532538
research-article2014
IJSXXX10.1177/1066896914532538International Journal of Surgical PathologyWang et al
Case Report
“Dominant” Myelolipoma Encasing Adrenal Cortical Carcinoma: An Unusual Variation of Myelolipoma Occurring as a Synchronous and Predominant Neoplasm
International Journal of Surgical Pathology 2014, Vol. 22(8) 731–735 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914532538 ijs.sagepub.com
Jayson Wang, MBBS, PhD, FRCPath1, Cyril Fisher, MD, DSc, FRCPath1, and Khin Thway, MBBS, BSc, FRCPath1
Abstract Although myelolipomas of the adrenal glands are detected with increasing frequency with advances in imaging, the occurrence of myelolipoma with adrenal cortical carcinoma remains very rare. We present a case of combined myelolipoma with adrenal cortical carcinoma in a 47-year-old man. In previously reported cases of adrenal cortical carcinoma and myelolipoma, the latter occurred as incidental foci within or peripheral to the carcinoma, perhaps representing “myelolipomatous metaplasia” rather than true neoplasia. We describe a new finding, in which the myelolipomatous component consisted of a large mass adjacent and dominant to the carcinoma. The presence of these 2 defined and apparently independent tumors suggests, in this case, the occurrence of collision or synchronous neoplastic events, rather than of metaplasia. Keywords adrenal gland, adrenocortical carcinoma, histopathology, myelolipoma
Introduction
Case Report
Tumors of the adrenal glands are an increasingly frequent finding antemortem, and are seen incidentally in about 5% of computed tomography (CT) or magnetic resonance imaging scans.1 Series reports have shown that up to 78% of adrenal neoplasms are functioning, presenting with Cushing’s or Conn’s syndrome, congenital adrenal hyperplasia or symptoms attributed to pheochromocytoma.2 The remaining adrenal tumors are nonfunctioning and often detected incidentally. The commonest adrenal neoplasms are adenomas (accounting for >50%), followed by pheochromocytomas (approximately 15%), adrenocortical carcinomas (about 5%), and myelolipomas (about 3%), with ganglioneuromas and adrenal cysts rarely seen. Here, we document an unusual case of combined adrenal cortical carcinoma and myelolipoma in which the adrenal myelolipoma comprised a large mass adjacent to and “dominant” to the carcinoma, rather than the smaller foci within or around the carcinoma that previous reports have described. The features here suggest synchronous neoplastic events rather than metaplasia, in contrast to previously reported adrenal “hybrid” lesions that contained myelolipomas.
A 47-year-old man presented with a history of shortness of breath, lethargy, and night sweats for several months. He was previously fit and healthy, with no significant past medical history. Routine biochemistry and hematological blood tests showed no significant abnormal findings apart from mild anemia (hemoglobin of 10.6 g/dL). In particular, the serum sodium, potassium and glucose were within reference ranges. CT scan showed a circumscribed 16 × 15 × 13 cm thinly encapsulated ovoid mass arising from the right adrenal gland (Figure 1) and displacing the right kidney inferiorly. Superiorly, the neoplasm contained solid and myxoid elements, and indented the undersurface of the right hepatic lobe, while inferiorly it had a more fatty morphology with coarse peripheral calcifications. The radiological differential diagnosis was of right renal 1
Royal Marsden Hospital, London, UK
Corresponding Author: Khin Thway, Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ, UK. Email: [email protected]
Downloaded from ijs.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 30, 2015
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International Journal of Surgical Pathology 22(8)
Figure 1. Cross-sectional computed tomography scan image shows a large, well-defined 16 × 15 × 13 cm, thinly encapsulated ovoid mass arising from the right adrenal gland, and consisting of 2 distinct components. The predominant element is of fatty morphology with areas of septation, and encases a smaller nodule that has solid and myxoid contents.
angiomyolipoma, well differentiated liposarcoma with a dedifferentiated focus or myelolipoma. The patient underwent a CT-guided biopsy, which showed necrotic material only, with ghost outlines of polygonal cells, suspicious for neoplasm. He proceeded to laparotomy and excision of the retroperitoneal mass with right adrenalectomy, preserving the right kidney. At operation it was noted that the mass was not surrounded by any abnormal fat.
Materials and Methods Immunohistochemical staining (streptavidin-biotin peroxidase complex method, with diaminobenzidine as the chromogen) was performed on formalin-fixed, paraffinembedded (FFPE) tumor tissue using a panel of commercial antibodies. Molecular cytogenetic analysis was performed on FFPE material, to assess for MDM2 amplification (to support the exclusion of well differentiated and dedifferentiated liposarcoma) by fluorescence in situ hybridization. One micrometer thick FFPE sections were dewaxed overnight at 60°C, treated with hot buffer wash at 80°C (2-3 hours) followed by proteolytic enzyme treatment at 37°C, and washed in distilled water then an alcohol series before addition of MDM2 and CEP12 DNA probes (Abbott Laboratories Ltd, Maidenhead, UK). Hybridization was performed overnight according to manufacturer’s protocols.
Results Gross examination of the specimen showed an 18 × 16 × 10 cm, 1.7 kg, thinly encapsulated, lobulated ovoid mass
with a largely smooth surface (Figure 2A) over which an 8 × 1 × 0.2 cm adrenal gland was stretched (Figure 2B). No capsular breaching was noted. Slicing the mass showed 2 different, well-demarcated components. The larger accounted for the majority of the specimen (estimated as 70% to 80% of its volume) and consisted of homogeneous yellow fatty tissue with pinpoint areas of hemorrhage. Within this fatty tissue, at one side, was a circumscribed 10 × 10 × 8 cm variegated nodule with necrotic, hemorrhagic, and solid firm white tissue (Figure 2B). Both lesions were sampled extensively with a total of 26 blocks taken, including 12 blocks of solid tumor and 14 blocks of fatty tumor. Histologically, there were 2 separate lesions, corresponding to the 2 separate macroscopic components (Figure 2C). The larger component was focally adjacent to the adrenal, and comprised mature adipose tissue with some fibrous septa, and varying amounts of admixed hematopoietic and blood elements (Figure 2D and E). No solid tissue component was present. The septa were of sparse cellularity, and no cellular atypia, mitotic figures or necrosis were identified within the adipose tissue or fibrous septa. The lesion was negative for HMB45 and MelanA (excluding angiomyolipoma), as well as for CDK4 and p16 (suggesting that well-differentiated liposarcoma was unlikely). Fluorescence in situ hybridization showed no evidence of MDM2 gene amplification, also helping to exclude well differentiated liposarcoma. The features were in keeping with myelolipoma. The second lesion was encased mostly within the myelolipoma and also adjacent to the stretched rim of adrenal gland, and was a demarcated, partially encapsulated cellular neoplasm that showed focal infiltration of the adrenal capsule. The tumor was composed of small nests and sheets of moderately to focally markedly pleomorphic polygonal cells (Figure 2F), with vesicular nuclei and granular eosinophilic or amphophilic cytoplasm. There were extensive areas of necrosis and a mitotic index of 41/10 high power fields, including prominent atypical forms (Figure 2F). No lymphovascular or perineurial invasion was identified. This lesion was focally positive for inhibin, AE1/AE3, MNF116, CAM5.2, CD56, synaptophysin, and CD117, and very focally so for S100 protein and NSE, while negative for MelanA, calretinin, EMA, chromogranin, DOG1, CD34, desmin, SMA, and h-caldesmon. The MIB1 proliferation index was high. The features were consistent with an adrenal cortical neoplasm, and in keeping with adrenal cortical carcinoma by Weiss criteria3 (showing ≥3/9 of Weiss’s criteria for prediction of biologic behavior of conventional adrenal cortical tumors [high nuclear grade (Fuhrman 3 to 4), mitotic rate >5/50 high-power field, atypical mitoses, clear cells comprising ≤25% of the tumor, diffuse architecture (greater than one third of the tumor), necrosis, and invasion of venous, sinusoidal, and capsular structures]). Both tumor components
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Wang et al
Figure 2. (A) Gross photograph of a transverse section of the combined tumor, showing the predominant myelolipomatous component encasing the solid nodule of adrenal cortical carcinoma. (B) Gross photograph of both tumor components, showing the thin, compressed rim of adjacent normal adrenal gland at the top of the field. (C) Histology of both tumor components showing the boundary of the myelolipoma (top left), comprising mature fat and scattered hematopoietic elements, and the cellular, partially necrotic adrenal cortical carcinoma (bottom right). The 2 neoplasms are separated by a thick fibrous capsule. (D, E) Adrenal myelolipoma. This comprised a mixture of mature adipose tissue and hematopoietic elements, the latter present in varying amounts throughout the lesion. While in many areas the fatty component predominated, in others (shown here) hematopoietic elements are abundant. All 3 hematopoietic lineages are represented, including prominent megakaryocytes. A small fragment of mature metaplastic bone is present, corresponding to the calcification seen radiologically (D) (×200). The myelolipoma abuts normal adrenal tissue (E) (×200). (F) Adrenal cortical carcinoma. The tumor is composed of nests and sheets of moderately and focally markedly pleomorphic polygonal cells, with vesicular nuclei and granular eosinophilic or amphophilic cytoplasm. Mitotic figures are abundant, including atypical forms (×200).
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were narrowly but completely excised, each separated from the inked margin by fascia/fibrous capsule. The patient made a good postoperative recovery. At clinical follow-up at 6 months, there was resolution of his clinical symptoms and return of hemoglobin level to within the normal range, at 16.0 g/dL. However, a follow-up CT scan showed new multiple bilateral pulmonary nodules measuring up to 6 mm in size. Blood tests for vasoactive intestinal peptide, pancreatic polypeptide, gastrin, glucagon, cocaine- and amphetamine-regulated transcript, somatostatin, and cortisol were within normal ranges. Likewise, urinary cortisol, 5-hydroxyidoleacetic acid, and catecholamines levels were within reference ranges. The patient was therefore thought to have metastases from his nonfunctioning adrenal cortical carcinoma. A further scan after 10 months showed minor progression of his metastases, and he remains under close monitoring by his oncology team.
Discussion Although adrenal neoplasms are an increasingly common finding with the widespread usage and improvement of CT and magnetic resonance imaging techniques, the majority are incidental. Most represent adrenal cortical adenomas or pheochromocytomas. Adrenal cortical carcinomas (ACC) are rare, accounting for only about 1 case per 1 million in the population, and tend to be aggressive neoplasms associated with up to 50% mortality. By contrast, myelolipomas, which are even rarer, are benign tumors composed of varying proportions of mature adipose tissue and hematopoietic elements resembling bone marrow. They occur most frequently in older adults, mainly between the fifth and seventh decades, with a roughly equal sex distribution. While the majority of them arise within the adrenal glands, they can rarely occur in ectopic adrenal tissue or in a variety of extra-adrenal sites without associated adrenal tissue, such as the presacral area of the retroperitoneum, and the kidney and mediastinum. They are hormonally inactive, and have not been associated with specific disturbances of the hematopoietic system. Most are small, asymptomatic unilateral lesions found incidentally on imaging or at autopsy. Large symptomatic lesions (presenting with clinical manifestations such as abdominal mass or pain, hemoperitoneum and hematuria due to tumor bulk or traumatic rupture and hemorrhage) are also described, including giant masses weighing several kilograms. The pathogenesis of myelolipoma remains uncertain. Areas of both lipomatous and myelolipomatous differentiation are described in a variety of lesions of the adrenal cortex, but it is thought that these foci often represent myelolipomatous metaplasia, rather than true myelolipomas.4 Various theories for their development have included myelolipomatous metaplasia of adrenal cortical cells,
intra-adrenal embryonic rests of bone marrow or metaplasia of uncommitted or pluripotential adrenal stromal cells.5 Pure myelolipomas have been reported to be associated with endocrinopathies, including Cushing’s and Conn’s syndromes and congenital adrenal hyperplasia with virilization. It has been suggested that they might arise under the influence of steroid hormones on adrenal cortical cells so that they undergo metaplasia, and this may explain the “micromyelolipomas” arising within adrenal tumors. The few molecular studies on adrenal myelolipomas suggest that they represent true neoplasms rather than reactive, metaplastic or hamartomatous processes. X-chromosome inactivation studies in a series of adrenal myelolipomas have demonstrated that most have nonrandom X-chromosome inactivation, suggesting a clonal origin.6 One incidental myelolipoma has shown a balanced translocation between bands 3q25 and 21p11 in cultured tumor cells by conventional cytogenetics.7 Myelolipomas arising in combination with other adrenal neoplasms are documented but rare. The commonest occurrence is with adrenal cortical adenoma,8 with only one report each of myelolipoma with pheochromocytoma9 and ganglioneuroma.10 There are 6 previous cases of myelolipoma with ACC,8,11-14 of which the majority of ACC were functioning neoplasms, with most patients exhibiting symptoms of Cushing’s syndrome, and less frequently hyperaldosteronism. This patient, however, had no biochemical or clinical features of endocrine abnormalities. Notably, in all previous reports of combined ACC and myelolipoma, the ACC formed the majority component of the tumor mass. All but one of the previous cases suggested only small foci of myelolipomatous tissue within or around the carcinoma. There is also a report of ACC containing pure fat elements.15 A pattern of “micromyelolipomatous” involvement has been seen in the majority of myelolipomas combined with adrenal adenomas, as well as in the case with ganglioneuroma.10 Only one previous case showed ACC with a separate smaller myelolipoma adjacent to the carcinoma microscopically, which was not apparent grossly.13 Our case is therefore unusual, since both grossly and microscopically, the ACC was separate and distinct from the myelolipoma, with no lipomatous or myelolipomatous elements within the carcinoma. As both neoplasms were seen adjacent to normal adrenal gland, this suggests that each may have arisen synchronously from it, with the myelolipoma subsequently encasing the ACC. The possibility of this representing synchronous or collision events of 2 independent neoplasms is in contrast to the previously noted incidental small foci of myelolipoma within or around ACC, which would be more in keeping with metaplasia within a single neoplasm. The microscopic features are consistent with the radiological picture, where the appearance was
Downloaded from ijs.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 30, 2015
735
Wang et al mainly of a lipomatous tumor, within which was a discrete mass of solid neoplasm, and suggesting a predominantly lipomatous tumor such as angiomyolipoma or well-differentiated liposarcoma with an area of dedifferentiation. The correct diagnosis was only made histologically. In summary this is, to our knowledge, the first description of the existence of myelolipoma as a “dominant” mass adjacent to adrenal cortical carcinoma, rather than occurring as small intermixed foci within or around it. This unusual relationship between these 2 lesions suggests the possibility of synchronous neoplastic (rather than metaplastic) events, for which the tumorigenic mechanisms remain to be elucidated. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge support from the National Institute for Health Research (NIHR) Royal Marsden/Institute of Cancer Research (ICR) Biomedical Research Centre.
References 1. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy. AJR Am J Roentgenol. 2008;190:1163-1168. 2. Ctvrtlik F, Herman M, Student V, Ticha V, Minarik J. Differential diagnosis of incidentally detected adrenal masses revealed on routine abdominal CT. Eur J Radiol. 2009;69:243-252. 3. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol. 1989;13:202-206.
4. Montone KT, Rosen M, Siegelman ES, Fogt F, Livolsi VA. Adrenocortical neoplasms with myelolipomatous and lipomatous metaplasia: report of 3 cases. Endocr Pract. 2009;15:128-133. 5. Lack EE. Other neoplasms and tumor-like lesions of the adrenal glands. In: Rosai J, ed. Tumors of the Adrenal Gland and Extra-Adrenal Paraganglia. Washington, DC: Armed Forces Institute of Pathology; 1997:174-180. 6. Bishop E, Eble JN, Cheng L, et al. Adrenal myelolipomas show nonrandom X-chromosome inactivation in hematopoietic elements and fat: support for a clonal origin of myelolipomas. Am J Surg Pathol. 2006;30:838-843. 7. Chang KC, Chen PI, Huang ZH, Lin YM, Kuo PL. Adrenal myelolipoma with translocation (3;21)(q25;p11). Cancer Genet Cytogenet. 2002;134:77-80. 8. Goetz SP, Niemann TH, Robinson RA, Cohen MB. Hematopoietic elements associated with adrenal glands. A study of the spectrum of change in nine cases. Arch Pathol Lab Med. 1994;118:895-896. 9. Ukimura O, Inui E, Ochiai A, Kojima M, Watanabe H. Combined adrenal myelolipoma and pheochromocytoma. J Urol. 1995;154:1470. 10. Merchant SH, Herman CM, Amin MB, Ro JY, Troncoso P. Myelolipoma associated with adrenal ganglioneuroma. Arch Pathol Lab Med. 2002;126:736-737. 11. Krpensky A, Strmiska M, Cerny E. Ossifying adrenocortical carcinoma with myelolipoma [in Czech]. Cesk Patol. 1977;13:7-12. 12. King DR, Lack EE. Adrenal cortical carcinoma: a clinical and pathologic study of 49 cases. Cancer. 1979;44:239-244. 13. Banik S, Hasleton PS, Lyon RL. An unusual variant of multiple endocrine neoplasia syndrome: a case report. Histopathology. 1984;8:135-144. 14. Sun X, Ayala A, Castro CY. Adrenocortical carcinoma with concomitant myelolipoma in a patient with hyperaldosteronism. Arch Pathol Lab Medial. 2005;129:e144-e147. 15. Egbert N, Elsayes KM, Azar S, Caoili EM. Computed tomography of adrenocortical carcinoma containing macroscopic fat. Cancer Imaging. 2010;10:198-200.
Downloaded from ijs.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 30, 2015
research-article2014
IJSXXX10.1177/1066896914532538International Journal of Surgical PathologyWang et al
Case Report
“Dominant” Myelolipoma Encasing Adrenal Cortical Carcinoma: An Unusual Variation of Myelolipoma Occurring as a Synchronous and Predominant Neoplasm
International Journal of Surgical Pathology 2014, Vol. 22(8) 731–735 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896914532538 ijs.sagepub.com
Jayson Wang, MBBS, PhD, FRCPath1, Cyril Fisher, MD, DSc, FRCPath1, and Khin Thway, MBBS, BSc, FRCPath1
Abstract Although myelolipomas of the adrenal glands are detected with increasing frequency with advances in imaging, the occurrence of myelolipoma with adrenal cortical carcinoma remains very rare. We present a case of combined myelolipoma with adrenal cortical carcinoma in a 47-year-old man. In previously reported cases of adrenal cortical carcinoma and myelolipoma, the latter occurred as incidental foci within or peripheral to the carcinoma, perhaps representing “myelolipomatous metaplasia” rather than true neoplasia. We describe a new finding, in which the myelolipomatous component consisted of a large mass adjacent and dominant to the carcinoma. The presence of these 2 defined and apparently independent tumors suggests, in this case, the occurrence of collision or synchronous neoplastic events, rather than of metaplasia. Keywords adrenal gland, adrenocortical carcinoma, histopathology, myelolipoma
Introduction
Case Report
Tumors of the adrenal glands are an increasingly frequent finding antemortem, and are seen incidentally in about 5% of computed tomography (CT) or magnetic resonance imaging scans.1 Series reports have shown that up to 78% of adrenal neoplasms are functioning, presenting with Cushing’s or Conn’s syndrome, congenital adrenal hyperplasia or symptoms attributed to pheochromocytoma.2 The remaining adrenal tumors are nonfunctioning and often detected incidentally. The commonest adrenal neoplasms are adenomas (accounting for >50%), followed by pheochromocytomas (approximately 15%), adrenocortical carcinomas (about 5%), and myelolipomas (about 3%), with ganglioneuromas and adrenal cysts rarely seen. Here, we document an unusual case of combined adrenal cortical carcinoma and myelolipoma in which the adrenal myelolipoma comprised a large mass adjacent to and “dominant” to the carcinoma, rather than the smaller foci within or around the carcinoma that previous reports have described. The features here suggest synchronous neoplastic events rather than metaplasia, in contrast to previously reported adrenal “hybrid” lesions that contained myelolipomas.
A 47-year-old man presented with a history of shortness of breath, lethargy, and night sweats for several months. He was previously fit and healthy, with no significant past medical history. Routine biochemistry and hematological blood tests showed no significant abnormal findings apart from mild anemia (hemoglobin of 10.6 g/dL). In particular, the serum sodium, potassium and glucose were within reference ranges. CT scan showed a circumscribed 16 × 15 × 13 cm thinly encapsulated ovoid mass arising from the right adrenal gland (Figure 1) and displacing the right kidney inferiorly. Superiorly, the neoplasm contained solid and myxoid elements, and indented the undersurface of the right hepatic lobe, while inferiorly it had a more fatty morphology with coarse peripheral calcifications. The radiological differential diagnosis was of right renal 1
Royal Marsden Hospital, London, UK
Corresponding Author: Khin Thway, Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ, UK. Email: [email protected]
Downloaded from ijs.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 30, 2015
732
International Journal of Surgical Pathology 22(8)
Figure 1. Cross-sectional computed tomography scan image shows a large, well-defined 16 × 15 × 13 cm, thinly encapsulated ovoid mass arising from the right adrenal gland, and consisting of 2 distinct components. The predominant element is of fatty morphology with areas of septation, and encases a smaller nodule that has solid and myxoid contents.
angiomyolipoma, well differentiated liposarcoma with a dedifferentiated focus or myelolipoma. The patient underwent a CT-guided biopsy, which showed necrotic material only, with ghost outlines of polygonal cells, suspicious for neoplasm. He proceeded to laparotomy and excision of the retroperitoneal mass with right adrenalectomy, preserving the right kidney. At operation it was noted that the mass was not surrounded by any abnormal fat.
Materials and Methods Immunohistochemical staining (streptavidin-biotin peroxidase complex method, with diaminobenzidine as the chromogen) was performed on formalin-fixed, paraffinembedded (FFPE) tumor tissue using a panel of commercial antibodies. Molecular cytogenetic analysis was performed on FFPE material, to assess for MDM2 amplification (to support the exclusion of well differentiated and dedifferentiated liposarcoma) by fluorescence in situ hybridization. One micrometer thick FFPE sections were dewaxed overnight at 60°C, treated with hot buffer wash at 80°C (2-3 hours) followed by proteolytic enzyme treatment at 37°C, and washed in distilled water then an alcohol series before addition of MDM2 and CEP12 DNA probes (Abbott Laboratories Ltd, Maidenhead, UK). Hybridization was performed overnight according to manufacturer’s protocols.
Results Gross examination of the specimen showed an 18 × 16 × 10 cm, 1.7 kg, thinly encapsulated, lobulated ovoid mass
with a largely smooth surface (Figure 2A) over which an 8 × 1 × 0.2 cm adrenal gland was stretched (Figure 2B). No capsular breaching was noted. Slicing the mass showed 2 different, well-demarcated components. The larger accounted for the majority of the specimen (estimated as 70% to 80% of its volume) and consisted of homogeneous yellow fatty tissue with pinpoint areas of hemorrhage. Within this fatty tissue, at one side, was a circumscribed 10 × 10 × 8 cm variegated nodule with necrotic, hemorrhagic, and solid firm white tissue (Figure 2B). Both lesions were sampled extensively with a total of 26 blocks taken, including 12 blocks of solid tumor and 14 blocks of fatty tumor. Histologically, there were 2 separate lesions, corresponding to the 2 separate macroscopic components (Figure 2C). The larger component was focally adjacent to the adrenal, and comprised mature adipose tissue with some fibrous septa, and varying amounts of admixed hematopoietic and blood elements (Figure 2D and E). No solid tissue component was present. The septa were of sparse cellularity, and no cellular atypia, mitotic figures or necrosis were identified within the adipose tissue or fibrous septa. The lesion was negative for HMB45 and MelanA (excluding angiomyolipoma), as well as for CDK4 and p16 (suggesting that well-differentiated liposarcoma was unlikely). Fluorescence in situ hybridization showed no evidence of MDM2 gene amplification, also helping to exclude well differentiated liposarcoma. The features were in keeping with myelolipoma. The second lesion was encased mostly within the myelolipoma and also adjacent to the stretched rim of adrenal gland, and was a demarcated, partially encapsulated cellular neoplasm that showed focal infiltration of the adrenal capsule. The tumor was composed of small nests and sheets of moderately to focally markedly pleomorphic polygonal cells (Figure 2F), with vesicular nuclei and granular eosinophilic or amphophilic cytoplasm. There were extensive areas of necrosis and a mitotic index of 41/10 high power fields, including prominent atypical forms (Figure 2F). No lymphovascular or perineurial invasion was identified. This lesion was focally positive for inhibin, AE1/AE3, MNF116, CAM5.2, CD56, synaptophysin, and CD117, and very focally so for S100 protein and NSE, while negative for MelanA, calretinin, EMA, chromogranin, DOG1, CD34, desmin, SMA, and h-caldesmon. The MIB1 proliferation index was high. The features were consistent with an adrenal cortical neoplasm, and in keeping with adrenal cortical carcinoma by Weiss criteria3 (showing ≥3/9 of Weiss’s criteria for prediction of biologic behavior of conventional adrenal cortical tumors [high nuclear grade (Fuhrman 3 to 4), mitotic rate >5/50 high-power field, atypical mitoses, clear cells comprising ≤25% of the tumor, diffuse architecture (greater than one third of the tumor), necrosis, and invasion of venous, sinusoidal, and capsular structures]). Both tumor components
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Figure 2. (A) Gross photograph of a transverse section of the combined tumor, showing the predominant myelolipomatous component encasing the solid nodule of adrenal cortical carcinoma. (B) Gross photograph of both tumor components, showing the thin, compressed rim of adjacent normal adrenal gland at the top of the field. (C) Histology of both tumor components showing the boundary of the myelolipoma (top left), comprising mature fat and scattered hematopoietic elements, and the cellular, partially necrotic adrenal cortical carcinoma (bottom right). The 2 neoplasms are separated by a thick fibrous capsule. (D, E) Adrenal myelolipoma. This comprised a mixture of mature adipose tissue and hematopoietic elements, the latter present in varying amounts throughout the lesion. While in many areas the fatty component predominated, in others (shown here) hematopoietic elements are abundant. All 3 hematopoietic lineages are represented, including prominent megakaryocytes. A small fragment of mature metaplastic bone is present, corresponding to the calcification seen radiologically (D) (×200). The myelolipoma abuts normal adrenal tissue (E) (×200). (F) Adrenal cortical carcinoma. The tumor is composed of nests and sheets of moderately and focally markedly pleomorphic polygonal cells, with vesicular nuclei and granular eosinophilic or amphophilic cytoplasm. Mitotic figures are abundant, including atypical forms (×200).
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were narrowly but completely excised, each separated from the inked margin by fascia/fibrous capsule. The patient made a good postoperative recovery. At clinical follow-up at 6 months, there was resolution of his clinical symptoms and return of hemoglobin level to within the normal range, at 16.0 g/dL. However, a follow-up CT scan showed new multiple bilateral pulmonary nodules measuring up to 6 mm in size. Blood tests for vasoactive intestinal peptide, pancreatic polypeptide, gastrin, glucagon, cocaine- and amphetamine-regulated transcript, somatostatin, and cortisol were within normal ranges. Likewise, urinary cortisol, 5-hydroxyidoleacetic acid, and catecholamines levels were within reference ranges. The patient was therefore thought to have metastases from his nonfunctioning adrenal cortical carcinoma. A further scan after 10 months showed minor progression of his metastases, and he remains under close monitoring by his oncology team.
Discussion Although adrenal neoplasms are an increasingly common finding with the widespread usage and improvement of CT and magnetic resonance imaging techniques, the majority are incidental. Most represent adrenal cortical adenomas or pheochromocytomas. Adrenal cortical carcinomas (ACC) are rare, accounting for only about 1 case per 1 million in the population, and tend to be aggressive neoplasms associated with up to 50% mortality. By contrast, myelolipomas, which are even rarer, are benign tumors composed of varying proportions of mature adipose tissue and hematopoietic elements resembling bone marrow. They occur most frequently in older adults, mainly between the fifth and seventh decades, with a roughly equal sex distribution. While the majority of them arise within the adrenal glands, they can rarely occur in ectopic adrenal tissue or in a variety of extra-adrenal sites without associated adrenal tissue, such as the presacral area of the retroperitoneum, and the kidney and mediastinum. They are hormonally inactive, and have not been associated with specific disturbances of the hematopoietic system. Most are small, asymptomatic unilateral lesions found incidentally on imaging or at autopsy. Large symptomatic lesions (presenting with clinical manifestations such as abdominal mass or pain, hemoperitoneum and hematuria due to tumor bulk or traumatic rupture and hemorrhage) are also described, including giant masses weighing several kilograms. The pathogenesis of myelolipoma remains uncertain. Areas of both lipomatous and myelolipomatous differentiation are described in a variety of lesions of the adrenal cortex, but it is thought that these foci often represent myelolipomatous metaplasia, rather than true myelolipomas.4 Various theories for their development have included myelolipomatous metaplasia of adrenal cortical cells,
intra-adrenal embryonic rests of bone marrow or metaplasia of uncommitted or pluripotential adrenal stromal cells.5 Pure myelolipomas have been reported to be associated with endocrinopathies, including Cushing’s and Conn’s syndromes and congenital adrenal hyperplasia with virilization. It has been suggested that they might arise under the influence of steroid hormones on adrenal cortical cells so that they undergo metaplasia, and this may explain the “micromyelolipomas” arising within adrenal tumors. The few molecular studies on adrenal myelolipomas suggest that they represent true neoplasms rather than reactive, metaplastic or hamartomatous processes. X-chromosome inactivation studies in a series of adrenal myelolipomas have demonstrated that most have nonrandom X-chromosome inactivation, suggesting a clonal origin.6 One incidental myelolipoma has shown a balanced translocation between bands 3q25 and 21p11 in cultured tumor cells by conventional cytogenetics.7 Myelolipomas arising in combination with other adrenal neoplasms are documented but rare. The commonest occurrence is with adrenal cortical adenoma,8 with only one report each of myelolipoma with pheochromocytoma9 and ganglioneuroma.10 There are 6 previous cases of myelolipoma with ACC,8,11-14 of which the majority of ACC were functioning neoplasms, with most patients exhibiting symptoms of Cushing’s syndrome, and less frequently hyperaldosteronism. This patient, however, had no biochemical or clinical features of endocrine abnormalities. Notably, in all previous reports of combined ACC and myelolipoma, the ACC formed the majority component of the tumor mass. All but one of the previous cases suggested only small foci of myelolipomatous tissue within or around the carcinoma. There is also a report of ACC containing pure fat elements.15 A pattern of “micromyelolipomatous” involvement has been seen in the majority of myelolipomas combined with adrenal adenomas, as well as in the case with ganglioneuroma.10 Only one previous case showed ACC with a separate smaller myelolipoma adjacent to the carcinoma microscopically, which was not apparent grossly.13 Our case is therefore unusual, since both grossly and microscopically, the ACC was separate and distinct from the myelolipoma, with no lipomatous or myelolipomatous elements within the carcinoma. As both neoplasms were seen adjacent to normal adrenal gland, this suggests that each may have arisen synchronously from it, with the myelolipoma subsequently encasing the ACC. The possibility of this representing synchronous or collision events of 2 independent neoplasms is in contrast to the previously noted incidental small foci of myelolipoma within or around ACC, which would be more in keeping with metaplasia within a single neoplasm. The microscopic features are consistent with the radiological picture, where the appearance was
Downloaded from ijs.sagepub.com at FLORIDA INTERNATIONAL UNIV on May 30, 2015
735
Wang et al mainly of a lipomatous tumor, within which was a discrete mass of solid neoplasm, and suggesting a predominantly lipomatous tumor such as angiomyolipoma or well-differentiated liposarcoma with an area of dedifferentiation. The correct diagnosis was only made histologically. In summary this is, to our knowledge, the first description of the existence of myelolipoma as a “dominant” mass adjacent to adrenal cortical carcinoma, rather than occurring as small intermixed foci within or around it. This unusual relationship between these 2 lesions suggests the possibility of synchronous neoplastic (rather than metaplastic) events, for which the tumorigenic mechanisms remain to be elucidated. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge support from the National Institute for Health Research (NIHR) Royal Marsden/Institute of Cancer Research (ICR) Biomedical Research Centre.
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