatic adrenocortical carcinoma with objectively measurable disease or biochemical abnormalities received cisplatin, 50 mg/m(2), intravenously on Days 1 and 2, and etoposide, 100 mg/m(2), on Days 1, 2, and 3. Cycles were repeated every 21 days. At the time of disease progression, patients who had not previously received mitotane received 1000 mg orally 4 times a day along with cortisone acetate and fludrocortisone acetate.
RESULTS: Of the 47 patients entered onto the study, 45 were eligible. Nine patients had received mitotane previously and 36 had not. Objective responses were noted in 11% of patients (5 of 45 patients) (95% confidence interval, 3.7-24%). The median survival was 10 months. The most common toxic effects were hematologic, gastrointestinal, and neurologic. Only 16 patients with no prior mitotane therapy went on to receive mitotane at the time of disease progression. An objective response was noted in 13% of patients (2 of 16 patients). The most common toxic effects were edema and gastrointestinal effects.
CONCLUSIONS: The current study demonstrates that the combination of cisplatin and etoposide has minimal activity in advanced and metastatic adrenocortical carcinoma and other treatment strategies are warranted.
Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature.
Wooten MD, King DK.
Department of Oncology, Good Samaritan Regional Medical Center, Phoenix, Arizona.
Cancer 1993 Dec 1;72(11):3145-55 Abstract quote
BACKGROUND. Adrenal cortical carcinoma is rare; the authors have treated only eight patients with the disease at Good Samaritan Regional Medical Center since 1974. No exhaustive collection of cases of this cancer has been done since 1952.
METHODS. The authors retrospectively reviewed the medical records of their eight patients with adrenal cortical carcinoma. They also searched the English literature from 1952 to 1992 for reports of patients with the disease. They treated each report as a series if two or more previously unreported patients were reported. They paid special attention to patients for whom stage of disease was noted at diagnosis, treatment with mitotane (o,p'-DDD) was used, and the outcome was reported.
RESULTS. Five were male and three were female patients. Five had nonfunctional tumors. None were pediatric. The authors found 1891 cases in the English literature. Adrenal cortical carcinomas are more common in women (58.6%) than in men (41.4%). The age distribution of tumors is bimodal, with peaks in the first and fifth decades. Tumors in children are more commonly functional (83.5% in female patients, 85.6% in male patients), although nonfunctional tumors are more common in older patients (84.7%). Most (68%) of these tumors are diagnosed late in disease when surgery is no longer curative. Only 35% of patients treated with mitotane had a clinical response.
CONCLUSIONS. Adrenal cortical carcinomas are diagnosed most often in children because of functionality and older men because of mass effect. Most tumors are discovered too late for curative resection. Treatment of metastatic disease with mitotane has limited success.
GENERAL Adrenocortical carcinoma. A clinical study and treatment results of 52 patients.
Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska AM.
Department of Endocrinology, Center of Postgraduate Medical Education, Warsaw, Poland.
Cancer 1995 May 15;75(10):2587-91 Abstract quote
BACKGROUND. Adrenocortical carcinoma is a rare tumor with a poor prognosis. This work was aimed at analyzing the clinical outlook and treatment results of 52 patients with this disease.
METHODS. This study included patients with adrenocortical carcinoma referred to the Department of Endocrinology at the Center of Postgraduate Medical Education (Warsaw, Poland) during the last 30 years. In 11 patients, the adrenal tumor was found incidentally by ultrasonographic scan. Hormonal examinations made it possible to define the endocrine activity of the tumors, whereas imaging techniques helped to determine their staging. Forty-eight patients underwent surgery, and 36 of them received mitotane. This drug was administered to 26 patients for a range of 10 months to 10 years; 13 patients received mitotane immediately after the operation, and 13 others after a delay. The patients with severe hypercorticism were pretreated before surgery with aminoglutethimide and mitotane.
RESULTS. The study comprised 10 men and 42 women; hormonally active tumors were diagnosed in 39 of them. Cushing's syndrome was the most frequent entity. At diagnosis, 17 cases were classified as localized disease, 15 as regional disease, and 20 as distant disease. Pretreatment with the inhibitors of steroidogenesis improved the survival perspectives in the early postoperative period. As of this writing, there were 12 survivors in the group of 26 patients treated by surgery and long term mitotane therapy and only 2 survivors of 7 patients treated with surgery only.
CONCLUSIONS. Surgery with immediate adjuvant long term mitotane administration was the most effective form of therapy for patients with adrenocortical carcinoma.
Adrenocortical carcinoma--our experience with 11 cases.
Langer P, Bartsch D, Moebius E, Rothmund M, Nies C.
Department of General Surgery, Philipps-University Marburg, Germany.
Langenbecks Arch Surg 2000 Oct;385(6):393-7 Abstract quote
BACKGROUND AND AIMS: Adrenocortical carcinoma (ACC) is a rare tumour with an incidence of approximately 0.5-2 cases per million per year. Diagnosis is mostly delayed and prognosis is poor. We report our experiences with 11 patients operated on within the last 10 years.
PATIENTS/METHODS: The data of the patients with ACC were reviewed and presenting symptoms, diagnostic procedures, treatment and results of follow-up were evaluated.
RESULTS: The group of patients consisted of eight women and three men with a mean age of 40.2 (15-57) years. Median follow-up was 16 (1-71) months. Six patients presented with Cushing's syndrome, two presented with virilism and hirsutism caused by androgen-producing tumours. Three patients had hormonally inactive tumours. At the time of diagnosis, five tumours were classified as stage II, two as stage III and four as stage IV. Four patients had tumours with intravascular extension, prompting recurrence in two cases. Eight adrenalectomies, one resection of local recurrence, one adrenalectomy with splenectomy and one adrenalectomy and resection of a liver metastasis were performed. Five patients received additional chemotherapy. Five of the 11 patients are still alive (three stage II, one stage III and one stage IV at the time of diagnosis), three of whom have no evidence of disease (14, 48 and 71 months after surgery). The other six patients died after a median postoperative period of 10 (1-21) months.
CONCLUSIONS: Venography should be performed prior to surgery to detect or exclude thrombotic tumour masses in the suprarenal vein, renal vein or inferior vena cava. Radical surgery is the only curative approach and is recommended for all patients with resectable tumours, including those patients with recurrent disease. There is no consensus concerning adjuvant therapy. The value of multidisciplinary strategies needs to be assessed in multicentre trials.
Clinical management of malignant adrenal tumors.
Kopf D, Goretzki PE, Lehnert H.
Department of Endocrinology and Metabolism, Otto von Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
J Cancer Res Clin Oncol 2001;127(3):143-55 Abstract quote
Malignant primary adrenal tumors are rare forms of cancer with an estimated incidence of two to ten new cases per one million inhabitants per year. The 5-year survival rate for adrenocortical carcinoma is approximately 35%, whereas the 10-year survival rate of malignant pheochromocytoma reaches 40%. Clinical studies support repeated surgery as the mainstay of treatment, either with curative or palliative intention.
For adrenocortical carcinoma, adjunctive treatment with oral mitotane leads to well-documented improvement of survival. Rare malignant pheochromocytomas with distant metastases are preferably treated by 131I-MIBG. Chemotherapy is reserved for unresectable tumors without sufficient response to mitotane or 131I-MIBG, respectively. Cisplatin and etoposide as single therapy, or in combination with doxorubicin or etoposide, appear to be effective in adrenocortical carcinoma.
Malignant pheochromocytoma may be treated with vincristine, dacarbazine, and cyclophosphamide. Treatment with octreotide is currently being evaluated. Radiotherapy is indicated if unresectable tumor masses cause local symptoms. If symptoms of endocrine activity are not sufficiently controlled by measures aiming at tumor mass reduction, specific inhibitors of hormone synthesis or action are available. Ketoconazole is widely used for adrenocortical carcinoma, and phenoxybenzamine and metyrosine are available for malignant pheochromocytoma.
This review provides guidelines for rational disease management based on still scanty clinical evidence.
Adrenocortical carcinoma: surgical progress or status quo?
Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS, Thompson GB, Rowland C, Young WF Jr, van Heerden JA.
Department of Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Arch Surg 2001 May;136(5):543-9 Abstract quote
HYPOTHESIS: Outcome of patients with adrenocortical carcinoma (ACC) has improved with the advent of more widely available and higher quality imaging. Operative management strategies and use of adjuvant therapy have not changed.
DESIGN: Retrospective review of patient histories, imaging studies, operative data, adjuvant therapy, and outcomes at a single institution. Follow-up was complete for a mean of 53 months. Data was compared with prior institutional experience.
SETTING: Tertiary care referral center.
PATIENTS: All patients undergoing operative management for ACC during the period from 1980 to 1996.
MAIN OUTCOME MEASURES: Determinants of recurrence, survival, and the effect of adjuvant therapy on overall outcome.
RESULTS: Fifty-eight patients (30 men, 28 women) with a mean age of 53 years underwent primary operative management for ACC. Functional tumors were identified in 27 patients (47%). Mean tumor size was 12.5 cm. Stage according to the TNM staging system (AJCC Cancer Staging Manual) at presentation was I (n = 0), II (n = 30), III (n = 7), and IV (n = 21). Surgical management included curative resection in 41 (71%), noncurative resection in 14 (24%), and open biopsy in 3 (5%). Perioperative mortality was 5%. Recurrence occurred in 30 patients (73%) with a median time to recurrence of 17 months. Five-year survival by the Kaplan-Meier method was 37%. Prognostic factors (P<.05) included functional status, stage, and chemotherapy in stage III/IV patients. When compared with our prior institutional experience (1960-1980), current patients were more likely to present with stages I to II (52% vs. 34%), have curative resections (71% vs. 50%), and have improved 5-year survival (37% vs. 16%).
CONCLUSIONS: (1) Surgical resection remains the principal treatment for stage I to III disease. (2) Adjuvant therapy may improve survival in patients with stage III or IV disease. (3) Current patients were more likely to present at an earlier stage, undergo curative resections, and have improved 5-year survival than institutional historical comparisons.
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