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]

  Most tumors in children are functional, and virilization is by far the most common presenting symptom, followed by Cushing's syndrome and precocious puberty. [youtube.com]

• Weakness

  In addition, antimitochondrial antibodies showed a weak reaction and nuclear expression of integrase interactor 1 (INI1) was preserved. [ncbi.nlm.nih.gov]

  “In other patients, adrenal cancer makes abnormally high levels of hormones and causes symptoms such as weight gain or loss, muscle weakness, trouble sleeping or a deepening voice. Women may develop facial hair.” [hopkinsmedicine.org]

  Weakness and diffuse muscular pain are common due to severe hypokalemia, but these symptoms are not useful in differentiating APAC from an aldosterone secreting adenoma or hyperplasia (5). [turkjem.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 adrenal cancer might include weight gain, muscle weakness, trouble sleeping, deepening voice and increased hair growth, usually on the face (in women), pain in the abdomen or lower back, weight loss or loss of appetite. [hopkinsmedicine.org]

  Adrenocortical carcinomas may also produce excess hormones that may cause weight gain, excess facial hair or early puberty. If an adrenal tumor is larger than 5 to 6 centimeters, it is usually assumed to be cancer. [cancercenter.com]

  and unexpected weight loss. [mskcc.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]

  Most tumors in children are functional, and virilization is by far the most common presenting symptom, followed by Cushing's syndrome and precocious puberty. [youtube.com]

  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]

• Buffalo Hump

  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) Virilization [mountsinai.org]

  For Cushing's syndrome (glucocorticoid excess) these include weight gain, muscle wasting, purple lines on the abdomen, a fatty "buffalo hump" on the neck, a "moonlike" face, and thinning, fragile skin. [youtube.com]

  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 [nlm.nih.gov]

• Abdominal Pain

  Large tumors can cause abdominal pain as a late manifestation. Physicians should perform a complete abdominal examination in every patient with varicocele or testicular 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]

  This abdominal CT image shows a large left-sided retroperitoneal mass. Figure 2 Sagittal view of abdominal computed tomography (CT) examination of the patient. [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]

  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]

  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]

  […] or flank pain), weight loss, fever, back pain, abdominal fullness, or symptoms related to metastases. [clinicaladvisor.com]

  Patients with large adrenal tumors may experience feelings of abdominal fullness or localized pain. Patients may feel as though they are quickly full when eating and may experience weight loss. [oncolink.org]

• Jaundice

  After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. [ncbi.nlm.nih.gov]

• Hypertension

  Hyperaldosteronism is a cause of secondary hypertension and its diagnosis is usually benign. [ncbi.nlm.nih.gov]

  In most cases clinical picture reveals classical signs of Conn’s syndrome; hypertension and hypokalemia. [turkjem.org]

• Thrombosis

  Also, renal vein thrombosis is frequent in ACC and is part of the European Network for the Study of Adrenal Tumours (ENSAT) staging system. [dx.doi.org]

  Acute kidney injury can occur as a result of mass effect or thrombosis of renal vessels. Large tumors can cause abdominal pain as a late manifestation. [ncbi.nlm.nih.gov]

  Adrenocortical carcinoma presenting as varicocele and renal vein thrombosis: a case report. J Med Case Rep 2011 ; 5 : 337 [Google Scholar] 3. Kumar S, Choudhary GR, Pushkarna A. [internationalsurgery.org]

• 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 serum [youtube.com]

  He had no chest pain or palpitations. He reported asthenia and anorexia in the last 6 months, with a 10 kg weight loss. Physical examination was unremarkable, and vital signs were normal, with the exception of fever. [archbronconeumol.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]

  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 serum [en.wikipedia.org]

• 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]

  A detailed enquiry of his family members revealed that he had history of anorexia, weight loss, low back pain, low-grade intermittent fever with evening rise of temperature for 1 month. He had two episodes of hemoptysis in the recent past. [ccij-online.org]

  • 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 Fever Loss of appetite Loss of weight without trying Causes It's not clear what causes adrenal cancer. [mayoclinic.org]

  For nonfunctional tumors, signs and symptoms include fever, weight loss, abdominal, flank and back pain. [symptoma.com]

• Muscle Weakness

  “In other patients, adrenal cancer makes abnormally high levels of hormones and causes symptoms such as weight gain or loss, muscle weakness, trouble sleeping or a deepening voice. Women may develop facial hair.” [hopkinsmedicine.org]

  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, excess hair production, changes in libido or voice, muscle weakness and acne are all potential warning signs. Sometimes, secondary conditions, such as Cushing’s syndrome, can develop as a result of an adrenal tumor’s hormone production. [moffitt.org]

  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 serum [youtube.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]

  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]

• Alopecia

  She noticed voice deepening and alopecia. Physical examination showed male-type alopecia and intense hirsutism. Tanner stage was 3 for breast tissue and 5 for pubic hair. There was no galactorrhea. Body mass index was 21.4 kg/m2. [ncbi.nlm.nih.gov]

• Flank Pain

  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. Imaging revealed a large left upper quadrant mass with a 1.8-cm left lung nodule. [ncbi.nlm.nih.gov]

  Non-functional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele and renal vein thrombosis or they may be asymptomatic and detected incidentally. [youtube.com]

  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]

• Amenorrhea

  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]

  In females, clitoral enlargement, facial and pubic hair with male escutcheon, amenorrhea and rarely temporal balding were the most common. Corresponding signs in males include penile enlargement and precocious isosexual pseudo-puberty. [scielo.br]

• 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 serum [youtube.com]

  Symptoms: Anxiety, Constipation, Diarrhea, Dizziness, Dry Mouth, Fatigue, Headache, Itchy/Dry Skin, Mouth Sores, Nausea, Numbness, Shortage of Breath, etc. [play.google.com]

  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]

  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 serum [en.wikipedia.org]

• Confusion

  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 serum [youtube.com]

  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 serum [en.wikipedia.org]

  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. [cancerjournal.net]

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.

• Nephrolithiasis

  History and/or current evidence of clinically relevant ectopic mineralization/calcification including but not limited to the soft tissue, kidneys, intestine, myocardium, and lung with the exception of calcified lymph nodes, asymptomatic nephrolithiasis [clinicaltrialsregister.eu]

• Hypoglycemia

  Other modes of presentation include profound weakness, hypertension, and/or ileus from hypokalemia related to hyperaldosteronism and hypoglycemia. [emedicine.medscape.com]

  Functional ACC clinical symptoms are associated with glucocorticoid excess: weight gain, weakness, and insomnia develop rapidly, hypertension, hypokalemia related to hyperaldosteronism, and hypoglycemia. [clinicaladvisor.com]

  Adrenocortical carcinoma and hypoglycemia: evidence for production of nonsuppressible insulin-like activity by the tumor. J. Clin. Endocrinol. Metab. 44, 1175–1184 (1977). 65. Wajchenberg, B. et al. [nature.com]

  In one patient, the abdominal mass was associated with symptomatic hypoglycemia. Table 3. Table 3. Functional Status of 105 Adrenocortical Carcinomas, as Determined by the Measurement of Steroids in Plasma, Urine, or Both. [nejm.org]

  This growth factor exerts insulin‐like activity, acting on the insulin receptor.9, 14, 20, 43, 44 No patients in our series exhibited hypoglycemia. [acsjournals.onlinelibrary.wiley.com]

• 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]

• Hepatocellular Carcinoma

  Fine- needle aspiration of the mass revealed malignant cells compatible with hepatocellular carcinoma. [ncbi.nlm.nih.gov]

  […] similar entities such as hepatocellular carcinoma, in fine-needle aspiration biopsy specimens. [archivesofpathology.org]

  carcinomas Jessica Zucman-Rossi INSERM U1162 Paris Génétique Humaine ALLOGENOMICS Whole exome sequencing inlivingDonor/Recipient kidney transplants Laurent Mesnard INSERM-IMR 1155-Hôpital Tenon Paris Génétique Humaine FCD-Genomics Large scale genomic [france-genomique.org]

  carcinoma development using liver stiffness measurement (FibroScanⓡ) (초) 저자 : Kyu Sik Jung, Seung Up Kim, Sang Hoon Ahn, Young Nyun Park, Do Young Kim, Jun Yong Park, Chae Yoon Chon, Kwang Hyub Han 발행기관 : 대한내과학회 간행물 : 대한내과학회 추계학술발표논문집 2010권 0호 발행 연도 [kiss.kstudy.com]

  Metastatic hepatocellular carcinoma. Metastatic renal cell carcinoma. Epithelioid angiomyolipoma. Images ACC - low mag. (WC/Nephron) ACC - intermed. mag. (WC/Nephron) ACC - high mag. (WC/Nephron) ACC with normal adrenal medulla - high mag. [librepathology.org]

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.

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

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

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.

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.

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.

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].

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.

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9. Stojadinovic A, Ghossein RA, Hoos A, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002; 20:941.
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