Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma.

Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=-0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.

Protein Expression of Cyclin B1, Transferrin Receptor, and Fibronectin Is Correlated with the Prognosis of Adrenal Cortical Carcinoma.

BACKGROUND: Adrenal cortical carcinoma (ACC) is a rare cancer with a variable prognosis. Several prognostic factors of ACC have been previously reported, but a proteomic analysis has not yet been performed. This study aimed to investigate prognostic biomarkers for ACC using a proteomic approach. METHODS: We used reverse-phase protein array data from The Cancer Proteome Atlas, and identified differentially expressed proteins in metastatic ACCs. Multivariate Cox regression analysis adjusted by age and staging was used for survival analysis, and the C-index and category-free net reclassification improvement (cfNRI) were utilized to evaluate additive prognostic value. RESULTS: In 46 patients with ACC, cyclin B1, transferrin receptor (TfR1), and fibronectin were significantly overexpressed in patients with distant metastasis. In multivariate models, high expression of cyclin B1 and TfR1 was significantly associated with mortality (hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.02 to 36.7; and HR, 6.59; 95% CI, 1.14 to 38.2; respectively), whereas high fibronectin expression was not (HR, 3.92; 95% CI, 0.75 to 20.4). Combinations of high cyclin B1/high TfR1, high cyclin B1/high fibronectin, and high TfR1/high fibronectin were strongly associated with mortality ([HR, 13.72; 95% CI, 1.89 to 99.66], [HR, 9.22; 95% CI, 1.34 to 63.55], and [HR, 18.59; 95% CI, 2.54 to 135.88], respectively). In reclassification analyses, cyclin B1, TfR1, fibronectin, and combinations thereof improved the prognostic performance (C-index, 0.78 to 0.82-0.86; cfNRI, all P values <0.05). CONCLUSION: In ACC patients, the overexpression of cyclin B1, TfR1, and fibronectin and combinations thereof were associated with poor prognosis.

Evaluating the effectiveness of computed tomography-guided 125I seed interstitial implantation in patients with secondary adrenal carcinoma.

AIM: This study aimed to evaluate the feasibility, safety, and clinical efficacy of computed tomography (CT)-guided 125 I seed interstitial implantation in patients with secondary adrenal carcinoma. MATERIALS AND METHODS: Twenty patients with secondary adrenal carcinoma received CT-guided 125 I seed interstitial implantation. A three-dimensional treatment planning system was used to calculate the dose distribution before 125 I seed interstitial implantation. CT scans were performed every 2 months after the treatment to evaluate local therapeutic efficacy according to the Response Evaluation Criteria in Solid Tumors. RESULTS: The mean follow-up time was 23.65 months (5-102 months). The mean maximum tumor diameter was 34.16 ± 18.94 mm at the beginning of follow-up and 14.42 ± 24.07 mm at the end of follow-up. Eleven patients had complete response (CR), seven had partial response (PR), one had stable disease, and one had progressive disease. Local control rate (CR + PR) was 90% (18/20). The median survival time was 19 months (5-71 months). The 1-, 2-, 3-, and 5-year overall survival rates were 83.70%, 46.8%, 20.80%, and 20.80%, respectively. CONCLUSION: CT-guided 125 I radioactive seed interstitial implantation may be a feasible, safe, effective, and minimally invasive treatment for secondary adrenal carcinoma.

[Adrenal cortical adenoma with increased uptake of 18F-fluoro-deoxy-glucose on PET/CT suspected as an adrenal metastasis from the cervical cancer : a case report].

A 61-year-old woman was referred to our department with a diagnosis of left solitary adrenal metastasis from cervical cancer in September 2011. She presented with postmenopausal bleeding in September 2010. The patient received seven courses of paclitaxel (175 mg/m2) and carboplatin (6 mg/GFR＋25) for stage IV cervical cancer with paraaortic, bilateral common iliac, mediastinal lymph node metastases and left adrenal metastasis from October 2010 to April 2011. Paraaortic radiation (50.4 Gy) was subsequently administered from May 2011 to July 2011. Abdominal nonenhanced computed tomography (CT) revealed a left 26×21 mm adrenal mass with regular margins (attenuation values 53 HU). On enhanced CT, the mass showed heterogeneous enhancement. F fluoro-2-deoxy D-glucose (FDG) positron emission tomography/CT images showed moderately increased FDG-avid uptake in the left adrenal tumor which was high enough to be suspicious of malignant tumor (standardized uptake value max : SUVmax 6.8). There were no other foci of pathologic uptake of FDG in the whole body. The plasma endocrinological examinations was all normal. Left laparoscopic adrenalectomy was performed. The final pathologic evaluation revealed adrenal cortical adenoma.

Primary adrenal gland carcinosarcoma associated with metastatic rectal cancer: a hitherto unreported collision tumor.

In this report we describe the case of a young woman with familial adenomatous polyposis who developed metastatic rectal cancer during pregnancy. At diagnosis, we decided to perform a transabdominal laparoscopic adrenalectomy, because of the high risk of bowel obstruction, and to define the origin of the adrenal gland lesion, suspected to be primary on the basis of imaging results. The histological specimen showed a collision tumor between an adrenal metastasis of a rectal tumor and a primary adrenal gland carcinosarcoma. The peculiarity of the case is due not only to its clinical presentation during pregnancy, but also to the presence of this uncommon adrenal collision tumor. A particular challenge for the clinician is to define the priority between these two tumors: the presence of two distinct and colliding aggressive neoplasms poses a problem in the choice of the best therapeutic approach, also given the impossibility to biopsy all metastatic sites. However, we decided to treat the patient as having a metastatic rectal cancer, because we had a solid histological confirmation of metastases.

[Laparoscopic resection of primary and metastatic malignant tumors of the adrenals].

An analysis was made of experience with treatment of 24 patients who underwent laparoscopic adrenalectomy for adrenocortical carcinomas (in 7 patients) and metastases in adrenals (in 17 cases). Laparoscopic adrenalectomy was shown to be a safe and effective method of treatment of primary and metastatic tumors of the adrenals. The method can replace open operative intervention in the majority of patients with metastases to adrenals and primary cancer of the adrenals.

Fine needle aspiration of metastatic prostate carcinoma simulating a primary adrenal cortical neoplasm: a case report and review of the literature.

Adrenal metastases usually occur in prostate cancer patients with widespread bone and visceral disease. Autopsy studies have shown that adrenal metastases may be found in up to 23% of these patients. However, the finding of an isolated adrenal metastasis without the involvement of other organs in a patient with prostate cancer is exceedingly rare. Thus, it may cause a diagnostic dilemma on FNA cytology. We report a patient with a history of prostate cancer, status post radiation, and hormonal therapy 4 years before, who presented with a new, single adrenal mass on abdominal imaging studies. The ultrasound-guided FNA cytology of the adrenal mass revealed cytomorphological features that were suggestive of a primary adrenal cortical neoplasm, but overlapped with those of a prostate metastasis. To our knowledge, FNA findings of metastatic prostate cancer simulating an adrenal cortical neoplasm have not been previously reported in the English literature. The purpose of our study is to discuss the differential diagnosis of these entities. The accurate diagnosis is important because of different prognosis and treatment implications for the various diseases.

Usefulness of transcription factors Ad4BP/SF-1 and DAX-1 as immunohistologic markers for diagnosis of advanced adrenocortical carcinoma.

BACKGROUND: We examined the expressions of Ad4BP/SF-1 and DAX-1 in primary and metastatic lesions of advanced adrenocortical carcinoma with normal hormonal findings by immunohistochemistry and discussed their usefulness as immunohistochemical markers for diagnosis. PATIENTS AND METHODS: Four patients (average age 54.3 +/- 3.9) with retroperitoneal and metastatic tumors were enrolled in this study. All patients had normal hormonal findings. Ad4BP/SF-1 and DAX-1 underwent immunohistochemical study using needle biopsy specimens from the retroperitoneal tumor or metastatic tumor of these patients to diagnose primary adrenocortical carcinoma. RESULTS: Immunoreactivity for Ad4BP/SF-1 and DAX-1 indicated that it was localized exclusively in the nuclei. Ad4BP/SF-1 immunoreactivity was observed in the carcinoma cells of 2 patients, but not in the others, whereas DAX-1 immunoreactivity was observed in the carcinoma cells of all 4 patients. CONCLUSION: The expressions of Ad4BP/SF-1 and DAX-1 are considered essential to maintain the biological characteristics of adrenocortical cells even without abnormal hormonal findings or even after malignant transformation and metastasis. These markers are useful to distinguish other retroperitoneal tumors, especially in patients with bulky tumors, and to diagnose the metastatic site of origin as adrenocortical carcinoma in patients clinically presenting with widespread metastasis.

[Pleomorphic carcinoma of the lung rapidly developed multiple metastases after surgery].

Pleomorphic carcinoma of the lung is a type of carcinoma with spindle and/or giant cells with a poor diagnosis. A 73-year-old male was referred to our hospital because of the pulmonary tumor. Lung biopsy revealed that the tumor was poorly differentiated adenocarcinoma. No distant metastasis were observed by systemic examination. A right middle lobectomy with partial resection of the right upper lobe and lymph node dissection were performed, because the tumor (5.3 x 4.0 x 4.0 cm) was located in peripheral S' and invaded S3 via the interlobular space. Histological findings showed adenocarcinoma comprised of spindle cell components that reacted positively to epithelial membrane antigen (EMA) and no lymph node metastasis. Therefore, he was diagnosed with pleomorphic carcinoma of the lung, pT2N0M0, stage IB. But metastatic lesions newly appeared in the thoracic skin, the liver, the diaphragm, the bilateral adrenal glands, and the retroperitoneal space on the 30th postoperative day. He died of peritonitis and pleuritis on only 60 days after the operation.

Comparison of immunomarkers for the identification of adrenocortical cells in cytology specimens.

We studied the immunoreactivity of three antibodies--A103, calretinin, and inhibin alpha in destained Papanicolaou (Pap) smears and cell-blocks of 40 fine-needle aspiration biopsy cases of adrenocortical lesions (35 cases of hyperplasia/adenoma and 5 cases of carcinoma). Five cases of carcinoma (4) and melanoma (1) metastases to the adrenal gland and five cases of renal-cell carcinoma were also included for comparison. In benign adrenocortical lesions, A103 staining was noted in 82% of the destained Pap smears and in 92% of cell-blocks. In malignant adrenocortical lesions, A103 staining was noted in 50% of the destained Pap smears and in 80% of cell-blocks. In comparison, calretinin staining was noted in 6% and 50% of destained smears and in 78% and 60% of the cell-blocks of benign and malignant adrenocortical lesions. Inhibin alpha was not positive in any of the smears and showed the lowest level of positivity in the cell-block sections, namely in 11% of the benign lesions and 25% of the malignant lesions. The sensitivity of A103 was 90% on cell-blocks and 74% on smears, that of calretinin 75% on cell-blocks and 11% on smears, and that of inhibin alpha, 13% on cell-blocks alone. The specificity of A103 was lower than the other two makers, 90% vs. 100% because of positivity in metastatic melanoma in the adrenal gland. Our data show A103 to be the immunomarker with the highest sensitivity for identifying cells of adrenocortical origin in destained Pap's smears and cell-block sections with, however, a lower specificity when compared with calretinin and inhibin alpha. Calretinin is comparable in sensitivity with A103 on cell-block sections alone and not on smears. The results of this study suggest that if metastatic melanoma in adrenal gland is not a consideration then A103 is the marker of choice for identifying cells of adrenocortical origin in the limited material available for diagnostic purposes in cytology specimens.

Abrupt enlargement of adrenal incidentaloma: a case of isolated adrenal metastasis.

A 56-year-old Japanese man was referred for examination of right adrenal tumor (3 cm). He had no apparent preexisting cancer by radiological workup and accordingly, the patient was considered as a nonfunctioning adrenocortical adenoma and scheduled for periodic CT scans every 6 months. However, five months after the initial diagnosis the patient complained of severe right back pain with remarkable enlargement of both adrenals (~20-fold volume). Although the origin of adrenal tumor was uncertain by pathological workup, positron emission tomography (PET) scan with (18)F-2-fluoro-D-deoxyglucose (FDG) eventually revealed a hot spot on left upper lung, which was consistent with a lesion of thickened bulla wall observed by chest CT. The present case is a very rare example of abrupt enlargement of bilateral adrenals due to clinically isolated adrenal metastasis, suggesting the requirement of frequent observation with greatest care regarding morphologic changes of adrenal incidentalomas.

[Thyroid metastases of an adrenocortical carcinoma 41 years after the diagnosis of the primary tumor]. / Métastases thyroïdiennes d'un corticosurrénalome 41 ans après le diagnostic de la tumeur initiale.

Thyroid metastasis are rare and represent less than 4% of malignant thyroid tumors in clinical series. They can develop many years after diagnosis of the primary tumor. We report a case of thyroid metastasis of adrenocortical carcinoma, 41 years after the diagnosis of the primary tumor. Such a long latent interval is exceptional. To our knowledge, this is the first case published. Based on current literature, we offer a brief review on thyroid metastasis and differential diagnosis of thyroid gland clear cell neoplasm.

[Diagnostic value of A103 and inhibin-alpha in adrenocortical tumors: an immunohistochemical study using tissue microarray techniques].

OBJECTIVE: To investigate the potential diagnostic value of A103 and inhibin-alpha in adrenocortical tumors and to evaluate the applicability of tissue microarray/tissue chip in pathological studies using immunohistochemistry. METHODS: A tissue microarray/tissue chip was constructed to contain 179 formalin-fixed, paraffin-embedded adrenal tissue samples which include 3 normal adrenal cortex, 2 fetal adrenal cortex, 2 nodular adrenocortical hyperplasia samples, 72 adrenocortical adenomas, 39 adrenocortical carcinomas, 3 adrenal medulla, 13 metastatic carcinomas, 4 metastatic malignant melanomas and 44 pheochromocytomas. Additional 20 cases of normal adult adrenal gland were used as controls. Immunohistochemical markers, including A103, inhibin-alpha, calretinin and Ki-67 were used on the tissue array sections by EnVision immunohistochemical staining methods. RESULTS: Positive staining of A103 was seen in all of the 23 (100%) adrenal cortex, 2 fetal adrenal cortex, 2 nodular adrenocortical hyperplasia samples, 60 of 66 (90.9%) adrenocortical adenomas samples, 35 of 37 (94.6%) adrenocortical carcinomas samples, 3 of 3 malignant melanomas, but in none of the adrenal medulla, pheochromocytomas or adrenal metastatic carcinoma samples. In all of the adrenal cortex, fetal adrenal cortex and nodular adrenocortical hyperplasia cases, inhibin-alpha immunoreactivity was limited to the zona reticularis and the innermost zona fasciculata. Fifty of the 66 (75.8%) adrenocortical adenomas, 28 of the 37 (75.7%) adrenocortical carcinomas were positive for inhibin-alpha. None of the adrenal medulla, pheochromocytoma, metastatic malignant melanoma or carcinoma samples showed a positive inhibin-alpha immunostain. CONCLUSIONS: The tissue microarray/tissue chip technique provides a reliable method to investigate marker expression by offering a rapid, economic and accurate screening of tissue specimens on a large scale. The combined use of A103 and inhibin-alpha is valuable in distinguishing adrenocortical tumor from pheochromocytoma and other metastatic neoplasms.

Primary adrenocortical carcinoma and delayed liver metastasis: is the surgery alone the right treatment? Case report.

Adrenocortical carcinoma is a very rare tumor which can develop at any age in either sex, with an estimated incidence of 0.5-2 new cases per million per year. Only few cases of adrenocortical carcinoma are reported in the literature, probably because the differential diagnosis between malignant and benign mass is not easy. Surgery represents the treatment of choice for adrenocortical carcinoma and for its possible recidivisms. We report the case of a 36-year-old female patient affected by adrenocortical carcinoma, operated on in 1999 and re-operated on in 2002 for a liver metastasis of the same tumor, without any other treatment. This case may be interesting for its rarity as well as for the several difficulties of the diagnosis and the choice of treatment. In conclusion, the follow-up of these patients is mandatory due to the difficulties of diagnosis and curative surgery represents the best choice of treatment.

Synchronous adrenal cortical carcinoma in a patient with lung cancer.

Workup of a patient with lung cancer involves adrenal imaging for evaluation of metastatic disease. When nodules are detected, biopsy is often attempted to differentiate a primary neoplasm from metastatic carcinoma or other lesions, such as granuloma. CT-guided biopsy of the deep seated adrenal glands is technically difficult and material is often scanty. We present a case and review histologic features enabling the diagnosis of adrenal cortical carcinoma.

Laparoscopic adrenalectomy: the New York-Presbyterian Hospital experience.

BACKGROUND AND PURPOSE: Laparoscopic adrenalectomy has become the standard technique for the surgical removal of the adrenal gland. The advantages of the laparoscopic approach include shorter length of stay (LOS), a decrease in postoperative pain, faster return to preoperative activity level, improved cosmesis, and reduced complications. We report our experience with laparoscopic adrenalectomy via a lateral transperitoneal approach. PATIENTS AND METHODS: Between September 1993 and April 2001, we performed 100 lateral transperitoneal adrenalectomies in 91 patients. In 82 cases, the adrenalectomy was unilateral and in the other 9, it was bilateral. A total of 59 left-sided lesions and 41 right-sided lesions were removed. The indications for surgery were Cushing's syndrome (24), aldosteronoma (34), pheochromocytoma (17), nonfunctioning adenoma (13), Carney's syndrome (1), and a metastasis from colon cancer (1) RESULTS: The overall success rate was 98%. Complications occurred in the two patients who required open conversion. In addition, three patients suffered pneumothoraces because of direct iatrogenic injury to the diaphragm during laparoscopic dissection. One additional patient suffered a splenic laceration. Operative time, blood loss, and intraoperative complications were similar in the laparoscopic and open surgery control group (N = 32). CONCLUSIONS: Laparoscopic adrenalectomy is technically feasible and reproducible. The lateral transperitoneal technique offers distinct advantages to the laparoscopist, including better visibility of familiar anatomic landmarks, easy access to other organ systems, the use of gravity to retract the spleen and liver, and a wide exposure, which allows removal of large adrenal lesions.

[Aggressively metastatic neuroendocrine carcinoma in the middle mediastinum].

A 50-year-old male patient with no symptoms was admitted to our hospital for further evaluation of a right superior mediastinal mass shadow found in chest radiographs during a health examination. Computed tomographic (CT) scans demonstrated a middle mediastinal mass of 4 cm in diameter surrounded by the SVC, the ascending aorta and the trachea at the subaortic level. Routine examination disclosed no metastatic or primary lesion elsewhere. A surgical biopsy resulted in a diagnosis of neuroendocrine carcinoma of unknown primary organ. The patient was given 1 course of chemotherapy with CAV-PE, but little effect was seen. However, when a PE regimen combined with thoracic radiation was used, the tumor shrank to half of its size. After the patient subsequently received high-dose treatment with Etoposide, CT imaging and cytologic analysis revealed multiple metastases to the subcutaneous tissue, both adrenal glands and the liver. Lung lesions also spread aggressively, and the patient died of metastasis. Although neuroendocrine carcinomas can arise from the systemic neuroendocrine cells including those in the mediastinum, their appearance in the middle mediastinum is rarely reported.