Adrenocortical carcinoma with delayed cutaneous metastasis
Adrenal cortical carcinoma (ACC) is an uncommon and aggressive malignancy. Patients often have metastatic disease at initial presentation, with the most common sites being the liver, local lymph nodes, lungs, peritoneum and bone. Despite a high frequency of metastases, there are only isolated reports of ACC that have metastasized to the skin. Herein, we report a case of an 82-year-old woman who presented with a cyst-like lesion on her back, which on biopsy proved to be ACC metastatic from a primary tumor diagnosed 30 years previously.
Satter EK, Barnette DJ. Adrenocortical carcinoma with delayed cutaneous metastasis. J Cutan Pathol 2008; 35: 677-680. @ Blackwell Munksgaard 2008.
Elizabeth K. Satter1 and David J. Barnette2
1Departments of Dermatology and Pathology, Naval Medical Center, San Diego, CA, USA and 2Departments of Dermatology and Pathology, Scripps Hospital, LaJolla, CA, USA
Elizabeth K. Satter, Departments of Dermatology and Pathology, Naval Medical Center, 34520 Bob Wilson Drive Suite 300, San Diego, CA 92134-2300, USA Tel: +1 619 532 9702
Fax: +1 619 532 9458
e-mail: elizabeth.satter@med.navy.mil
Accepted for publication July 8, 2007
Adrenal cortical carcinoma (ACC) is a rare tumor accounting for only 0.02-0.2% of all malignancies, with an estimated annual incidence of 0.5-2 cases per million people.1,2 The tumor has a bimodal age distribution, with peaks in the first and fifth decade. Although ACC typically shows a slight female preponderance, tumors that are non-functional or have an anaplastic phenotype are more commonly seen in males. 1,3
At the time of presentation, 30-85% of adult patients have distant metastases, the most common sites being the liver, local lymph nodes, lungs, peritoneum and bone.4,3 However, even in patients with widely disseminated disease, cutaneous metas- tases have been rarely reported.3,6 9 Herein, we report an 82-year-old woman who presented with an erythematous nodule on her back that was clinically diagnosed as a cyst but histologically was determined to be metastatic ACC.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense or the United States Government.
Case report
An 82-year-old white female presented in January 2007 with a 19 × 26 mm erythematous nodule on her left lower back, which was clinically suspicious for a ruptured epidermal (follicular infundibular) cyst (Fig. 1). At the time of tissue submission, the only past medical history available was that the patient had a cystic squamous cell carcinoma on her mid upper back in 2005.
Received was a 3.2 × 1.2 × 1.2 cm ellipse of skin that extended to the subcutaneous fat. Upon tissue sectioning a white to tan, rubbery, friable cyst that measured 1.0 × 1.0 × 7.0 cm was discovered. Histological evaluation of the ellipse showed a nor- mal epidermis, with a diffuse, multilobular pro- liferation that filled the lower dermis and extended to the subcutaneous fat; and at the inferior pole, a small, encapsulated nodule was appreciated (Fig. 2).
The proliferation consisted of sheets of large atypical clear cells and cells with granular eosino- philic cytoplasm. Fibrous bands and a rich vascular network separated the clusters of cells. The cells exhibited a moderate degree of nuclear pleomor- phism with a variable number of nucleoli per cell (Fig. 3). In addition, there were multinucleated cells
and numerous mitoses, inclusive of atypical mitoses. The cells were intimately associated with a dense inflammatory infiltrate consisting of neutrophils and nuclear debris, and focally there were areas of necrosis en mass. The encapsulated nodule located at the inferior aspect, consisted of back-to-back plump ovoid cells with similar cytological features to those of the larger mass.
Upon obtaining further clinical history, it was shown that the patient initially presented in 1977 with Cushing’s syndrome, which lead to the discovery of a left ACC. At that time, the patient had primary resection of the tumor. The patient did well until 1989, when she again presented with Cushing’s syndrome caused by recurrence of the tumor within the adrenal bed and a metastasis to the lung. The patient underwent local resection of both lesions and was started on mitotane; however, she was intolerant of the chemotherapy and discontin-
ued treatment shortly after initiation. Since 1989, she has experienced local recurrence of the tumor, as well as multiple metastases to the lungs. She has undergone repetitive surgical interventions inclusive of metastasectomies, a complete left nephrectomy, splenectomy and partial colectomy. Despite these recurrences, the patient has remained asymptomatic since 1989 and has been clinically stable.
Review of a biopsy from a prior lung nodule showed a well-circumscribed tumor composed of sheets of large cells with eosinophilic cytoplasm and marked nuclear pleomorphism, similar to that seen in the cutaneous lesion (Fig. 4).
Immunohistochemical stains performed on the cutaneous lesion showed diffuse strong reactivity with Neuron specific enolase (NSE), a weaker, but diffuse reactivity with a-inhibin, and focal staining with synaptophysin. There was no reactivity with Melan-A or CD10. Based upon the clinical history, as
well as, the tumor’s cytological features and immu- nohistochemical profile, a diagnosis of ACC meta- static to the skin was made.
Subsequent to the excision of the cutaneous meta- stasis, a computed tomography scan of chest and abdomen showed enlargement of a previously stable left upper lobe lung nodule, and a new 8 × 16 mm posterior thoracic subcutaneous nodule.
Discussion
ACC is a rare malignancy that in general has a dismal prognosis. Typically, ACCs are classified as functional or non-functional; however, all ACC secrete hormones, albeit some hormones are functionally inactive and fail to elicit clinical symptoms.1º Approximately 95% of children and 50-79% of adult patients have biologically active tumors. Children with ACC most commonly present with virilization, while adults more often have a mixed Cushing and virilizing syndrome.2,4,11,12 Non-functional tumors, on the other hand, are more frequently identified in adult males as either an incidental finding or because of a mass effect.12 Although several studies have shown that patients with functional tumors have a slightly better out- come, other studies contradict this finding.12
Adults tend to present with advanced disease (stage IV), with approximately 30-85% of patients having distant metastasis at the time of presentation. In contrast, 75% of children present with tumors that are localized to the adrenal gland (stage I and II).12,13 The most common sites of metastases are the liver, local lymph nodes, lungs, peritoneum, opposite adrenal gland, bones, intestines and less commonly other sites.14 There have only been isolated reports that have mentioned metastases to the skin or mucosa.3,6-9,15 Interestingly, the ACCs described in these reports were often non-functional and anaplastic, with pleomorphism of at least 50% of the cells, as was the case in our patient.3,6,7,9,15
In general, cutaneous metastases from visceral carcinomas are relatively uncommon and often the
cytomorphological features are nondescript; there- fore, as the overall incidence of ACC is low, they are rarely considered in the differential diagnosis of cutaneous metastatic tumors.º Although no immu- nohistochemical stain is specific for ACC, a panel of stains can be helpful in differentiating ACC from other tumors with similar cytomorphological fea- tures. Some of the most commonly used immuno- histochemical stains includes A103, inhibin A, D11, chromogranin and calretinin (Table 1).16-22
A103 and M2-7C10 are monoclonal antibodies generated against various epitopes on recombinant Melan-A (MART-1). Initially, these antibodies were thought to be restricted to melanocytic lesions; yet, subsequent studies have shown that up to 90% of adrenocortical tumors and other steroid producing tumors also show immunoreactivity with Melan-A, when A103 is employed.17-20 Furthermore, ACC can exhibit similar cytomorphological features with melanomas; but fortunately, S-100 and HMB-45 can be utilized in differentiating these tumors. Another beneficial immunohistochemical stain that can be of assistance in suspected cases of ACC is a-inhibin. In general, a-inhibin is fairly sensitive for ACC; however, it is slightly more reactive in functional vs. non-functional tumors.21 Moreover, it lacks specificity, as it also stains sex cord stromal tumors and pituitary adenomas. Overall, A103 is margin- ally more specific and a-inhibin is slightly more sensitive for identification of adrenal cortical tumors.22 D11 has also been utilized and labels the nuclei of adrenal cortical cells; however, it too is non-specific, and a similar pattern of staining is seen in hepatocellular carcinomas, lung carcinomas and renal cell carcinomas.17 Lastly, in view of the fact that ACCs and pheochromocytomas often exhibit similar cytomorphological features and show evidence of neuroendocrine differentiation, chromogranin is often utilized, as ACC are typically non-reactive.2
In general the prognosis of ACC in adults is dismal and despite curative resection, most tumors display aggressive behavior, with 58% of patients
| ACC | Melanoma | Pheochromocytoma | Renal carcinoma | Hepatocellular carcinoma | |
|---|---|---|---|---|---|
| A103/melan-A | ++ | ++ | – | - | - |
| S-100 | – | ++ | 1 | 1 | – |
| HMB-45 | – | 1 | – | Rare | – |
| a-inhibin | ++ | Rare | – | – | Rare |
| D11 | ++ | – | – | 1 | ++ |
| Calretinin | ++ | Rare | – | – | – |
| Synaptophysin | ++ | Rare | ++ | – | – |
| Chromogranin | – | – | ++ | – | – |
| CD10 | – | – | – | ++ | 1 |
| EMA | – | – | – | ++ | 1 |
| Keratin | Rare | – | Rare | ++ | 1 |
‘Rare’ means between 10% and 20% of tumors shows immunoreactivity for a particular immunohistochemical stain, ’+’ means between 20% and 80% and ’++’ means between 80% and 100% of the tumors are immunoreactive. ACC, adrenocortical carcinoma; EMA, epithelial membrane antigen.
Satter & Barnette
experiencing a relapse within 2 years of initial treatment.3,7,13 Despite the fact that the overall 5- year survival rate ranges from 10% to 25%, some patients will exhibit prolonged survival, as was seen in the case presented in this report.” At this time, it is uncertain whether any histological criteria can assist in determining patient prognosis. It has been hypothesized that tumors with a high mitotic activity (greater than 5/50 HPF) might be associated with a poorer prognosis; however, several studies have not found the mitotic index to be prognostically significant when patients were analyzed separately in regards to their metastatic status.13,21 It has also been suggested that patients who had anaplastic ACC, in which more than 50% of cells exhibited nuclear pleomorphism have reduced survival. This hypothesis was supported by one study which found patients with anaplastic ACC had a median survival of 5 months, compared with a 40-month survival in patients with more differentiated tumors.3 Other studies have further confirmed that nuclear grade alters the patient’s prognosis. Moreover, two recent retrospective studies that analyzed large cohorts with ACC, showed that tumor grade, in addition to the presence metastatic disease at the time of diagnosis and overall tumor burden were the most important prognostic indicators in determining survival.7,23
In conclusion, we presented an unusual case of a cutaneous metastasis that arose 30 years after a primary ACC was first discovered. Because of the rarity of this tumor, the diagnosis can be difficult and often an immunohistochemical panel can be a useful adjunct in distinguishing this tumor from other tu- mors with similar cytomorphological features, such as renal cell carcinoma, melanoma and poorly differ- entiated adenocarcinoma. Although metastases to the skin from ACC have rarely been reported, it must be considered in patients with a history of ACC.
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