Metastatic Adrenocortical Carcinoma to the Skin: A Case Report and Review of This Unusual Neoplasm
Efrain Lee-Diaz, MD,* Carlo Contreras, MD,¡ and Jose A. Plaza, MD*
Abstract: Adrenocortical carcinoma is a very rare oncologic condition with poor prognosis that usually metastasizes to the lungs, liver, local lymph nodes, and peritoneum at initial presentation. However, skin metastasis is very uncommon and has rarely been reported even in advanced stages of the disease. We present a case of a 41-year-old man with a known history of adrenocortical carcinoma of the right adrenal gland that presented with an arm mass. The histopathologic sections showed a multinodular necrotic malignant neoplasm in dermis and subcutaneous fat composed of atypical epi- thelioid cells with ample granular cytoplasm and pleomorphic vesic- ular nuclei with frequent intranuclear inclusions and atypical mitoses. The immunohistochemical stains showed tumor cells that were strongly positive for synaptophysin and inhibin, only focally positive for Melan-A, and negative for AE1/AE3. The histopatho- logic features and the immunohistochemical profile confirmed the diagnosis of metastatic carcinoma consistent with adrenal cortical origin. The diagnosis can be difficult (especially when no clinical data are provided), and an immunohistochemical battery is often useful in distinguishing this tumor from other tumors with similar cytomorphological features.
Key Words: adrenocortical carcinoma, cutaneous metastasis, meta- static carcinoma
(Am J Dermatopathol 2024;46:696-699)
INTRODUCTION
Adrenocortical carcinoma (ACC) is a very rare endo- crine malignancy with an incidence of 0.72 per million in the United States and 0.5 to 2 per million worldwide.1-3 ACC affects women more frequently than men with a ratio that ranges from 1.5 to 2.5:1 and displays a bimodal distribution in pediatric population younger than 5 years and adults aged between 40 and 60 years.2 There are several etiological risk factors and conditions associated with this malignancy such as cigarette smoking in men, use of oral contraceptives in women before age 25 years, and many genetic syndromes (ie, Li-Fraumeni syndrome, familial adenomatous polyposis, multiple endocrine neoplasia type I, neurofibromatosis-1, Beckwith-Wiedemann syndrome, and Lynch syndrome).2,4
Fifteen percent to 20% of the patients with ACC are diag- nosed incidentally, whereas most patients have a clinical pre- sentation consistent with abdominal mass effects and steroid hormone excess.5,6
ACC is considered a very aggressive tumor with an overall median survival of 17 months and a 5-year cancer- specific survival rate of 38%.6,7 Nonetheless, surgery signif- icantly improves the overall and cancer-specific survival rate, even with metastatic disease.8 The 5-year survival ranges from 40% to 70% in adult patients with ACC after surgery.9 Usually, the metastatic disease affects the liver, lungs lymph nodes, and bones.1º However, cutaneous metastasis is con- sidered extremely rare and has rarely been reported even in advanced stages of the disease.11-14
CASE REPORT
A 41-year-old man with a known history of ACC presented to the clinic for evaluation of a painful mass located in the left proximal arm. The lesion appeared approximately 2 months before and had enlarged over the past several weeks. The patient reported feeling a sensation of pinching and shooting pain down his upper arm. He denied any associated erythema, drainage, numbness, tingling, or weakness of his left arm. Physical examination re- vealed a left proximal arm subcutaneous mass that measured 2.0 cm in diameter, and it was mobile and tender to palpation (Fig. 1). The ACC was incidentally discovered after a motor vehi- cle crash 2 years before. On that admission, the patient presented with a hypertensive crisis and elevated levels of cortisol, estrone, and androstenedione. The CT with contrast of abdomen and pelvis found a large heterogeneous appearing mass in the expected loca- tion of the right adrenal gland measuring approximately 7.7 x 5.7 cm, which demonstrated heterogeneous enhancement. The mass was infiltrating the right retroperitoneum, encasing and invading the inferior vena cava, and extending medially to the aortocaval region. The patient underwent a biopsy of the mass, and the histopathologic sections of the adrenal tumor showed a malignant neoplasm with necrosis, calcifications, and hemor- rhage. The tumor cells were large with granular eosinophilic cyto- plasm, often pleomorphic with frequent intranuclear inclusions and atypical mitoses. The immunostains were positive for inhibin, synaptophysin, weakly positive for Melan-A, and focally positive for AE1/AE3 and were negative for calretinin, TTF1, PAX8, CK7, S100, and chromogranin. At the time of diagnosis, the CT scan of the chest showed numerous scattered small pulmonary nodules throughout the lungs that were consistent with pulmonary metas- tasis. The patient started treatment with 4 cycles of combination chemotherapy with etoposide, doxorubicin, cisplatin, and oral mi- totane and radiation therapy (in the adrenal gland). After approx- imately 2 years, the patient underwent CT of the abdomen and pelvis that showed at least 2 hypodense hepatic lesions that were consistent with metastatic disease.
From the *Division of Dermatopathology, Department of Pathology, The Ohio State University Wexner Medical Center (OSUWMC), Columbus, OH; and ¡Department of Surgery, The Ohio State University Wexner Medical Center (OSUWMC), Columbus, OH.
The authors declare no conflicts of interest.
Correspondence: Jose A. Plaza, MD, Department of Pathology, 901 Woody Hayes Drive, 2042 Blankenship Hall, Columbus, OH 43210 (e-mail: JoseA.Plaza@osumc.edu).
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The excisional biopsy of the left proximal arm mass showed a multinodular lesion located in dermis and subcutaneous fat (Fig. 2A). The tumor was not connected to the overlying epidermis or adnexal structures. The neoplasm was composed of malignant epithelioid cells with ample granular cytoplasm and pleomorphic vesicular nuclei with intranuclear inclusions (Figs. 2B, C). Many atypical mitoses were noted, and tumor necrosis was seen throughout the tumor (Fig. 2D). The immunohistochemical staining demon- strated tumor cells that were strongly positive for synaptophysin (Fig. 3A) and inhibin (Fig. 3B), only focally positive for Melan-A
(Fig. 3C), and negative for AE1/AE3 (Fig. 3D). The histopathologic pattern and immunohistochemical profile were consistent with the diagnosis of metastatic ACC.
DISCUSSION
Skin metastasis from ACCs has been very rarely reported, even in disseminated and advanced stages of the disease.11-13,15-17 It is very important to be aware of such an event as approximately one-third of patients with ACC have a distant metastasis at the initial presentation.9,17 Metastases are usually detected in the liver (45%-85% of cases), in the lungs (30%-60% of cases), lymph nodes (7%-20% of cases), and bones (7%-13% of cases).18 Other unusual metastatic locations have been reported in the brain, meninges, spleen, tongue, stomach, and pancreas.9 Taking into consideration the very low incidence of ACC, cutaneous metastasis from ACC is rarely considered in the differential diagnosis of skin met- astatic tumors.11 The histopathologic diagnosis of ACC can be difficult and nonspecific in the absence of clinical history, and an immunohistochemical battery is often useful in distin- guishing this tumor from other neoplasms with similar cyto- morphological features; however, it should be kept in mind that there are no specific immunostains to diagnose ACC.
ACCs are aggressive malignant neoplasms with bad prognosis. ACCs are classified as functional or nonfunctional; however, all ACCs produce hormones, but some hormones are inactive and fail to elicit clinical symptoms. According to the ESMO-EURACAN Clinical Practice Guidelines for diag- nosis of ACCs and malignant pheochromocytomas, an immu- nohistochemical panel staining that includes steroidogenesis factor 1 (SF-1), adrenocortical-specific marker or alternatively inhibin-alpha, calretinin, Melan-A, and synaptophysin should be done for identification of adrenocortical tumors.19 In addi- tion, the Ki-67 labeling index, as a marker of proliferative activity, can also be useful and is very helpful in establishing prognosis.20 SF-1 is a transcriptional factor expressed by adrenocortical cells, especially in the zona glomerulosa and
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D
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fasciculate. Its high expression is correlated with a high Ki-67 index and high mitotic count, so it can be used as a diagnostic and prognostic marker in ACC.19,21 Inhibin-alpha is considered sensitive for the diagnosis of ACC, but it is important to take into consideration that it is more reactive in functional adreno- cortical tumors compared with nonfunctional tumors.22 In addi- tion, inhibin-alpha lacks specificity, as it also stains sex cord stromal tumors and pituitary adenomas.11,23 Calretinin is a cal- cium-binding protein that is normally expressed in the adrenal cortex, but not in the medulla; therefore, it is a very sensitive and specific marker in differentiating cortical adrenal tumors.24 Melan-A is a melanoma antigen recognized by autologous cytotoxic T cells.25 Initially, it was believed to be exclusive from melanocytic tumors, but subsequent studies showed that some steroid producing tumors and most adrenocortical tumors also show immunoreactivity with Melan-A.23,25 We have to consider that S-100 and HMB-45 can be used to differentiate ACC from melanomas.13 Synaptophysin is commonly used to identify neuroendocrine tumors. It is useful to identify pheo- chromocytomas and paragangliomas; however, positive results for synaptophysin are also possible in adrenocortical tu- mors.20,23 A comprehensive study of ACC found 92.5% of expression with inhibin-alpha, 80% expression for calretinin, 72.5% expression with synaptophysin, and 65% expression with Melan-A.23 Other studies have found 100% expression with SF-1 and 0% expression with AE1/AE3.26
The differential diagnosis of metastatic ACC can be broad and is important to distinguish it from other tumors that can display similar histopathological features, especially renal cell carcinomas, melanomas, and others poorly differentiated carcinomas. Immunohistochemistry can play an essential role in differentiating these entities. Renal cell carcinomas are positive for RCC, PAX8, CD10, EMA, and vimentin and negative for Melan-A and inhibin.27,28 However, metastatic melanomas histologically can show that overlapping features almost always express positivity for Melan-A, S-100, SOX- 10, and HMB-45.29
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To conclude, although skin metastases from ACCs are a very rare presentation, we have to consider this diagnosis in patients with a known history of ACC who develop a new cutaneous lesion. In addition, the histopathologic diagnosis can be challenging, so an appropriate immunohistochemical battery can be useful in distinguishing this tumor from other with similar cytomorphological features.
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