Metastatic and Unusual Presentations of ACC

Clinical Presentation

Adrenocortical carcinoma (ACC) is a rare malignant tumor of the adrenal cortex that most often presents through an adrenal mass, steroid hormone excess, or symptoms related to local tumor growth. A smaller body of literature describes metastatic and otherwise unusual presentations in which the first recognized problem is distant disease, major venous extension, hemorrhage, or a systemic paraneoplastic syndrome rather than a clearly identified primary adrenal lesion.¹²³⁴ Within the broader hierarchy of ACC clinical presentation, these patterns generally reflect advanced disease biology, atypical endocrine behavior, or both.

These presentations are clinically important because they may obscure the adrenal origin and redirect the diagnostic workup toward more common pulmonary, vascular, hepatobiliary, neurologic, or inflammatory disorders. ACC may therefore enter the differential only after evaluation for metastatic cancer of unknown primary, pulmonary embolism, spontaneous retroperitoneal hemorrhage, refractory hypoglycemia, or unexplained systemic syndromes.³⁵⁴ In contrast with more typical ACC presentations, the dominant clinical problem in these cases is often extra-adrenal.

The evidence base is limited and is dominated by single case reports and small retrospective experiences, usually from tertiary centers and often involving dramatic or advanced presentations.⁶⁷ As a result, the literature is more reliable for pattern recognition than for estimating frequency, prognosis, or comparative treatment benefit. Reported paraneoplastic associations in particular may be affected by publication bias, and causality is often inferred from temporal association with tumor treatment rather than demonstrated mechanistically.⁸⁹

Diagnostic Context

ACC has heterogeneous hormonal activity and a strong tendency toward both local invasion and distant spread. Typical presentations include abdominal or flank symptoms, incidental discovery of an adrenal mass, or endocrine syndromes driven by cortisol, androgen, or mixed steroid excess. By contrast, unusual presentations are often associated with larger tumors, clinically silent or nonfunctioning primaries, or metastatic deposits that dominate the initial presentation.¹⁰¹¹⁷

Metastatic and recurrent ACC may also show endocrine behavior that differs from the primary tumor, including persistence, loss, or change in steroid secretion.¹²¹³ This observation is supported mainly by case-level data and should not be treated as a quantified rule, but it has a practical implication: recurrent or metastatic disease should not be assumed to reproduce the hormonal phenotype present at diagnosis.

Taken together, the literature supports a task-oriented framework that groups atypical presentations into metastasis-dominant disease, vascular invasion and thromboembolic complications, hemorrhagic presentation, paraneoplastic or systemic syndromes, and unusual endocrine phenotypes.

Metastasis-Dominant Presentation

Some patients with ACC first come to medical attention because of symptomatic metastatic lesions, with the adrenal primary recognized only later. In such cases, ACC may mimic a primary tumor of the involved organ, especially when thoracic, ocular, or neurologic symptoms dominate the clinical picture.¹⁴³¹⁵

Pulmonary metastases are the most frequently described example of this pattern. Reported manifestations include dominant lung lesions, diffuse cannon-ball metastases, and rare endobronchial involvement producing cough, dyspnea, hemoptysis, atelectasis, or post-obstructive infection.¹⁴³¹⁶ These reports reliably show that thoracic disease may overshadow the adrenal primary, but they do not establish incidence or a prognosis distinct from advanced-stage ACC in general. Clinically, an adrenal source may warrant consideration when metastatic thoracic disease coexists with an adrenal mass or unexplained steroid-related findings.

More unusual metastatic presentations involve the orbit or eye, including extraocular muscle metastasis causing diplopia and isolated retinal manifestations.¹⁵¹⁷ The evidence for these phenotypes is especially sparse and mainly illustrative. Their main value is to broaden the differential diagnosis of metastatic disease rather than to define a routine ACC screening target.

Venous Invasion, Tumor Thrombus, and Thromboembolism

A distinct presentation pattern involves direct venous extension from the adrenal vein into the renal vein, inferior vena cava, hepatic veins, and occasionally the right atrium.¹¹⁸¹¹ Patients may present with lower-extremity edema, venous congestion, cardiac inflow obstruction, or signs discovered during evaluation of advanced metastatic disease.

ACC may also present with venous thromboembolism separate from contiguous tumor thrombus, including deep vein thrombosis and pulmonary embolism.¹⁹⁴ Available reports suggest that both mechanical vascular invasion and hypercoagulability may contribute, with hypercortisolism providing a plausible additional prothrombotic mechanism in functional tumors.¹⁹⁴ This relationship is clinically credible but not well quantified. The practical implication is that thrombosis in a patient with an adrenal mass may indicate locally advanced or biologically aggressive disease and may require coordinated endocrine, oncologic, vascular, and cardiothoracic evaluation.¹¹¹

This vascular pattern overlaps with another emergency presentation in the literature: spontaneous rupture and hemorrhage.

Spontaneous Rupture and Hemorrhagic Presentation

Spontaneous rupture of ACC with retroperitoneal or intraperitoneal hemorrhage is an uncommon but repeatedly described emergency presentation.²²⁰⁷ Patients may present with acute abdominal or flank pain, hypotension, anemia, or shock, sometimes without prior hormonal clues or a known adrenal lesion.

Case reports suggest that large and clinically silent tumors may be overrepresented among ruptured lesions, plausibly because delayed recognition permits progressive growth until bleeding occurs.¹³⁷ This pattern is suggestive rather than definitive because comparative datasets are lacking. In practice, these reports support including adrenal malignancy in the differential diagnosis of spontaneous retroperitoneal hemorrhage, while recognizing that hemodynamic stabilization usually precedes complete oncologic characterization.²²⁰

Paraneoplastic and Systemic Syndromes

Paraneoplastic manifestations expand the apparent clinical spectrum of ACC but remain supported mainly by isolated reports. The most coherent syndrome is non-islet cell tumor hypoglycemia, typically characterized by severe or recurrent hypoglycemia with suppressed insulin and C-peptide and biochemical findings consistent with IGF-II-mediated tumor activity.^21222324 Improvement after tumor resection in several reports makes this association relatively persuasive, although its true frequency is unknown. Clinically, otherwise unexplained hypoglycemia in a patient with a large adrenal tumor may justify consideration of tumor-mediated glucose dysregulation rather than insulin excess alone.

Other reported systemic syndromes include fever of unknown origin, erythrocytosis, polymyositis-like weakness, thrombotic microangiopathy, cholestatic liver dysfunction resembling Stauffer syndrome, and possible autoimmune phenomena such as vitiligo.^102526659 These reports support the general point that ACC may coincide with inflammatory, hematologic, or autoimmune-appearing abnormalities, but causality is often uncertain and mechanism usually unproven. The practical implication is not that these syndromes are characteristic of ACC, but that they may occasionally prompt diagnosis or suggest recurrence when more common explanations have been excluded.

Rare neurologic and ophthalmologic paraneoplastic associations, including neuromyelitis optica spectrum disorder and retinal disease, remain hypothesis-generating only.⁸¹⁷ Their main research value is in defining the outer limits of the ACC phenotype rather than guiding routine care.

Unusual Endocrine Phenotypes

Although ACC is classically associated with cortisol and androgen excess, the unusual-presentation literature includes rarer endocrine patterns such as isolated testosterone secretion, gynecomastia, adrenal insufficiency from bilateral adrenal destruction, and severe hypercortisolism presenting with cardiovascular complications such as stress cardiomyopathy.^27281918

These reports support the broader principle that endocrine phenotype in ACC may be heterogeneous, particularly in advanced or metastatic disease. However, the evidence does not define stable endocrine subtypes with known prevalence or independent prognostic significance. The practical implication is that hormonal assessment may need to remain broad when ACC is suspected, especially when symptoms do not fit a standard cortisol-androgen pattern.

Clinical Implications and Limits of the Evidence

Across these atypical presentations, the most consistent theme is diagnostic misattribution. ACC may initially resemble primary lung cancer, isolated thromboembolic disease, hepatobiliary dysfunction, autoimmune illness, or nonspecific constitutional decline.³⁵⁴ The literature is therefore most useful as a source of clinical pattern recognition when an adrenal mass coexists with unexplained metastases, venous tumor thrombus, spontaneous retroperitoneal bleeding, severe hypoglycemia, or unusual systemic syndromes.

At the same time, the available evidence is too limited to support firm conclusions about incidence, prognosis, or optimal management for most of these presentations.⁶⁷ Poor outcomes reported in unusual presentations may simply reflect advanced stage rather than a distinct biologic subtype. For research, these cases are best viewed as descriptive phenotypes that highlight gaps in registry-based characterization, endocrine-metastatic correlation, and multidisciplinary management rather than as well-defined ACC subgroups.

Included Articles

• PMID 559689: This case report describes adrenocortical carcinoma presenting with severe hypoglycemia despite low or undetectable immunoreactive insulin, with evidence of elevated nonsuppressible insulin-like activity and NSILA-s related peptides in serum and tumor extracts. The findings support a rare paraneoplastic hypoglycemic presentation caused by tumor-derived insulin-like factors.²¹

• PMID 3340389: This case series highlights prolonged fever of unknown origin as a possible presenting manifestation of adrenal tumors, including nonfunctional adrenocortical carcinoma. In the reviewed ACC literature cited by the authors, fever appeared mainly in nonfunctioning and often advanced tumors, and occasionally was the first sign of disease.¹⁰

• PMID 6021528: This case report describes bilateral nonfunctioning adrenocortical carcinoma presenting with flank pain, weight loss, weakness, and an Addisonian picture from extensive bilateral adrenal destruction. It also notes metastases to pleura, periaortic lymph nodes, and brain, highlighting an unusual metastatic presentation.²⁷

• PMID 6852356: This case report provides experimental evidence that metastatic ACC tissue can remain hormonally active and synthesize corticosteroids, potentially causing biological and clinical relapse after apparent remission. It also notes that metastatic lesions may differ in secretory behavior, with some metastases reported as non-secreting.¹²

• PMID 8776824: This case report describes a very rare paraneoplastic presentation of adrenocortical carcinoma with erythrocytosis and elevated erythropoietin, which normalized after adrenal tumor resection. The tumor also caused local mass effects including a palpable retroperitoneal mass, left varicocele, and venous tumor thrombus.²⁵

• PMID 10490573: This case report describes ACC presenting with lower-limb oedema, hypertension, a large abdominal mass, and extensive venous tumor thrombus extending through the inferior vena cava into the right atrium, with concurrent liver, lung, and cerebral metastases. It highlights intracardiac venous extension as a rare but dramatic presentation pattern.¹

• PMID 11518119: This case report highlights non-islet cell tumor hypoglycemia as a rare presenting manifestation of ACC, associated with elevated serum IGF-II, low IGF-I and IGFBP-3, and resolution of hypoglycemic attacks after tumor resection. The report also describes concurrent hypokalemia that improved postoperatively.²²

• PMID 12849123: A case report describes recurrent adrenocortical carcinoma presenting with paraneoplastic polymyositis, marked by proximal painless muscle weakness and creatine kinase elevation. Serial creatine kinase levels fell after metastasectomy and rose with relapse, preceding some clinical manifestations of recurrence.²⁶

• PMID 13573307: This case report describes adrenocortical carcinoma presenting with profound recurrent hypoglycemia, coma, and death in a young woman with a large upper abdominal mass. The excerpt highlights hypoglycemia as an unusual paraneoplastic manifestation that may persist despite glucose support and occur alongside metastatic disease.²³

• PMID 14708644: This case report describes adrenocortical carcinoma presenting as acute flank pain, shock, and large retroperitoneal hemorrhage from spontaneous tumor rupture, with no endocrine dysfunction and stage I nonmetastatic disease after adrenalectomy. It highlights rupture-related hemorrhage as a rare but possible initial presentation of ACC.²

• PMID 19571451: This case report highlights endobronchial metastasis as an exceptionally rare metastatic presentation of adrenocortical carcinoma. It can cause cough, dyspnea, atelectasis, and obstructive pneumonia, and should be considered in patients with prior ACC who develop endobronchial lesions.¹⁴

• PMID 23155219: This case report describes metastatic cortisol-secreting adrenocortical carcinoma presenting with Takotsubo syndrome, cardiogenic shock, refractory hypertension, and severe hypercortisolism. It highlights an unusual paraneoplastic clinical presentation in which marked cortisol excess may have contributed to stress cardiomyopathy.²⁸

• PMID 24783099: This case report describes a nonfunctional adrenocortical carcinoma presenting acutely with tumor rupture and extensive retroperitoneal hemorrhage, causing severe abdominal pain, fullness, giddiness, hypotension, and pallor. It highlights spontaneous hemorrhagic rupture as a rare presenting manifestation of advanced ACC with metastatic disease.²⁰

• PMID 25391823: This case report describes adrenocortical carcinoma initially presenting with a lung lesion and mimicking primary lung cancer, illustrating that ACC can present through metastatic-appearing thoracic disease before the adrenal origin is clarified. The timeline also reflects subsequent adrenalectomy, lung wedge resection, and mitotane initiation.³

• PMID 25868890: This case report highlights a rare presentation and complication of ACC: prolonged gynecomastia with constitutional symptoms, metastatic disease, and sudden death from pulmonary thromboembolism arising from thrombus adherent to tumor extending through the adrenal vein and inferior vena cava.¹⁹

• PMID 27957352: This case report describes a rare paraneoplastic presentation of nonfunctioning adrenocortical carcinoma with recurrent nonislet cell tumor hypoglycemia, characterized by suppressed insulin and C-peptide and a markedly elevated IGF-II/IGF-I ratio despite normal total IGF-II. Hypoglycemia resolved after tumor resection, supporting IGF-II-mediated tumor-related hypoglycemia as an unusual ACC presentation.²⁴

• PMID 29367375: This case highlights an unusual presentation of ACC as isolated testosterone secretion causing prolonged hirsutism and secondary amenorrhea in a normotensive woman, with extensive venous tumor thrombus extending from the adrenal vein through the inferior vena cava into the right atrium.¹⁸

• PMID 31149433: This case report describes spontaneous retroperitoneal hemorrhage from ACC as an exceptionally rare emergency presentation, including metachronous rupture of a contralateral adrenal metastasis. It also notes that hypercortisolism may emerge with rapidly progressive metastatic disease despite initially limited hormonal abnormalities.¹³

• PMID 31442387: This case highlights metastatic nonfunctioning ACC presenting with extensive venous tumor thrombus from the hepatic veins and inferior vena cava into the right atrium, causing dynamic right ventricular inflow obstruction. It also underscores that ACC may remain clinically silent until advanced disseminated disease produces mass effect and thrombotic complications.¹¹

• PMID 31631642: This case report describes ACC presenting with extensive cannon-ball pulmonary metastases, a rare metastatic imaging pattern associated with cough, hemoptysis, wheezing, and respiratory failure. It highlights that lung metastatic recurrence can occur years after prior treatment and may show variable clinical course.¹⁶

• PMID 32000700: This case series describes thrombotic microangiopathy as a rare paraneoplastic presentation of adrenocortical carcinoma, marked by mechanical hemolytic anemia, thrombocytopenia, and sometimes acute kidney injury. TMA appeared at initial ACC diagnosis or metastatic progression, improved transiently with plasma exchange, and in one case resolved after tumor resection.⁶

• PMID 35719290: This case report describes ACC presenting through an unusual metastatic manifestation: isolated ocular symptoms with unilateral abduction deficit and diplopia caused by lateral rectus muscle metastasis. It emphasizes that systemic malignancy, including ACC, can rarely masquerade as sixth nerve palsy in older patients with accompanying systemic symptoms.¹⁵

• PMID 35811575: This case report describes severe cholestatic jaundice consistent with Stauffer syndrome as a rare paraneoplastic presentation of ACC, occurring without liver metastases or biliary obstruction and resolving after tumor resection. It expands the differential for liver dysfunction in ACC beyond hormone excess and direct metastatic involvement.⁵

• PMID 36545164: This case report highlights a rare presentation of non-functioning ACC with spontaneous tumor rupture causing retroperitoneal and intraperitoneal hemorrhage, hemodynamic instability, and acute abdomen. It also notes that large nonfunctional tumors may initially cause only vague abdominal or flank symptoms before catastrophic bleeding and early metastatic recurrence.⁷

• PMID 38707658: This case report describes abrupt-onset vitiligo as a possible paraneoplastic manifestation of ACC recurrence. In the reported patient, finger depigmentation appeared with intra-abdominal recurrent disease and regressed rapidly after resection, suggesting new vitiligo may rarely accompany ACC onset or relapse.⁹

• PMID 39086789: This case report highlights venous thromboembolism as a rare presenting manifestation of functional ACC, driven by hypercortisolism, direct venous thrombosis, or vascular invasion. It emphasizes that pulmonary embolism, recurrent DVT, and IVC or renal vein thrombus can signal advanced disease and poor prognosis.⁴

• PMID 20726969: A veterinary case report of a peri-renal carcinoma, with ACC included in the differential diagnosis, presented initially with acute lameness from humeral osseous metastasis. While not a confirmed human ACC case, it indirectly supports the broader point that metastatic lesions can overshadow the primary retroperitoneal tumor at presentation.²⁹

• PMID 29291482: A single-center cohort of paraneoplastic neuromyelitis optica spectrum disorder included one patient with adrenocortical carcinoma diagnosed within months of neurologic disease onset. The report is hypothesis-generating and suggests only a possible rare autoimmune neurologic association with ACC rather than a defined presentation pattern.⁸

• PMID 32241589: A single case report described diffuse retinal pigment epitheliopathy secondary to adrenocortical carcinoma, extending the spectrum of unusual extra-adrenal manifestations into ophthalmologic presentation. The report is limited but supports considering ACC in rare cases of unexplained retinal disease occurring in the setting of malignancy.¹⁷

References

Footnotes

1. Right atrial thrombus from an adrenocortical carcinoma.. Heart. 1999. PMID: 10490573. Local full text: 10490573.md ↩ ↩² ↩³ ↩⁴

2. Chance diagnosis of low stage non-metastasized adrenal cortical carcinoma in a young woman with retroperitoneal hemorrhage.. Pathol Res Pract. 2003. PMID: 14708644. Local full text: 14708644.md ↩ ↩² ↩³ ↩⁴

3. Adrenocortical carcinoma mimicking lung cancer and responding to vinorelbine/carboplatin and pemetrexed/carboplatin.. BMJ Case Rep. 2014. PMID: 25391823. Local full text: 25391823.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

4. Paraneoplastic Syndrome in Adrenocortical Carcinoma: The Unexpected Mime.. Cureus. 2024. PMID: 39086789. Local full text: 39086789.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

5. Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma.. J Endocr Soc. 2022. PMID: 35811575. Local full text: 35811575.md ↩ ↩² ↩³ ↩⁴

6. Adrenocortical carcinoma complicated by renal thrombotic microangiopathy, a case-series.. BMC Nephrol. 2020. PMID: 32000700. Local full text: 32000700.md ↩ ↩² ↩³ ↩⁴

7. Non-Functioning Adrenocortical Carcinoma Presenting as Retroperitoneal Hemorrhage With Early Metastasis.. Cureus. 2022. PMID: 36545164. Local full text: 36545164.md ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

8. Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation.. Mult Scler Relat Disord. 2018. PMID: 29291482. Local full text: 29291482.md ↩ ↩² ↩³

9. Paraneoplastic Vitiligo Associated With Adrenocortical Carcinoma.. JCEM Case Rep. 2024. PMID: 38707658. Local full text: 38707658.md ↩ ↩² ↩³

10. Prolonged fever as a presenting symptom in adrenal tumors.. Oncology. 1988. PMID: 3340389. Local full text: 3340389.md ↩ ↩² ↩³

11. A Man with a Clot on his Platelets: Adrenal Carcinoma and Dynamic Right Ventricular Inflow Obstruction.. Am J Med. 2020. PMID: 31442387. Local full text: 31442387.md ↩ ↩² ↩³ ↩⁴

12. Experimental evidence for biosynthesis of steroids in metastatic tissue originating from a primitive adrenocortical carcinoma.. Int J Biochem. 1983. PMID: 6852356. Local full text: 6852356.md ↩ ↩²

13. Spontaneously metachronous ruptures of adrenocortical carcinoma and its contralateral adrenal metastasis.. Int Cancer Conf J. 2016. PMID: 31149433. Local full text: 31149433.md ↩ ↩² ↩³

14. Endobronchial metastasis from adrenocortical carcinoma.. Intern Med. 2009. PMID: 19571451. Local full text: 19571451.md ↩ ↩² ↩³

15. Abduction Deficit Mimicking Sixth Nerve Palsy due to Metastasis in Systemic Malignancy: Rare Case Report.. Middle East Afr J Ophthalmol. 2021. PMID: 35719290. Local full text: 35719290.md ↩ ↩² ↩³

16. An extremely rare case of adrenocortical cancer with cannon ball pulmonary metastasis.. Monaldi Arch Chest Dis. 2019. PMID: 31631642. Local full text: 31631642.md ↩ ↩²

17. [Diffuse retinal pigment epitheliopathy secondary to adrenocortical carcinoma].. J Fr Ophtalmol. 2020. PMID: 32241589. Local full text: 32241589.md ↩ ↩² ↩³

18. Delayed presentation of a virilising, pure testosterone-secreting adrenocortical carcinoma with coexistent composite myelolipoma and a venous thrombus extending to the heart.. BMJ Case Rep. 2018. PMID: 29367375. Local full text: 29367375.md ↩ ↩² ↩³

19. Adrenocortical carcinoma and sudden death.. Forensic Sci Med Pathol. 2007. PMID: 25868890. Local full text: 25868890.md ↩ ↩² ↩³ ↩⁴

20. Adrenocortical carcinoma presenting as a rupture and extensive retroperitoneal haemorrhage.. J Clin Diagn Res. 2014. PMID: 24783099. Local full text: 24783099.md ↩ ↩² ↩³

21. Adrenocortical carcinoma and hypoglycemia: evidence for production of nonsuppressible insulin-like activity by the tumor.. J Clin Endocrinol Metab. 1977. PMID: 559689. Local full text: 559689.md ↩ ↩²

22. Hypoglycemia associated with the production of insulin-like growth factor II in adrenocortical carcinoma.. Intern Med. 2001. PMID: 11518119. Local full text: 11518119.md ↩ ↩²

23. Adrenal cortical carcinoma associated with hypoglycaemia.. Can Med Assoc J. 1958. PMID: 13573307. Local full text: 13573307.md ↩ ↩²

24. Nonislet Cell Tumor Hypoglycemia in a Patient with Adrenal Cortical Carcinoma.. Case Rep Endocrinol. 2016. PMID: 27957352. Local full text: 27957352.md ↩ ↩²

25. Erythropoietin-producing adrenocortical carcinoma.. Urol Int. 1996. PMID: 8776824. Local full text: 8776824.md ↩ ↩²

26. Paraneoplastic polymyositis in recurring adrenal gland carcinoma.. Lancet Neurol. 2003. PMID: 12849123. Local full text: 12849123.md ↩ ↩²

27. Bilateral adrenocortical carcinoma.. South Med J. 1967. PMID: 6021528. Local full text: 6021528.md ↩ ↩²

28. Takotsubo syndrome secondary to adrenal adenocarcinoma: cortisol as a possible culprit.. Am J Respir Crit Care Med. 2012. PMID: 23155219. Local full text: 23155219.md ↩ ↩²

29. Acute lameness associated with osseous metastasis of a peri-renal carcinoma in a horse.. Aust Vet J. 2010. PMID: 20726969. Local full text: 20726969.md ↩