ADRENAL CORTICAL CARCINOMA WITH LATE PULMONARY METASTASES CAUSING CLINICICAL CUSHING’S SYNDROME: CASE REPORT WITH IMMUNOHISTOCHEMICAL ANALYSIS OF STERIODOGENIC ENZYME PRODUCTION
Erika F. Brutsaert, MD, MPH1; Hironobu Sasano, MD2; Pamela Unger, MD3; Mary Beth Beasley, MD3; Brian K. Golden, MD4; William B. Inabnet III, MD, FACS3; Alice C. Levine, MD3
ABSTRACT
Objective: To present a case of pulmonary metastases from adrenocortical carcinomas (ACC) that were secreting fully-functional cortisol resulting in clinical Cushing’s syn- drome and to compare the steroidogenic enzyme expres- sion in the primary tumor and lung.
Methods: We analyzed and summarized the patient’s medical history, physical examination results, labora- tory data, imaging studies, and histopathologic results. The original tumor and the pulmonary metastases were then immunohistochemically evaluated for steroidogenic enzymes.
Results: Initial endocrinological workup revealed hyperandrogenism and adrenocorticotropic hormone (ACTH) independent Cushing’s due to a 4 cm left adrenal mass. The patient was initially diagnosed with an adrenal adenoma. Four years later, the patient developed recurrent Cushing’s syndrome. Repeat magnetic resonance imaging (MRI) showed no adrenal masses; however, chest com- puted tomography (CT) showed multiple bilateral lung nodules and biopsy revealed metastases of adrenal origin. Upon immunohistochemical analysis, side chain cleavage, 17a hydroxylase, 3ß hydroxysteroid dehydrogenase, and 21 hydroxylase immunoreactivity were detected in both the original and pulmonary metastatic lesions with patterns
From the Memorial Sloan Kettering Cancer Center, New York, New York, 2Tohoku University, Sendai, Japan, 3Mount Sinai School of Medicine, New York, New York, and 4Diabetes and Endocrinology Consultants PC, West Nyack, New York.
Address correspondence to Erika Brutsaert, MD, MPH; E-mail: erika.brutsaert@gmail.com
Published as a Rapid Electronic Article in Press at http://www.endocrine practice.org on July 11, 2012. DOI:10.4158/EP12018.CR
To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright @ 2012 AACE.
of disorganized steroidogenesis. Dehydroepiandrosterone- sulfotransferase (DHEA-ST) immunoreactivity was detected in the original tumor but not in the lung metastases.
Conclusion: This case demonstrates some inter- esting features of ACC that pose challenges to its man- agement, including the difficulties in establishing the pathologic diagnosis, the potential for fully functional steroidogenesis even in late metastases, and the plasticity of steroidogenic potential in tumor cells. (Endocr Pract. 2012;18:e138-e143)
Abbreviations:
ACA = adrenal cortical adenoma; ACC = adrenal cortical carcinoma; ACTH = Adrenocorticotropic hormone; DHEA-S = dehydroepiandrosterone sulfate; DHEA-ST = dehydroepiandrosterone sulfotransferase; MRI = magnetic resonance imaging
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare cancer with a generally poor prognosis, although its clinical course can be somewhat variable (1-3). It is among the least common of the malignant endocrine tumors and the second most aggressive, after anaplastic thyroid cancer (4). Pathologic assessment is the gold standard for distinguishing between an adrenal cortical adenoma (ACA) and ACC. The most commonly used system is the Weiss score, which incorpo- rates 9 histological criteria (5-6).
Approximately 60% of cases present with evidence of steroid hormone excess with Cushing’s syndrome and vir- ilization being the most common findings. Cosecretion of androgens and cortisol is also common. In contrast, aldo- sterone and estradiol secreting tumors are quite rare (7, 2-3).
Although hormone secretion by the primary carcinoma is common, there are only a few cases reported where a late metastatic lesion was producing hormones without evi- dence of recurrence of the primary tumor. We present a rare
case of a cortisol and androgen-secreting adrenal tumor (initially diagnosed as an adenoma) that metastasized to the lungs and was secreting cortisol 4 years after the initial tumor was removed. We also compare the immunohisto- chemical expression of steroidogenic enzymes in the initial tumor and its metastases.
CASE REPORT
A 63-year-old postmenopausal female with hyperten- sion and osteoporosis presented to her local endocrinolo- gist in May 2006 because of facial hirsutism, hair thinning on the scalp, central weight gain, and difficulty climbing stairs. On physical examination she had a blood pressure of 140/90 mmHg. She was 153.67 cm tall and weighed 4.05398 kg (body mass index [BMI], 27.5). She had a round, plethoric face, thin scalp hair, mild hirsutism of her chin, central adiposity, pale abdominal striaie, and increased dorsocervical fat. Laboratory studies revealed an elevated random cortisol, and undetectable adrenocorticotropic
hormone (ACTH). Twenty-four hour urine free cortisol was not obtained. Low dose dexamethasone (1 mg) failed to suppress cortisol (Table 1). In addition, total testosterone was elevated at 163 ng/dL (5-51), estradiol was elevated at 60 pg/ mL (<32), and FSH was suppressed at <0.7mIU/ mL (23-116.3). Magnetic resonance imaging (MRI) of the abdomen (Figure 1) demonstrated a 4.3 × 3.5 × 2.7 cm left adrenal mass. She underwent left adrenalectomy and was diagnosed with a benign adrenal adenoma. Postoperatively, the patient’s Cushing’s syndrome and hyperandrogenism resolved.
Four years later, in February 2010, the patient noticed that her hair was thinning again and she had gained weight. She denied shortness of breath, chest pains, or cough. Her 24-hour urine free cortisol was markedly elevated again and ACTH was suppressed. Low dose dexamethasone (1 mg) did not suppress cortisol. In contrast to her May 2006 presentation, her testosterone was normal although it was slightly high for her postmenopausal status (Table 1). Repeat MRI showed no recurrent or residual mass
| Table 1 The patient's laboratory values, precursors, and regulating hormones .* a | |||
|---|---|---|---|
| March-May 2006 | March-April 2010 | May 2010 (after ketoconazole) | |
| 17-alpha OH progesterone | . . . | .. . | 344 b ng/dL (<70) |
| Cortisol | .. . | ... | ... |
| Cortisol AM | 25.1b ug/dL (6.2-19.4) | 21.1b ug/dL (6.2-19.4) | 25.1b ug/dL (6.2-19.4) |
| Cortisol PM | 36.9b ug/dL (3-17) | 24.6 ug/dL (2.3-11.9) | ... |
| Low dose dexamethasone (1mg) | 29.4b ug/dL (4-22) | 25.4 µg/dL (2.31-19.4) | ... |
| 24 hr urine free cortisol | ... | 318 µg/24h (0-50) | ... |
| ACTH | <5 pg/mL (5-27) | <1.7 b pg/mL (7.2-63.3) | <1.1b pg/mL (7.2-63.3) |
| DHEA-S | 80 µg/dL (15-170) | 23.9 ug/dL (18.9-205) | 9 ug/dL (18.9-205) |
| Androstenedione | ... | ... | 51 ng/dL (<10-93) |
| Testosterone | ... | ... | ... |
| Total testosterone | 163b ng /dL (5-51) | 42 ng/dl (6-82) | 5 ng/dL (6-82) |
| Free testosterone | 18.7b pg/mL (0.6-6.7) | 0.1 pg/ml (0-1/8) | 1.2 pg/mL (0-1.8) |
| FSH | <0.7 mIU/mL (23-116.3) | ... | ... |
| Estradiol | 60b pg/mL (<32) | ... | |
| TSH | 0.87 (0.49-4.67) | 1.85 mIU.mL (0.49-4.67) | ... |
| Prolactin | 11.58 ng/ml (1.39-24.2) | ... | ... |
“The results are arranged according to time: March-May 2006, prior to adrenalectomy; March-April 2010, after recurrence of Cushing’s syndrome; and May 2010, after initiation of ketoconazole.
bAbnormal results are bolded. Normal values for postmenopausal females are between parentheses.
*Abbreviations: ACTH = adrenocorticotropic hormone; DHEA-S = Dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; TSH = thyroid stimulating hormone;
in the left suprarenal location, and the right adrenal was normal appearing; however, MRI and follow-up chest computed tomography (CT) (Figure 2) showed mul- tiple lung nodules, the largest 1.5 cm in size. She was started on ketoconazole 200 mg twice daily. Repeat lab- oratory testing showed little change in her hypercorti- solemia, but did show a decrease in total testosterone and dehydroepiandrosterone-sulfotransferase immunoreactiv- ity (DHEA-ST) levels. 17a-hydroxyprogesterone was ele- vated. The patient was referred to our institution for open lung biopsy and further management. Pathology from the wedge resection was reported as metastases of the adre- nal origin. Postoperatively, the patient initiated mitotane. She achieved a therapeutic level of 14 mcg/mL within 2 months of treatment. Serum cortisol was suppressed and required replacement with hydrocortisone. Serial CT scans of the chest revealed an increase in the number and size of the lung metastases after 6 months of mitotane. She was
R
continued on mitotane but also started carboplatin, etopo- side, and doxorubicin; however, she stopped after 1 cycle because the patient developed neutropenic fever and a port-a-cath infection and decided to discontinue treatment. She is now considering enrolling in a clinical trial.
Histopathology
The primary tumor was reexamined by 3 independent pathologists. Initially, it appeared that none of the 9 Weiss criteria were met; however, upon repeated light micro- scopic examination, the tumor cells associated with clear cytoplasm actually represented degenerated tumor cells with intracellular edema, and the viable portions of the tumor had compact and eosinophilic cytoplasm, distorted architecture, and increased mitosis (Figure 3). In addition, there were several foci of definitive capsular invasion and probable sinusoidal invasion. Therefore, with closer scru- tiny, at least 4 of the 9 Weiss criteria were met and the lesion was rediagnosed as ACC.
Immunohistochemistical Analysis of Primary vs. Metastatic Lesions
The primary tumor and lung metastases were immu- nostained for various antigens with methods described pre- viously (8-9). Both stained positively for inhibin-a, melan- A, and adrenal-4 binding protein/ steroidogenic factor 1 (Ad4BP/ SF-1), which is consistent with adrenocortical origin of the primary and lung metastases (8).
Immunohistochemical staining for steroido- genic enzymes was carried out in both the primary and lung metastatic lesions. Side-chain cleavage (CYP11A1), 17a-Hydroxylase/17, 20 Lyase (CYP17), 3ß-Hydroxysteroid dehydrogenase (3ß-HSD), 21-hydrox- ylase (CYP21A2), and DHEA-ST were all detected in
Distorted architecture
Capsular invasion
Nuclear atypia
Ki-67 labeling
carcinoma cells with eosinophilic cytoplasm. We did not stain for 11ß-Hydroxylase (CYP11B1) as the antibody binds poorly to both 11ß-Hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). Figure 4 demonstrates the immunoreactivity of steroidogenic enzymes in the adre- nal and lung masses. The pattern of the enzymes revealed disorganized steroidogenesis.
The lung metastases also displayed a pattern of dis- organized steroidogenesis as well expression of side- chain cleavage (CYP11A1), 3ß-Hydroxysteroid dehy- drogenase (3ß-HSD), 21-hydroxylase (CYP21A2), and 17a-Hydroxylase/17, 20 Lyase (CYP17). There was no immunoreactivity of DHEA-ST detected in contrast to the primary tumor (Figure 4).
DISCUSSION
We herein present a case of a woman who initially had hypercortisolemia and hyperandrogenism due to an adre- nal mass and developed cortisol-secreting lung metasta- ses without evidence of recurrence of the primary adrenal lesion 4 years later. The tumor was originally diagnosed as ACA, but after retrospective review, turned out to have subtle features of ACC. There are other cases of adrenal masses that were diagnosed as adenomas but later turned out to be carcinomas (10-11), underscoring the pitfalls of the widely-used Weiss diagnostic criteria in differentiat- ing between ACC and ACA. It is increasingly thought that there is an “intermediate” category of low-grade tumors
Immunohistochemical expression patterns of steroidogenic enzymes in adrenal primary and lung metastases
Adrenal: CYP11A1
Lung: CYP11A1
Cholesterol
DHEAS
ADRENAL
LUNG
CYP11A1
ADRENAL
LUNG
DHEA-ST
Adrenal: 38-HSD
CYP17
CYP17
Pregnenolone
ADRENAL
17a-OH Pregnenolone
ADRENAL LUNG
LUNG
DHEA
Lung: 36-HSD
ADRENAL
LUNG
ADRENAL
3ß-HSD
LUNG
ADRENAL
3B-HSD
LUNG
3B-HSD
CYP17
CYP17
17ß-HSD
Adrenal: CYP17
Progesterone
ADRENAL
ADRENAL
LUNG
17a-OH Progesterone
LUNG
Androstendione
Testosterone
Lung: CYP17
ADRENAL
LUNG
ADRENAL
CYP21A2
LUNG
CYP21A2
Deoxycorticosterone
11-Deoxycortisol
Adrenal: CYP21A2
Lung: CYP21A2
CYP11B1
CYP11B1
KEY
Expressed enzyme
Corticosterone
Cortisol
Unexpressed enzyme
Adrenal: DHEA-ST
CYP11B2
Lung: DHEA-ST
Enzyme not stained for
Aldosterone
that may not fulfill the Weiss criteria but have metastatic potential (12); therefore, additional immunohistochemi- cal and genomic markers that distinguish benign from malignant lesions and correlate with aggressivity are under investigation (12).
Our case is also noteworthy because it highlights the capacity for advanced and metastatic cancers to maintain their hormonal functional capacity. Although there are other published cases of ACC where a late-recurring meta- static lesion alone produced hormonal end-products (11, 13), we are the first to compare the immunohistochemical expression of steroidogenic enzymes in functional metas- tases from ACC with the primary tumor to our knowledge. Immunohistochemical staining of both the primary lesion and the lung metastases confirmed that they were express- ing all of the steroidogenic enzymes necessary for cortisol biosynthesis. The patient initially presented with hyper- cortisolemia and hyperandrogenism and, upon recurrence, had only Cushing’s syndrome. As expected, the enzymes required for cortisol synthesis (CYP11A1, CYP17, 3ß-HSD, CYP21A2) were expressed in both the primary adrenal and lung metastatic lesions (Figure 4). Although we did not stain for 11ß-hydroxylase (CYP11B1), we can infer that it was being expressed in both the primary tumor and the lung metastases since the patient had elevated lev- els of cortisol.
Interestingly, the patient’s DHEA-S serum levels were within the normal range at the time of her initial presenta- tion, and yet her primary adrenal lesion displayed marked immunoreactivity for DHEA-ST. The most likely expla- nation for this apparent contradiction is that the adrenal tumor raised her serum DHEA-S values above her post- menopausal baseline but not above the normal laboratory range. This would also explain why her DHEA-S level was higher when she first presented than when she returned with lung metastases (which did not express DHEA-ST). Another notable finding is that although both the adre- nal and lung tumors stained positively for CYP17, the enzyme that catalyzes both 17-hydroxylase reaction and 17,20-lyase reaction, she only had hyperandrogenism at the time of initial presentation, and not when she presented with lung metastases. Most likely the lung metastases had decreased conversion of androstenedione to testosterone in the lung metastases. Unfortunately, we did not stain for 17ß-hydroxysteroid dehydrogenase to confirm this hypothesis.
Serum hormone levels and immunostaining proved that the hormone secretion pattern of our patient’s cancer evolved between initial presentation and the recurrence. This change in functionality is consistent with prior reports. There have been cases of inert cells that develop functional capacity (14). There are also reports of ACC switching hormonal functionality (15-16). Barzon et al described a patient with Conn’s syndrome secondary to ACC who developed Cushing’s after 8 cycles of chemotherapy.
They used deoxyribonucleic acid (DNA) microarray data to show plasticity in the gene expression of steroidogenic enzymes in malignant adrenocortical cells (15).
Although advanced ACC can produce hormonal end-products, the pattern of steroidogenesis is one of dysfunctional steroidogenesis that manifests clinically with elevations in serum steroid precursor levels (17-18). Sasano et al have also described an immunohistochemi- cal pattern of “disorganized steroidogenesis” (18). They have shown that in ACC there is marked heterogeneity between cells in the same tumor in their enzyme expres- sion unlike normal adrenal tissue. Our patient’s primary tumor and lung metastases both demonstrated disorga- nized steroidogenesis.
Currently surgery remains the only way to cure ACC but, as seen in our case, there is a high rate of recurrence even with complete resection (19). Treatment options are limited for metastatic ACC. Mitotane, an adrenolytic, is the only chemotherapeutic agent approved for treatment of ACC in the United States. Adjuvant mitotane has been shown to increase recurrence free survival and is recom- mended for all metastatic disease in addition to higher risk localized disease or incompletely resected disease (19-20). The role of mitotane in lower risk, completely resected ACC is unclear and is currently under investigation (21). Studies have also shown improved outcomes with mito- tane combined with etoposide, doxorubicin, and cisplatin (EDP) (22) and mitotane with streptozosin (23). The recent Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT trial) compared these two regimens (mitotane plus EDP and mitotane plus strep- tozosin) in advanced ACC and found that mitotane-EDP was associated with an improved, progression-free survival and response rate compared to mitotane with streptozosin, but overall survival was similar between the two groups (24). More “targeted therapies,” especially inhibitors of IGF-1 receptor, are also under investigation (25). Medical treatment may also be needed to address hormonal effects of secretory tumors. Mitotane functions to decreases cor- tisol secretion. Agents such as ketoconazole, metyrapone, and etoposide can also be useful in treating hypercorti- solemia. Radiotherapy may have a role in decreasing local recurrence in incompletely resected disease or in palliation of symptomatic lesions (19).
ACC is a rare cancer with a generally dismal prog- nosis. This case demonstrates some interesting features of ACC that pose challenges to its management, including the difficulties in establishing the pathological diagnosis and the potential for fully functional steroidogenesis in late metastases and the plasticity of steroidogenesis in tumor cells.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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