ENDOCRINE SOCIETY
OXFORD
Paraneoplastic Vitiligo Associated With Adrenocortical Carcinoma
David Alan Goodkin, 10 Richard Alan Failor,2 and Mouhammed Amir Habra3
1Goodkin Biopharma Consulting LLC, Bellevue, WA 98005, USA
2Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA 98105, USA
3Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Correspondence: David A. Goodkin, MD, Goodkin Biopharma Consulting LLC, 3807 134th Ave NE, Bellevue, WA 98005, USA. Email: davidagoodkin@comcast.net.
Abstract
Malignancies may induce clinical sequelae distant from the sites of the tumor. Such paraneoplastic phenomena are known to affect many organs, including the skin. Vitiligo is a disorder of patchy depigmentation, appearing as white macules with distinct margins. Rarely, vitiligo has been reported as a paraneoplastic occurrence, in the settings of pituitary adenoma, thymoma, gastric carcinoma, and lymphoma. We now describe a man presenting with the abrupt onset of vitiligo on the hands coinciding with recurrence of adrenocortical carcinoma (ACC) in the abdomen. The vitiligo rapidly dissipated following resection of his cancer. We believe this to be the first report of paraneoplastic vitiligo associated with ACC. Endocrinologists typically manage ACC and should be aware of this link, as the de novo observation of vitiligo may signal the onset or recurrence of underlying tumor. Other practitioners that encounter patients with new vitiligo should add ACC to their differential diagnosis of potential underlying conditions.
Key Words: vitiligo, adrenocortical carcinoma, paraneoplastic syndrome Abbreviations: ACC, adrenocortical carcinoma; CT, computed tomography.
Introduction
Up to 20% of patients with cancer experience paraneoplas- tic syndromes: signs and symptoms that occur at locations remote from the sites of the primary malignancy and metas- tases [1]. Paraneoplastic phenomena may be due to tumoral release of substances such as peptide hormones, cytokines, or growth factors, or due to the cross-reaction of antitumor antibodies with normal tissues, but pathogenesis is often unclear [1, 2]. The syndromes are varied and many different organs may be affected. Diarrhea, electrolyte disturbances, polycythemia, hypertension, and abnormalities of the endocrine or nervous system have commonly been cited. Cutaneous manifestations of paraneoplastic syndromes in- clude itching, flushing, keratoses (eg, Bazex syndrome), pigmented skin growths, pemphigus, migratory necrolytic erythema, florid cutaneous papillomatosis, erythema gyra- tum repens, malignant acanthosis nigricans, acanthosis palmaris, and, rarely, vitiligo. This case report describes an instance of vitiligo associated with adrenocortical car- cinoma (ACC), a phenomenon that has not been described previously.
Case Presentation
A 68-year-old man noted the rapid development of nontender depigmented macules and small patches on both hands. The patient has no history of autoimmune disease. He was not ex- periencing unusual emotional stress. He had not been exposed
to toxic substances and had not been sunburned. The patient has experienced sporadic, mild eczema but has no history of vitiligo or other dermatologic disorders. There was no fam- ily history of vitiligo. Three years previously he had been diag- nosed with stage 3 ACC and underwent resection of a 27-cm tumor above the right kidney, a 3-cm satellite lesion, the right lobe of the liver, and the right kidney [3]. There were no metastases identified, and 26 lymph nodes were negative for tumor. Endocrine laboratory values revealed elevations of serum cortisol concentration (18.0 µg/dL [496.6 nmol/L]; PM normal <11.3 µg/dL [<311.8 nmol/L]), 24-hour urinary cortisol (73 µg [201 nmol]; normal 3.5-45 µg [9.7-124 nmol]), and serum dehydroepiandrosterone sulfate (734 µg/dL [19.9 umol/L]; normal 35-212 µg/dL [1.0-5.7 pmol/L]). Corresponding suppressions of serum adrenocorticotropin concentration (<5.0 pg/mL [<1.1 pmol/ L]; normal 7.2-63 pg/mL [1.6-14.2 pmol/L]) and serum free testosterone (28 pg/mL [97.1 pmol/L]; normal 30-140 pg/mL [104.0-485.4 pmol/L] were noted. Normal results were attained for plasma metanephrine (<0.20 nmol/L; normal 0.00-0.49 nmol/L), plasma normetanephrine (<0.20 nmol/L; normal 0.00-0.89 nmol/L), plasma renin ac- tivity (6.6 ng/ml/h [156.42 pmol/L/h]; normal 2.9-10.8 ng/ mL/h [68.7-256.0 pmol/L/h] sodium depleted), serum aldosterone (7.9 ng/dL [219.1 pmol/L]; normal ≤21 ng/dl [≤582.5 pmol/L]), serum estradiol (25 pg/mL [91.8 pmol/L]; normal male < 32 pg/mL [<117.5 pmol/L]), and serum thyro- tropin (2.5 U/ml; normal 0.3-4.2 uU/mL).
Serum sodium concentration was 136 mmol/L (normal 135- 145 mmol/L), potassium 4.1 mmol/L (normal 3.6-5.2 mmol/L), chloride 103 mmol/L (normal 98-108 mmol/L), and total carbon dioxide 26 mmol/L (normal 22-32 mmol/L). Other routine blood and urine studies were also within normal ranges except for a serum alkaline phosphatase concentration of 327 U/L (normal 36-161 U/L).
He then underwent 2 years of daily oral mitotane adju- vant chemotherapy, completing the treatment 9 months be- fore the current event. Serial surveillance computed tomographic (CT) studies of the chest, abdomen, and pelvis detected no tumor recurrence as recently as 3 months prior to the skin findings. He was taking only 2 medications, which he had been receiving for years: rosuvastatin 40 mg daily for well-controlled hypercholesterolemia and hydro- cortisone 10 mg daily, being tapered, for resolving, partial adrenal insufficiency secondary to the prior cancer and mitotane medication. Table 1 shows the results of serial cosyntropin stimulation testing to assess recovery of adre- nocortical function.
Diagnostic Assessment
The dorsal aspects of all fingers were involved, with vitiligo most prominent on the thumbs and index fingers (Fig 1). No other skin was affected and there was no change in hair color. Physical examination was otherwise unremarkable except for scars at the sites of prior surgical incisions. Skin was not biop- sied and no Wood’s lamp examination was performed. Four weeks after the onset of vitiligo, CT revealed a 2.6-cm soft tis- sue nodule in the left upper quadrant of the abdomen, without evidence of malignancy elsewhere in the abdomen or in the chest or pelvis. Positron emission tomography demonstrated intensely avid uptake of radiolabeled fluorodeoxyglucose at the nodule. The original tumor had been hormonally active (discussed earlier), with elevations of serum cortisol and
| Date of test | Hydrocortisone dose | Baseline AM serum cortisol concentration | Serum cortisol concentration 1 h post cosyntropin |
|---|---|---|---|
| 20 wk pre vitiligo | 10 mg AM/7.5 mg 4-6 h after awakening | 4.5 µg/dL (124.2 nmol/ L) | 5.3 µg/dL (146.2 nmol/ L) |
| 6 wk pre vitiligo | 7.5 mg AM | 8.9 µg/dL (245.6 nmol/ L) | 10.4 µg/dL (286.9 nmol/ L) |
| 6 wk after onset vitiligo | 10 mg AM | 10.8 µg/dL (298.0 nmol/ L) | 12.8 µg/dL (353.2 nmol/ L) |
| 18 wk after onset vitiligo and 5 wk after ACC resection | 10 mg AM | 9.8 µg/dL (270.4 nmol/ L) | 12.4 µg/dL (342.1 nmol/ L) |
Hydrocortisone dose held prior to blood sampling on testing days. A dose of 250 µg cosyntropin administered intramuscularly. Normal AM serum cortisol concentration 5.0 to 22.6 µg/dL (137.9-623.5 nmol/L).
Abbreviation: ACC, adrenocortical carcinoma.
dehydroepiandrosterone sulfate concentrations, but at the time of the ACC recurrence neither serum cortisol (10.8 µg/ dL [298.0 nmol/L]; normal <11.3 µg/dL [<311.8 nmol/L]) nor serum dehydroepiandrosterone sulfate concentration (14 µg/dL [0.4 pmol/L]; normal 35-212 µg/dL [1.0-5.7 pmol/ L]) was above normal limits. Adrenocorticotropin (26 pg/mL [5.9 pmol/L]; normal 7.2-63 pg/mL [1.6-14.2 pmol/L]) and thyrotropin (3.2 µU/ml; normal 0.3-4.2 uU/mL) levels were within normal limits.
Treatment
At laparoscopy 9 weeks after the CT, the patient was in fact found to have 2 omental tumors. The nodule observed on CT and positron emission tomography had grown to 3.5 cm and was located within the gastrosplenic ligament. A second, 1.5-cm tumor was detected within the gastrocolic ligament. Both were resected and proved to be ACC, similar in histology to the original cancer. No residual, inoperable ACC was evident.
Outcome and Follow-up
The vitiligo regressed following resection of the tumors. Repigmentation was near complete in 2 weeks. No tumor was reported on CT of the lungs, abdomen, and pelvis 6 weeks postoperatively. Fig. 2 shows the hands 12 weeks following ACC resection. Hydrocortisone medication was discontinued 18 weeks following the surgery, after evaluation of the cosyn- tropin stimulation test results shown in the final row of Table 1.
Discussion
Vitiligo, skin depigmentation due to loss of melanocytes that results in nonscaly, white macules with distinct margins, has an estimated worldwide prevalence up to 2% [4]. The patho- physiology is not well defined, but proposed mechanisms in- clude genetics, autoimmune phenomena, and oxidative stress. Vitiligo has also been observed as a paraneoplastic oc- currence in the settings of pituitary adenoma [5], thymoma [6], gastric carcinoma [7], and lymphoma [8].
In the present case, the abrupt onset of vitiligo on the fingers of a 68-year-old man coincided with recurrence of ACC and the condition rapidly regressed following cancer resection, strongly suggesting a paraneoplastic etiology. The patient had no known risk factors or predisposing conditions for the development of vitiligo, although eczema has been associ- ated with it. A limit in the evaluation of this case is the lack of a skin biopsy to consider histopathology, but biopsy is not re- quired for the diagnosis of vitiligo. We do not believe the viti- ligo was drug induced, as the patient had been taking statin medication for decades and low-dose hydrocortisone would unlikely be related.
To the best of our knowledge, this is the first report of par- aneoplastic vitiligo associated with ACC. Endocrinologists typically manage ACC and should be aware of this link, as the de novo observation of vitiligo may signal the onset or recurrence of an underlying tumor. Other practitioners that encounter patients with new vitiligo should add ACC to their differential diagnosis of potential underlying conditions.
Learning Points
· Cancers may cause paraneoplastic phenomena, including dermatoses, due to tumoral release of substances such as peptide hormones, cytokines, or growth factors, or due to the cross-reaction of antitumor antibodies with normal tissues.
· Vitiligo is a depigmentation disorder that results in white skin macules and patches that has, rarely, been reported to complicate malignancies.
· This case report now associates paraneoplastic vitiligo with ACC; endocrinologists should be aware that vitiligo may be a sign of tumor onset or recurrence.
Acknowledgments
Dr Jeffrey Lee resected the tumors.
Contributors
All authors made individual contributions to authorship. D.A.G., R.A.F., and M.A.H. were involved in the diagnosis and management of this patient. D.A.G. wrote the original draft and completed the manuscript submission. All authors reviewed and approved the final manuscript draft.
Funding
No public or commercial funding.
Disclosures
All authors declare no conflict of interest.
Informed Patient Consent for Publication
Signed informed consent obtained directly from the patient.
Data Availability
Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.
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