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Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex. Adrenocortical masses are common, but only approximately 1 per 1500 adrenal tumors are malignant.

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Presentation

The findings during examination are variable and dependent on the endocrine syndromes that occur (if any exist) [6]. The majority of patients with functional tumors shows symptoms of Cushing syndrome including truncal obesity, striae, malar flushing, supraclavicular and dorsocervical fat pads. Hypertension with weakness and ileus resulting from hypokalemia (Conn syndrome), virilization, precocity, feminization and combined hormone excess also may be present. For nonfunctional tumors, signs and symptoms include fever, weight loss, abdominal, flank and back pain.

Adrenocortical carcinomas may be classified as [7]:

  • Functional
  • Nonfunctional
  • Well differentiated
  • Intermediate
  • Poorly differentiated to anaplastic
Virilization
  • A dramatic regression of virilization features occurred after adrenalectomy.[ncbi.nlm.nih.gov]
  • SETTING: Report virilizing oncocytic adrenocortical carcinoma in a 50-year-old woman. PATIENT: She presented a recent and progressive virilization syndrome, associated with high blood pressure.[ncbi.nlm.nih.gov]
  • As use of topical testosterone becomes more prevalent, exogenous exposure must be considered in the differential diagnosis of childhood virilization.[ncbi.nlm.nih.gov]
  • KEYWORDS: adrenocortical carcinoma; forensic science; pulmonary embolism; sudden death; tumor embolism; virilization[ncbi.nlm.nih.gov]
  • During follow-up, she gradually developed Cushingoid features and virilization. After a series of endocrine investigations, including urinary steroid profiling, a diagnosis of adrenocortical carcinoma was made.[ncbi.nlm.nih.gov]
Weakness
  • Without experience in the approach of this kind of tumor, managing becomes challenging and, moreover, we have only few recommendations, based on weak evidence. We report a case that has some peculiarities and is an excellent food for thought.[ncbi.nlm.nih.gov]
  • In 4 (50%) samples, IHC revealed a weak expression of progesterone receptor. Less frequent alterations were expression of PDGFR-α, c-KIT, and estrogen receptor, each in 1 case.[ncbi.nlm.nih.gov]
  • In addition, antimitochondrial antibodies showed a weak reaction and nuclear expression of integrase interactor 1 (INI1) was preserved.[ncbi.nlm.nih.gov]
  • High levels of cortisol may cause patients to develop Cushing's syndrome, characterized by obesity, high blood pressure, edema, muscle weakness, thin skin, easy bruising and increased blood sugar.[montefiore.org]
Weight Gain
  • A 9-year-old Japanese girl was hospitalized, because of the unstable emotions and excessive weight gain. She was diagnosed as having Cushing's syndrome and a left adrenal tumor.[ncbi.nlm.nih.gov]
  • Symptoms of these tumors include: weight gain fluid retention (leading to bloating) unusual excess hair growth unusual skin changes If the tumor presses against other organs, it may cause symptoms such as abdominal pain, an unusual feeling of fullness[mskcc.org]
  • […] blood sugar and pressure muscle weakness in the legs bruising in the body excessive weight gain in the chest and abdomen Both functioning and nonfunctioning tumors can cause abdominal pain if they become enlarged.[healthline.com]
Buffalo Hump
  • Symptoms of increased cortisol or other adrenal gland hormones may include: Fatty, rounded hump high on the back just below the neck ( buffalo hump ) Flushed, rounded face with pudgy cheeks ( moon face ) Obesity Stunted growth ( short stature ) Virilization[medlineplus.gov]
  • Symptoms Symptoms of increased cortisol or other adrenal gland hormones may include: Fatty, rounded hump high on the back just below the neck ( buffalo hump ) Flushed, rounded face with pudgy cheeks ( moon face ) Obesity Stunted growth ( short stature[ufhealth.org]
Precocious Puberty
  • Hetro-sexual precocious puberty could be the initial presentation of a rare adrenocortical neoplasm in the pediatric age group. Features of hetro-sexual precocious puberty in a girl should alert the possibility of such a rare disease.[ncbi.nlm.nih.gov]
  • Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time[ncbi.nlm.nih.gov]
  • Most tumors in children are functional, and virilization is by far the most common presenting symptom, followed by Cushing's syndrome and precocious puberty. [1] Among adults presenting with hormonal syndromes, Cushing's syndrome alone is most common,[en.wikipedia.org]
  • Virilization (in girls) or precocious puberty (in boys) is the most common endocrine presentation of a functional AC. Hirsutism, facial acne, oligo/amenorrhea, and increased libido all are possible presenting symptoms.[emedicine.medscape.com]
  • puberty (puberty occurring too early because of excess sex steroids produced) hyperaldosteronism (Conn's syndrome) (excess aldosterone leading to hypertension and low potassium) Updated on: 04/18/16 Adrenoleukodystrophy: Rare Genetic Neurological and[endocrineweb.com]
Abdominal Pain
  • Conversely, patients with non-functioning tumors may present with symptoms related to a mass-occupying lesion, such as abdominal pain and flank pain.[ncbi.nlm.nih.gov]
  • Symptoms of these tumors include: weight gain fluid retention (leading to bloating) unusual excess hair growth unusual skin changes If the tumor presses against other organs, it may cause symptoms such as abdominal pain, an unusual feeling of fullness[mskcc.org]
Abdominal Mass
  • Because the left abdominal mass was unresectable, the patient underwent a biopsy of the abdominal mass and a radical resection of the pelvic teratoma.[ncbi.nlm.nih.gov]
  • The third patient presented with a huge abdominal mass and weight loss. Local and distant metastases (both lungs) were detected at the time of diagnosis. The patient expired after 36 days of hospitalization.[ncbi.nlm.nih.gov]
  • When the common causes of bilateral oedema have been ruled out, no delay should be experienced seeking abdominal mass with vascular invasion potential, as early diagnosis and treatment may be lifesaving.[ncbi.nlm.nih.gov]
  • PubMed Google Scholar Roy CR, Wilson T, Raife M, Horne D: Varicocele as the presenting sign of an abdominal mass. J Urol. 1989, 141: 597-599.[dx.doi.org]
Abdominal Fullness
  • . • Tumor-related symptoms – Local symptoms: abdominal fullness, back pain, nausea and vomiting. – Systemic / metastatic futures: Anorexia, anaemia, asthenia and weight loss and features of metastasis. – Hormone secreting ACC (50% to 79% of adult and[slideshare.net]
  • fullness, or symptoms related to metastases.[clinicaladvisor.com]
  • Patients complain of pain in the abdomen, flank or back, often with associated nausea, vomiting or abdominal fullness. Weight loss and loss of appetite are common. Metastases can occur within the abdomen to liver, but also to lungs and bones. 3.[endocrinesurgery.net.au]
  • Although in some cases, they are found incidentally, during either examination or radiologic imaging, nonfunctional ACs typically present with any of the following: Fever Weight loss Abdominal pain and tenderness Back pain Abdominal fullness Symptoms[emedicine.medscape.com]
  • fullness Symptoms related to metastases See Clinical Presentation for more detail.[emedicine.com]
Hypertension
  • Hyperaldosteronism is a cause of secondary hypertension and its diagnosis is usually benign.[ncbi.nlm.nih.gov]
  • CASE PRESENTATION: A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia.[ncbi.nlm.nih.gov]
  • Moreover, aldosterone-producing adrenocortical carcinomas without hypertension are exceedingly rare, with only two previously reported cases. KEYWORDS: Aldosterone; Carcinoma; Hyperaldosteronism; Hypertension[ncbi.nlm.nih.gov]
  • Disruption of adrenal steroid production results in a variety of diseases that can lead to hypertension, metabolic syndrome, infertility and androgen excess.[ncbi.nlm.nih.gov]
  • In this paper, we report a 12-year-old Chinese girl who was diagnosed with female pseudohermaphroditism characterized by clitoridauxe, hirsutism, acne, hypertension, and karyotype 46 XX.[ncbi.nlm.nih.gov]
Palpitations
  • Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache and hypokalemia (low serum potassium, which can in turn produce muscle weakness, confusion, and palpitations ), low plasma renin activity, and high[en.wikipedia.org]
  • Historically patients with pheochromocytomas would have symptoms of headaches, sweating and heart palpitations, but in modern times many patients are totally asymptomatic. Adrenocortical cancer is uncommon.[ucdmc.ucdavis.edu]
Back Pain
  • Abstract Hormonally inactive adrenocortical carcinoma (ACC) is a rare disease where abdominal discomfort and back pain are common presenting symptoms due to mass effect from a large tumor.[ncbi.nlm.nih.gov]
  • For nonfunctional tumors, signs and symptoms include fever, weight loss, abdominal, flank and back pain.[symptoma.com]
  • . • Tumor-related symptoms – Local symptoms: abdominal fullness, back pain, nausea and vomiting. – Systemic / metastatic futures: Anorexia, anaemia, asthenia and weight loss and features of metastasis. – Hormone secreting ACC (50% to 79% of adult and[slideshare.net]
  • pain caused by mass effect Highly necrotic tumors may cause fever and clinically simulate infectious process Tend to invade adrenal vein, vena cava, adjacent kidney and retroperitoneum; may cause thromboemboli Metastases to liver (60%), regional lymph[pathologyoutlines.com]
  • The common signs and symptoms of Adrenocortical Carcinoma that are observed are: Presence of a mass in the abdomen Abdominal and back pain Virilization: Due to an overproduction of androgens (hormone type), females may present with a deepened voice, acne[dovemed.com]
Muscle Weakness
  • High levels of cortisol may cause patients to develop Cushing's syndrome, characterized by obesity, high blood pressure, edema, muscle weakness, thin skin, easy bruising and increased blood sugar.[montefiore.org]
  • Having too much of this hormone may lead to high blood pressure muscle weakness or cramps frequent urination feeling thirsty fluid build-up in the body's tissues Androgens and estrogen are hormones that help develop and maintain sex characteristics that[drugs.com]
  • weakness in the legs bruising in the body excessive weight gain in the chest and abdomen Both functioning and nonfunctioning tumors can cause abdominal pain if they become enlarged.[healthline.com]
Hirsutism
  • We present a case of a testosterone-secreting oncocytic adrenocortical carcinoma in a 19-year-old female who presented with acne, hirsutism and irregular menses.[ncbi.nlm.nih.gov]
  • In this paper, we report a 12-year-old Chinese girl who was diagnosed with female pseudohermaphroditism characterized by clitoridauxe, hirsutism, acne, hypertension, and karyotype 46 XX.[ncbi.nlm.nih.gov]
  • Hirsutism, acne and deepening of the voice may be apparent in both sexes. Girls may also present with cliteromegaly and facial hair, while boys present with phallomegaly and early virilisation.[orpha.net]
  • , Bishop Auckland General Hospital, Cockton Hill Road, Bishop Auckland, Co Durham DL 14 6AD, UK; s.nag{at}btopenworld.com Statistics from Altmetric.com adrenocortical carcinoma Cushing’s syndrome A 46 year old woman presented with a short history of hirsutism[pmj.bmj.com]
Decreased Libido
  • Feminization ( estrogen excess) is most readily noted in men, and includes breast enlargement, decreased libido, and impotence. [1] [2] [7] Pathophysiology [ edit ] The main etiologic factor of ACC is unknown, although families with Li–Fraumeni syndrome[en.wikipedia.org]
Flank Pain
  • CASE PRESENTATION: We herein report a case of a 30-year-old Sri-Lankan woman who presented with a 3-month history of left flank pain associated with nausea, vomiting, and weight loss.[ncbi.nlm.nih.gov]
  • Conversely, patients with non-functioning tumors may present with symptoms related to a mass-occupying lesion, such as abdominal pain and flank pain.[ncbi.nlm.nih.gov]
  • Regarding clinical features, 14 patients presented with flank pain, 8 patients presented generalized edema or general weakness. 3 patients presented with virilizing features.[sages.org]
  • Rarely, pheochromocytoma -like hypersecretion of catecholamines has been reported in adrenocortical cancers. [5] Nonfunctional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele, and renal vein thrombosis [6][en.wikipedia.org]
  • pain), weight loss, fever, back pain, abdominal fullness, or symptoms related to metastases.[clinicaladvisor.com]
Amenorrhea
  • Abstract A Chinese adolescent girl presented with secondary amenorrhea. During follow-up, she gradually developed Cushingoid features and virilization.[ncbi.nlm.nih.gov]
  • We discuss the frequently erroneous routine treatment with oral hormonal contraception without thorough differential diagnosis in female patients with oligo-/amenorrhea and subsequent delay in the proper diagnosis of adrenocortical carcinoma.[ncbi.nlm.nih.gov]
  • Hirsutism, facial acne, oligo/amenorrhea, and increased libido all are possible presenting symptoms. Feminization as a presentation of AC is quite rare.[emedicine.medscape.com]
Secondary Amenorrhea
  • Abstract A Chinese adolescent girl presented with secondary amenorrhea. During follow-up, she gradually developed Cushingoid features and virilization.[ncbi.nlm.nih.gov]
Headache
  • Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache and hypokalemia (low serum potassium, which can in turn produce muscle weakness, confusion, and palpitations ), low plasma renin activity, and high[en.wikipedia.org]
  • Historically patients with pheochromocytomas would have symptoms of headaches, sweating and heart palpitations, but in modern times many patients are totally asymptomatic. Adrenocortical cancer is uncommon.[ucdmc.ucdavis.edu]
Confusion
  • In most cases, the drug-induced changes are not large enough to cause diagnostic confusion, but, when interpreting mild abnormalities in DHEA-S levels, drug and hormone interactions should be taken into account.[clinicaladvisor.com]
  • Conn syndrome (mineralcorticoid excess) is marked by high blood pressure, which can result in headache and hypokalemia (low serum potassium, which can in turn produce muscle weakness, confusion, and palpitations ), low plasma renin activity, and high[en.wikipedia.org]

Workup

All hormonal syndromes need to be confirmed with laboratory testing. In Cushing syndrome, the laboratory findings include increased urine cortisol and serum glucose. Adrenal virilism is confirmed by the finding of an excess of low serum potassium, low plasma renin activity and also high serum aldosterone. Exces serum estrogen depicts feminization [8]. To identify the site of the tumor, imaging studies of the abdomen, such as CT scans and magnetic resonance imaging are useful. They aid in differentiating ACC from other masses and in determining the extent of invasion of the tumor into surrounding tissues and organs. CT scans of the chest and bone scans are routinely performed to examine for metastases to the bones or lungs.

Androgens Increased
  • Testosterone and other androgens: increased facial and body hair, particularly in females deepened voice in females Estrogen: early signs of puberty in children enlarged breast tissue in males Aldosterone: weight gain high blood pressure Cortisol: high[healthline.com]

Treatment

Presently, the major treatment is total surgical excision of the tumor. This can be done even if the tumor has invaded large blood vessels like inferior vena cava or the renal vein. The 5-year survival rate after a successful surgery is around 60% however, majority of the patients are not surgical candidates [9]. For patients who are not surgical candidates, radiation therapy and radiofrequency ablation are used as palliation. For chemotherapy regimens, the drug mitotane and other standard cytotoxic drugs are used. Mitotane is an inhibitor of steroid synthesis and this is toxic to the cells of the adrenal cortex.

Prognosis

The efficacy of treatment is largely dependent on the stage of the cancer. Therefore early detection is paramount if the individual is to survive.

Etiology

Although the mutation-induced inactivation of tumor suppressor genes appears to be a plausible mechanism for ACC development, other potential mechanisms, including activation of various protooncogenes (eg, ras, PKC), inhibition of apoptosis, or changes in various adrenocortical tissue-specific factors (eg, the steroidogenic acute regulatory protein (StaR)) are possible [3]. Potential mechanisms for adrenocortical tumorigenesis are as follows:

  • Activation of various protooncogenes -Ras, PKC, C myc, C fos, G proteins, G protein-coupled receptors (eg, for vasoactive intestinal peptide (VIP), gastric-inhibitory peptide (GIP), luteinizing hormone (LH), and catecholamines)
  • Inactivation of tumor suppressor genes (antioncogenes) -TP53, TP57, TP16, H19, retinoblastoma gene, APC gene, various DNA repair enzyme genes
  • Inhibition of senescence and/or apoptosis - Mutations involving telomerase and/or BCL-2 genes
  • Changes in adrenocortical tissue-specific factors - Mutations involving the genes for StaR, SF-1 (steroidogenic factor), and Dax-1 transcription factor
  • Aberrant expression of receptors to normal adrenocortical trophic agents and ligands - Adrenocorticotropic hormone, angiotensin 2, catecholamines, and endorphins
  • Ectopic expression of receptors on adrenocortical cells to atypical trophic factors and ligands - Cytokines, growth factors, and neurotransmitters

Epidemiology

Internationally, the tumors are uncommon [1] [2]. With approximately 0.6-1.67 cases per 1 million people each year, the incidence is relatively low. Some reports say that incidence is ten times higher in southern Brazilian children for reasons unknown. Overall however, ACC accounts for 0.02-0.2% of all cancer-related deaths so the disease is rightly adjudged as rare.

ACC does not have any racial predilection and the female to male ration is 2.5-3.1. The male patients tend to be older than the females and the prognosis is better for females. However, the females are more likely than the male counterparts to have an associated endocrine syndrome. Nonfunctional ACCs occur equally between both sexes. ACC has two major periods of occurrence, the first decade of life and the fourth and fifth decade of life. 75% of children who have ACC are younger than 5 years of ages. Nonfunctional tumors are more common in adults but functional tumors are common in children.

Sex distribution
Age distribution

Pathophysiology

Although some reports point to an increased predilection for the left adrenal, majority of reports show no side preference. The exact etiopathogenesis of sporadic ACC is unclear but analysis of the syndromic variants of the condition provides some insight [4]. The role of tumor suppressor gene mutations is suggested by their association with Li-Fraumeni syndrome, which is characterized by inactivating germline mutations of the TP53 gene (a vital tumor suppressor gene or antioncogene) on chromosome 17. This syndrome also is associated with a predisposition to other malignancies, including breast carcinoma, leukemia, osteosarcoma, and soft-tissue sarcoma.

A few reports describe an association between AC and familial adenomatous polyposis, which also is due to a germline inactivating mutation of a tumor suppressor gene (in this case, the adenomatous polyposis coli gene, APC) [5]. However, such mutations have not been found in sporadic APC cases.

Suggestions have been made that adrenal hyperplasia predisposes patients to develop ACC. A few cases of congenital adrenal hyperplasia are associated with functional adrenocortical adenomas but not carcinoma.

Prevention

Majority of adrenal gland tumors are not linked to family history but some are linked to genetic defects. This means that there is really no way to prevent the disease. The best bet is to focus on early detection.

Summary

Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex and can be equally referred to as adrenal cortical carcinoma. The adrenal cortex represents the outer layer of the adrenal glands which are located at the upper poles of the kidneys. The adrenal cortex secretes mineralocorticoids, glucocorticoids and adrenal androgen. The presentation varies depending on hormone excess or local tumor growth and adrenal incidentalomas are common [1].

Patient Information

Adrenocortical carcinoma is a rare cancerous growth in the adrenal cortex. Patients have to be on the lookout for reoccurrence of growth. This will be dealt with by surgery as well [10]. For healthy individuals or people in a family with history of ACC, family members around the peak years for ACC occurrence should be monitored for symptoms like lump in the abdomen, pain in the abdomen or back, unusual hair growth, irregular menstrual cycles, irregular sexual behavior and in children, early puberty.

References

Article

  1. Angeli A, Osella G, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res. 1997;47(4-6):279-83.
  2. Villelli NW, Jayanti MK, Zynger DL. Use and Usefulness of Adrenal Core Biopsies Without FNA or On-site Evaluation of Adequacy: A Study of 204 Cases for a 12-Year Period. Am J Clin Pathol. Jan 2012;137(1):124-31.
  3. Lau SK, Weiss LM. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum Pathol. Jun 2009;40(6):757-68.
  4. Soon PS, Gill AJ, Benn DE, Clarkson A, Robinson BG, McDonald KL, et al. Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr Relat Cancer. Jun 2009;16(2):573-83.
  5. Miller BS, Gauger PG, Hammer GD, et al. Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch Surg 2010; 395:955.
  6. Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf) 2004; 60:273
  7. Reibetanz J, Jurowich C, Erdogan I, et al. Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg 2012; 255:363.
  8. Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 1981; 71:855.
  9. Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002; 20:941.
  10. Hough AJ, Hollifield JW, Page DL, Hartmann WH. Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Am J Clin Pathol 1979; 72:390.

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Last updated: 2018-06-21 22:27