CrossMark
Sarcomatoid Adrenal Carcinoma: Case Report with Contribution to Pathogenesis
Wolfgang Saeger1 . Werner Mohren2 . Matthias Behrend3 . Peter Iglauer4. Waldemar Wilczak 4
C Springer Science+Business Media New York 2016
Abstract A tumor in the adrenal region with two metasta- ses in the liver was classified as poorly differentiated sar- coma on the base of extensive immunostainings (expres- sion of vimentin, desmin, myogenin, and CD31, no expres- sion of inhibin, melan A). Four years later in a second examination with molecular methods for a study of adrenal sarcomas, this diagnosis must be revised due to the lack of MDM-2 gene amplification and FKHR translocation which exclude sarcoma. Further immunostainings of many other parts of the tumor showed in one area more mature tumor tissue expressing synaptophysin, SF-1, and melan A. From these findings we classified an adrenal cortical cancer with predominant dedifferentiation into a sarcomatoid adrenal carcinoma. The properties of this very rare cancer type are presented and discussed.
Keywords Adrenal carcinoma · Sarcomatoid carcinoma · Sarcoma · Molecular pathology · Immunostaining
☒ Wolfgang Saeger w.saeger@uke.de
1 Institute of Pathology and Neuropathology of the University of Hamburg, Martinistraße 52, 20246 Hamburg, UKE, Germany
2 Institute of Pathology, Hospital Deggendorf, 94469 Deggendorf, Germany
3 Clinic for Surgery, Hospital Deggendorf, 94469 Deggendorf, Germany
4 Institute of Pathology of the University of Hamburg, 20246 Hamburg, UKE, Germany
Introduction
The subclassification of adrenal cortical carcinomas appears to be a frequently ignored field, since the ordinary type pre- dominates strongly. Nevertheless, textbooks of pathology [12, 14, 19] mention some subtypes: the rare mucoid subtype, the oncocytic subtype, and the very rare sarcomatoid subtype. The latter subtype is often undistinguishable from poorly differen- tiated or undifferentiated sarcomas of the retroperitoneum or adrenals [15, 19], whereas epitheloid angiosarcomas of the adrenals may appear as ordinary adrenal cancers before immunostainings with CD31 [8]. The identification of sarcomatoid adrenal cancer is very important for the patient since this diagnosis is associated with a very poor prognosis. Only very few patients live longer than 1 year after cancer resection [25].
In a recent review of sarcomatoid adrenal carcinomas with complete research of the literature [25], eight such cancers are listed. From our files of more than 500 adrenal cancers, we would like to present a further case with problematic history and clarification by immunocytochemistry and molecular pathology.
Case Report
A 53-year-old woman suffering from arterial hyperten- sion, diabetes mellitus type II, and hyperlipidemia was examined by her general practitioner with ultrasound of the abdomen that revealed a tumor in the region of the right adrenal. Magnetic resonance tomography showed a tumor with a diameter of 123 mm but without sharp bor- der to the liver. An adrenalectomy and hemihepatectomy were performed. In the first report by the local pathologist
| Antibody | Sarcomatoid tumor part | More mature tumor part | Metastases |
|---|---|---|---|
| Keratin KL1 | − | - | - |
| CK 20 | − | - | - |
| Synaptophysin | − | ++ | − |
| Chromogranin A | − | - | - |
| SF-1 | (+) | + | (+) |
| Ki-67 (MiB-1) | 60 % | 10 % | 60 % |
| P53 | − | - | - |
| CD31 | + | − | + |
| CD34 | − | - | - |
| MDM2 | − | n.d. | − |
| EMA | − | n.d. | − |
| Vimentin | ++ | ++ | n.d. |
| Melan A | − | + | − |
| Hmb 45 | n.d. | n.d. | − |
| SMA | − | n.d. | − |
| Desmin | +++ | − | +++ |
| Myogenin | (+) | − | (+) |
| Myf4 | − | - | - |
(+) very weakly positive, + weakly positive, ++ moderately positive, +++ strongly positive, n.d. not done
(W.M.), an undifferentiated adrenal cancer was supposed. One paraffin block was sent to a consultant endocrine pathologist (W.S.) who diagnosed a poorly differentiated sarcoma of the adrenal, likely of angiosarcomatous type. Five years later, the tumor was re-evaluated by W.S. for a retrospective study of adrenal and para-adrenal sarcomas using new immunohistological antibodies and molecular biological methods. From these examinations, the diagno- sis of an adrenal sarcoma could not be maintained since a sarcomatoid adrenal carcinoma has to be realized.
The patient was controlled by CT scan every 6 months after surgery. Chemotherapy was refused by the patient. A recurrent tumor was not found. The patient is alive and well.
S
Material and Methods
The tumor was fixed in 10 % buffered formalin, embedded in paraffin, and stained with hematoxlin-eosin and PAS. Immunostainings were performed with primary antibodies listed in Table 1. Molecular markers (Table 2) were deter- mined by Fluorescence-in-situ-hybridization: MDM2 (Murine Double Minute 2) amplification; FKHR (Forkhead Homologe In Rhabdomyosarcoma) translocation, and KRAS (Kirsten Rat Sarcoma Viral Oncogene Homologe)/ Chromosome 12 amplification/deletion.
Pathologic Findings
In microscopic examination, the tumor measured 130 × 80 × 65 mm and is fixed with the liver. Cut surfaces showed solid gray areas and necroses. Residual adrenal tissue could not be identified. In the liver, two additional tumors were found separated from the main tumor. One of these tu- mors was totally necrotic.
| Molecular marker (FISH) | Sarcomatiod tumor part | More mature tumor part | Metastases |
|---|---|---|---|
| MDM-2 | No amplification detected | Not determined | No amplification detected |
| FKHR | No translocation detected | Not determined | No translocation detected |
| KRAS/chr 12p | 90 % 1 chr12 copy | 1-2 chr12 copies | 2 chr12 copies |
| 10 % 2-4 chr12 copies |
In microscopic examination, far most parts of the tumor are poorly differentiated and rich in medium-sized cells often in spindle outlines forming bundles to an irregular pattern of presumably of mesenchymal character (Figs. 1 and 2). PAS reaction is negative. Mitoses are frequent. Small and large areas of necroses are frequent. The content of capillaries is high.
A smaller part of the tumor shows solid or trabecular growth pattern (Figs. 3 and 4). The cells are less pleomorphic and reveal an epithelial character. The number of mitoses is less frequent than in the undifferentiated part but exceed 2/10
per HPF. The tumor infiltrates the capsule and veins around the capsule. The marker expression of both parts is similar but not identical (Table 1). The poorly differentiated part presents desmin in moderate degree (Figs. 5 and 6), a very weak ex- pression of SF-1 (Fig. 7) and a high Ki-67 index (60 %) (Fig. 8), whereas inhibin and Melan A are not expressed. The more mature part is positive for SF-1 and Melan A (Fig. 9). The Ki-67-index is much lower (10 %) (Fig. 10). The liver is not directly infiltrated but shows two metastases of poorly differentiated type near the primary tumor but with- out direct contact that present identical structures and marker expressions (Tables 1 and 2). One of these is nearly complete- ly necrotic.
Molecular pathology reveals different results in the differ- ent parts (Table 2) (Figs. 11 and 12). In the sarcomatoid part and the metastases, no gene amplification of MDM-2 and no translocation of FKHR are found. From these data, a sarcoma appears to be excluded. In both parts of the tumor and the metastases, the KRAS gene was not amplificated.
The scoring systems for adrenocortical tumors examined in the differentiated part only (Tables 3, 4, and 5) revealed ma- lignant counts: moderately increased indices in the systems of Weiss et al. [26] and Hough et al. [9] and a stronger increased value in the system of van Slooten et al. [23].
Conclusions of Pathological Findings
The structure and the immunostainings (Table 2) of the undif- ferentiated part with expression of desmin and CD 31 and negative Melan A and Hmb 45 speak in favor for an immature sarcoma likely of angiomatous type whereas a melanoma and an angiomyolipoma appear very unlikely, but the molecular findings are incompatible with the diagnosis of a sarcoma.
| Kriteria | Definition | Index |
|---|---|---|
| Nuclear atypia | High grade | 1 |
| Mitoses | More than 5/50 HPF | 1 |
| Atypical mitoses | Atypical figures | 0 |
| Spongiotic cells | Less than 25 % of tumor cells | 1 |
| Architecture | More than 33 % diffuse | 0 |
| Necroses | More than single cells | 0 |
| Venous invasion | Smooth muscle in wall | 1 |
| Sinusoidal invasion | No smooth muscle in wall | 0 |
| Capsular invasion | – | 1 |
| Sum | – | 5 |
| Presence of more than 3 criteria correlates with malignancy | ||
| Kriteria | Definition | Index |
|---|---|---|
| Pleomorphism | Moderate or marked | 0.39 |
| Mitoses | More than 1/10 HPF | 0.60 |
| Architecture | Diffuse growth pattern | 0 |
| Necroses | More than single cells | 0 |
| Fibroses | Broad fibrous bands | 0 |
| Vessels | Invasion | 0.92 |
| Capsule | Invasion | 0.37 |
| Sum | – | 2.28 |
| Mean histological index of malignancy is 2.91 | ||
MDM-2 amplification as well FKHR translocations is accept- ed as common molecular markers for particular sarcoma sub- types [2, 16]. As both markers are negative in the immature tumor part, no evidence for a sarcoma is found. An oncogenic amplification of the KRAS gene is excluded in the examined tumor samples [17]. Interestingly, both parts of the tumor share a partial monosomy for chromosome 12 pointing to an identical origin of both tumor parts.
The mature part could be identified as a typical adrenal cancer with specific marker spectrum and elevated counts in the scoring systems. So, final diagnosis is an adrenal cortical cancer with extensive dedifferentiation into a sarcomatoid ad- renal cancer and two liver metastases.
Discussion
The mix of sarcomatoid and more mature parts in adrenal cancers was also emphasized in other case reports [3, 7, 20]. As in our case, the sarcomatoid part in the case of Coli et al. [3] showed immunostainings for muscle markers. Adrenal carcinosarcoma-the term indicates a mix of carcinoma and sarcoma-were diagnosed by others [1, 5, 7, 10, 13]. The
| Kriteria | Definition | Index |
|---|---|---|
| Nuclear atypia | High grade | 2.1 |
| Nuclear hyperchromasia | Moderate or marked | 2.6 |
| Nucleoli | Abnormal | 0 |
| Mitoses | More than 2/10 HPF | 9.0 |
| Loss of normal structure | Diffuse pattern, <25 % spongiotic cells | 0 |
| Vessel or capsule | Invasion | 3.3 |
| Extensive regressive changes | Necroses, hemorrhages, fibrosis, calcification | 0 |
| Sum | – | 17.0 |
| Index of more than 8 correlates with malignancy | ||
sarcomatous component was an osteosarcoma [1], a rhabdo- myosarcoma [5, 7, 21], a spindle cell sarcoma [3, 7, 13, 20], or composed of neuroectodermal elements [10].
Following data and parameters are typical for sarcomatoid adrenal cancers as known from the literature [25]: tumor di- ameter 70 to 240 mm, no preponderance of side or sex, by immunostainings negativity of SF-1 and inhibin, intracellular accumulation of ß-Catenin, Ki-67 index 20-60 %, nuclear p53 index 30-60 %, and poor prognosis.
For our case, only the lack of p53-expression and the so far (5 years) lack of recurrence are not in context with these. Data from sarcomatoid cancers in other organs with exception of the esophagus [18] demonstrate similar worse prognosis (kidney [4, 11], urinary bladder [6], lung [24, 27]), but also in these organs exceptions are published showing no apparent prog- nostic difference in the biologic behavior between sarcomatoid carcinomas and ordinary carcinomas [22]. The apparently bet- ter prognosis in our case may be explained by the complete resection of the primary tumor and the liver metastases.
From our experiences, we recommend the use of molecular methods and many immunostainings for identification or ex- clusion of this very rare adrenal carcinoma type.
Authors’ Contributions W.Saeger: Histopathology, immu- nocytochemistry, conception
W.Mohren: First examinations of specimens
M.Behrend: Clinical examinations and surgery
P.Iglauer: Molecular pathology
W.Wilczak: Immunocytochemistry, molecular pathology
Compliance with Ethical Standards
Conflict of Interests The authors declare that they have no conflict of interests.
Ethics Due to the subtitle (case report) of the manuscript, an approval on ethics appears to be not necessary.
Reference
1. Barksdale, S.K., Marincola, F.M., Jaffe, G .: Carcinosarcoma of the adrenal cortex presenting with mineralocorticoid excess. Am.J.Surg.Pathol. 17: 941-945 (1993)
2. Coindre, J.M., Pedeutour, F., Aurias, A .: Well differentiated and dedifferentiated liposarcomas. Virchows Archiv 456: 167-179 (2010)
3. Coli, A., Di Giorgio, A., Castri, F., Destito, C., Marin, A.W., Bigotti, G .: Sarcomatoid carcinoma of the adrenal gland: A case report and review of literature. Pathology Research and Practice 206: 59-65 (2010)
4. de Peralta-Venturina, M., Moch, H., Amin, M., Tamboli, P., Hailemariam, S., Mihatsch, M., Javidan, J., Stricker, H., Ro, J.Y., Amin, M.B .: Sarcomatoid differentiation in renal cell carcinoma - A study of 101 cases. Amer J Surg Pathol 25: 275-284 (2001)
5. Decorato, J.W., Gruber, M., Petti, M., Levowitz, B.S .: Adrenal carcinosarcoma. J Surg Oncol 45: 134-136 (1990)
6. Fatima, N., Canter, D.J., Carthon, B.C., Kucuk, O., Master, V.A., Nieh, P.T., Ogan, K., Osunkoya, A.O .: Sarcomatoid urothelial car- cinoma of the bladder: a contemporary clinicopathologic analysis of 37 cases. Canadian Journal of Urology 22: 7783-7787 (2015)
7. Fischler, D.F., Nunez, C., Levin, H.S., McMahon, J.T., Sheeler, L.R., Adelstein, D.J .: Adrenal Carcinosarcoma Presenting in A Woman with Clinical Signs of Virilization - A Case-Report with Immunohistochemical and Ultrastructural Findings. Amer J Surg Pathol 16: 626-631 (1992)
8. Hart, J., Mandavilli, S .: Epithelioid Angiosarcoma. A Brief Diagnostic Review and Differential Diagnosis. Arch Pathol Lab Med 135: 268-272 (2011)
9. Hough, A.J., Hollifield, J.W., Page, D.L., Hartmann, W.H .: Prognostic factors in adrenal cortical tumours. Am.J.Clin.Pathol. 72: 390-399 (1979)
10. Kao, C.S., Grignon, D.J., Ulbright, T.M., Idrees, M.T .: A case re- port of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features. Hum Pathol 44: 1947-1955 (2013)
11. Kunene, V., Miscoria, M., Pirrie, S., Islam, M.R., Afshar, M., Porfiri, E .: Sarcomatoid Renal Cell Carcinoma: Clinical Outcome and Survival After Treatment With Sunitinib. Clinical Genitourinary Cancer 12: 251-255 (2014)
12. Lack, E.E .: Adrenal cortical carcinoma. In: Edited by Lack,E.E .: Tumors of the adrenal glands and extraadrenal paraganglia, Ed.1: pp.131-160. Armed Forces Institute of Pathology, Washington: 2007.
13. Lee, M.S., Park, I.A., Chi, J.G., Ham, E.K., Lee, K.C., Lee, C.W .: Adrenal carcinosarcoma a case report. J Korean Med Sci 12: 374- 377 (1997)
14. Lloyd, R.V., Tischler, A.S., Kimura, N., McNicol, A.M., Young, W.F. Jr., Weiss, L.M., Bertagna, X., Chrousos, G.P., Kawashima, A., Kleihues, P., Giordano, T.J., Medeiros, L.J., Merino, M.J., Ordonez, N.G., Sasano, H., Koch, C.A., Thompson, L.D.R., Komminoth, P., Chetty, R., Capella, C., Albores-Saavedra, J., Lam, K.Y., Cheng, L., Ulbright, T.M .: Tumours of the adrenal gland. In: DeLellis, R.A., Lloyd, R.V., Heitz, P.U. (Eds.) : Pathology and Genetics. Tumours of Endocrine Tumours, Ed.1: 135-173. International Agency for Research and Cancer (IARC), Lyon: 2004.
15. Mclaughlin, S.A., Schmitt, T.M., Huguet, K.L., Menke, D.M., Nguyen, J.H .: Myofibrosarcoma of the adrenal gland. American Surgeon 71: 191-193 (2005)
16. Mercado, E., Barr, F.G .: Fusions involving PAX and FOX genes in the molecular pathogeneis of alveolar rhabdomyosarcoma: Recent advances. Curr Mol Med 7: 47-61 (2007)
17. Modrek, B., Ge, L., Pandita, A., Lin, E., Mohan, S., Yue, P., Guerrero, S., Lin, W.M., Pham, T., Modrusan, Z., Seshagiri, S., Stem, H.M., Waring, P., Garraway, L.A., Chant, J., Stokoe, D., Cavet, G .: Oncogenic activating mutations are associated with local copy gain. Mol Cancer Res 7: 1244-1252 (2009)
18. Raza, M.A., Mazzara, P.F .: Sarcomatoid Carcinoma of Esophagus. Arch Pathol Lab Med 135: 945-948 (2011)
19. Saeger, W .: Nebennierenrinde. In: Amann, K., Kain, R., Klöppel, G. (Eds.): Urogenitale und endokrine Organe, Gelenke und Skelett, Ed.3. Aufl: 735-772. Springer, Heidelberg: 2015.
20. Sturm, N., Moulai, N., Laverriere, M., Chabre, O., Descotes, J., Brambilla, E .: Primary adrenocortical sarcomatoid carcinoma: case report and review of literature. Virchows Archiv 452: 215-219 (2008)
21. Thway, K., Ohms, D., Shah, C., Flora, R., Shipley,J ., Fisher, C .: Oncocytic Adrenal Cortical Carcinosarcoma With Pleomorphic Rhabdomyosarcomatous Metastases. Amer J Surg Pathol 36: 470-477 (2012)
22. Tissier, F .: Classification of adrenal cortical tumors: What limits for the pathological approach? Best Practice & Research Clinical Endocrinology & Metabolism 24: 877-885 (2010)
23. van Slooten, H., Schaberg, A., Smeenk, D., Moolenaar, A.J .: Morphologic characteristics of benign and malignant adrenocorti- cal tumors. Cancer 55: 766-773 (1985)
24. . Vieira, T., Antoine, M., Ruppert, A.M., Fallet, V., Duruisseaux, M., Leprieur, E.G., Poulot, V., Rabbe, N., Sclick, L., Beau-Faller, M., Lacave, R., Lavole, A., Cadranel, J., Wislez, M .: Blood vessel in- vasion is a major feature and a factor of poor prognosis in sarcomatoid carcinoma of the lung. Lung Cancer 85: 276-281 (2014)
25. Wanis, K.N., Kanthan, R .: Diagnostic and prognostic features in adrenocortical carcinoma: a single institution case series and review of the literature. World Journal of Surgical Oncology 13: 117 (2015)
26. Weiss, L.M .: Comparative histologic study of 43 metastasizing and non-metastasizing adrenocortical tumors. Am.J.Surg.Pathol. 8: 163-169 (1984)
27. 7. Zhang, L., Yao, M., Hisaoka, M., Sasano, H., Gao, H.W .: Primary Ewing sarcoma/primitive neuroectodermal tumor in the adrenal gland. APMIS 124: 624-629 (2016)