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Malignant steroidogenic tumor arising from sacrococcygeal mature teratoma
Human Pathology (2011) 42, 1568–1572
www.elsevier.com/locate/humpath
Case study
Malignant steroidogenic tumor arising from sacrococcygeal mature teratoma☆ Mariko Yoshida MD a,d,⁎, Mio Tanaka MD a , Kiyoshi Gomi MD, PhD a , Youkatsu Ohama MD, PhD b , Hisato Kigasawa MD, PhD c , Tadashi Iwanaka MD, PhD d , Yukichi Tanaka MD, PhD a a
Division of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan Division of Surgery, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan c Division of Oncology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan d Department of Pediatric Surgery, The University of Tokyo, Tokyo 113-8656, Japan b
Received 10 November 2010; revised 13 December 2010; accepted 22 December 2010
Keywords: Sacrococcygeal teratoma; Somatic malignant transformation; Steroidogenic tumor
Summary We report a case of malignant steroidogenic tumor arising from a sacrococcygeal teratoma in a 5-year-old girl. A congenital gluteal mass and a 7-month history of precocious puberty had been noted, and a large estrogen-producing tumor in the sacrococcygeal area was found. After a biopsy, chemotherapy and tumor resection were performed, and no recurrence has been observed. The biopsy specimen showed small clusters of atypical round cells adjacent to a mature teratoma. They had large round nuclei with prominent nucleoli and abundant eosinophilic cytoplasms and were positive for vimentin, steroidogenic factor-1, inhibin α, and melan-A. Increased mitoses, vascular invasion, and necrosis were noted. The tumor was diagnosed as sacrococcygeal mature teratoma, with malignant steroidogenic tumor as somatic malignant transformation. Although several kinds of somatic malignant transformation of sacrococcygeal teratoma have been reported, to the best of our knowledge, this is the first case of malignant steroidogenic tumor arising from sacrococcygeal teratoma. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Sacrococcygeal teratomas (SCTs) are the most common germ cell tumors (GCTs) in infancy and early childhood, occurring with an incidence of one in 20,000 to 40,000 live births, with a significant female predominance. Most SCTs in infants and children are considered ☆
This study received financial support from Kanagawa Prefecture Hospitals' Pediatric Research Fund. ⁎ Corresponding author. Division of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan. E-mail address: [email protected] (M. Yoshida). 0046-8177/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.12.022
to be benign, and malignancies associated with SCTs occur in approximately 10% of cases. Although most of them have a germ cell origin, such as yolk sac tumor, nongerm-cell malignancies also rarely develop. It is called somatic malignant transformation (SMT), in which a malignancy arises from one of the somatic components of mature or immature teratoma. Previously described SMT in pediatric SCTs included cases taking the form of neuroblastoma [1], adenocarcinoma [1], ependymoma [2], or nephroblastoma [3]. We herein report a case of malignant steroidogenic tumor arising from SCT as SMT, which has never been documented to the best of our knowledge.
Malignant steroidogenic tumor
1569
2. Case report A 5-year-old girl was referred to our hospital for the evaluation of 7-month history of precocious puberty and a congenital sacrococcygeal tumor. The tumor had remained stable in size since her birth. Endocrinologic findings suggested that the tumor produced estradiol. α-Fetoprotein (AFP) and β-human chorionic gonadotropin (βHCG) levels were within the normal limits. Pelvic computed tomographic imaging showed a 9 × 6 × 5-cm well-circumscribed softtissue mass present in the presacral area to the left buttock. After a tumor biopsy, chemotherapy with bleomycin, etoposide, and cisplatin was remarkably effective for tumor shrinkage and resolution of precocious puberty. The tumor was resected 3 months after the biopsy. Adjuvant chemotherapy was continued for another year, and the patient was alive without recurrence at the 13-year follow-up.
3. Pathologic findings 3.1. Macroscopic and microscopic findings The tissue that underwent biopsy showed 2 distinct adjacent elements. The first consisted of small solid clusters of atypical round cells, containing necrosis (Fig. 1A). The nuclei of these cells were large, round, and vesicular, with single prominent nucleoli, and the cytoplasms were abundant and eosinophilic (Fig. 1B). There were no intracytoplasmic structures, such as crystalloids of Reinke. There were as many as 2 mitotic figures per high-power field (Fig. 1B). Focal vascular invasion was observed (Fig. 1A, inset, and Fig. 2A). The other element was a mature teratoma (MT), in which ciliated columnar epithelium, adipose tissue, peripheral nerve tissue, pancreatic islets, and pancreatic acini were observed (Fig. 2A). Some small vacuolated cells were also noted within the MT (Fig. 2B), which appeared similar to benign steroidogenic cells, including adrenocortical cells, ovarian hilus cells, and testicular Leydig cells. The resected specimen was 4.5 × 4.0 × 3.5 cm in size and yellowish in color, containing cartilaginous tissue, musclelike tissue, and variously sized cysts. Microscopically, it consisted of only MT admixed with fibrosis and necrosis. The atypical round cells and the benign-looking small vacuolated cells seen in the tissue that underwent biopsy were not detected in the resected material.
3.2. Immunohistochemical findings The atypical round cells in the tissue that underwent biopsy showed diffuse immunoreactivity for vimentin, CD99, and steroidogenic factor-1 (SF-1) and were focally positive for S-100, inhibin α, and melan-A (Fig. 3, Table 1). They did not stain for cytokeratin (using the clone AE1/AE3 and CAM 5.2), epithelial membrane antigen, placental
Fig. 1 Atypical round cell element in the tissue that underwent biopsy. A, Small solid clusters of atypical round cells containing necrosis are seen. Focal vascular invasion is evident (inset). B, The nuclei of the atypical cells are large, round, and vesicular, with prominent nucleoli. The cytoplasms are eosinophilic, and the cell borders are indistinct. Several mitotic figures are also visible (arrowheads).
alkaline phosphatase, OCT3/4, AFP, HCG, CD30, CD117, or Wilms tumor 1. The MIB-1 labeling index was 5% to 10%. The benign-looking small vacuolated cells in the MT were also positive for SF-1 and inhibin α (Fig. 3, inset). Based on its morphology and immunoprofile, the atypical round cell element was interpreted as a malignant tumor originating from steroidogenic cell lineage, that is, adrenocortical cell, hilus cell, or Leydig cell, and the tumor was considered to be related to the small vacuolated cells in the MT. A diagnosis of sacrococcygeal MT with malignant steroidogenic tumor as SMT was made.
4. Discussion This report describes an extremely rare case of malignant steroidogenic tumor arising from SCT as SMT. As far as we
1570
M. Yoshida et al.
Fig. 2 MT in the tissue that underwent biopsy. A, Ciliated epithelium (arrow), adipose tissue, and pancreatic islets are visible. Atypical round cells are also evident as vascular invasion (arrowhead). B, Benign-looking small vacuolated cells similar to steroidogenic cells (arrowheads) are noted within the MT, adjacent to pancreatic islet cells (P).
are aware, there has been no report of steroidogenic tumor arising from SCT, such as an adrenocortical tumor, steroid cell tumor, or Leydig cell tumor. Adrenocortical tumor has never been reported to occur within a teratoma. Extragonadal sex cord-stromal tumors are very uncommon, either alone [4] or with teratoma [5]. The diagnosis of the present patient was confirmed both morphologically and immunohistochemically. It is virtually impossible to distinguish adrenocortical tumors from steroid cell tumors or Leydig cell tumors purely on histologic grounds [6]. However, their differentiation usually does not pose diagnostic problems because adrenocortical tumors and steroid/Leydig cell tumors each have specific sites of origin: the adrenal glands and the gonads, respectively. These tumors also share common clinical characteristics in that they are relatively rare in young children, and feminization may occur but is less frequent than virilization [7-9]. Microscopically, these tumors often contain sheets, trabec-
Fig. 3 Immunohistochemistry of the tissue that underwent biopsy. Atypical round cells show positive staining for vimentin (A), inhibin α (B), and steroidogenic factor-1 (C). Small vacuolated cells in the MT are also immunoreactive for inhibin α (b, inset) and steroidogenic factor-1 (c, inset).
ulae, or nests of polygonal cells that have large round nuclei with prominent nucleoli and abundant eosinophilic cytoplasms [7-9]. Immunohistochemically, they also display
Malignant steroidogenic tumor Table 1
1571
Immunohistochemistry results for the atypical round cells
Antigen
Antibody source
Dilution/antigen retrieval (buffer pH)
Reactivity
Vimentin Pan-CK a Low-molecular-weight CK b EMA Synaptophysin Chromogranin A S-100 NSE GFAP CD68 CD163 HepPar-1 Placental ALP OCT3/4 AFP HCG CD30 CD99 CD117 Inhibin α Calretinin Steroidogenic factor-1 Melan-A WT1
Dako BD BD Dako Dako Dako Dako Dako Dako Dako Novocastra Dako Dako Santa Cruz Dako Dako Dako Dako Dako AbD Novocastra Perseus Dako Dako
1:100/microwave (pH 6) prediluted/microwave (pH 6) prediluted/microwave (pH 6) 1:50/untreated 1:20/microwave (pH 6) 1:300/microwave (pH 6) 1:400/untreated 1:100/untreated 1:100/untreated 1:50/microwave (pH 6) 1:50/microwave (pH 6) 1:50/microwave (pH 6) 1:100/untreated 1:100/autoclave (pH 9) 1:1000/untreated 1:500/untreated 1:10/proteinase K digestion 1:50/untreated 1:50/microwave (pH 9) 1:100/autoclave (pH 6) 1:100/microwave (pH 6) 1:100/autoclave (pH 6) 1:40/microwave (pH 6) 1:25/proteinase K digestion + autoclave (pH 6)
++ − − − − − + − − − − − − − − − − ++ − + − ++ + −
Abbreviations: CK, cytokeratin; EMA, epithelial membrane antigen; NSE, neuron-specific enolase; GFAP, glial fibrillary acidic protein; ALP, alkaline phosphatase; WT1, Wilms tumor 1. NOTE. Dako, Dako, Glostrup, Denmark; BD, Becton Dickinson, Franklin Lakes, NJ; Novocastra, Novocastra Laboratories, Newcastle-upon-Tyne, United Kingdom; AbD, AbD Serotec, Oxford, United Kingdom; Santa Cruz, Santa Cruz Biotechnology, Santa Cruz, CA; Perseus, Perseus Proteomics, Tokyo, Japan. NOTE. −, negative ; +, focally positive; ++, diffusely positive. a pan-CK are CK 1/3/4/5/6/7/8/10/12/14/15/16 detected by the clone AE1/AE3. b Low-molecular-weight CK are CK 8/18/19 detected by the clone CAM 5.2.
identical features, staining positively for inhibin α, SF-1, and melan-A [6,9-11]. These similarities between adrenocortical tumors and steroid/Leydig cell tumors can be attributed to their common embryonic origin, the adrenogenital primordium [12]. In the present case, some small vacuolated cells resembling benign steroidogenic cells (adrenocortical cells, hilus cells, or Leydig cells) were observed within the teratoma. Their line of differentiation could not be determined because the teratoma lacked both coexisting adrenomedullary tissue and other gonadal components. The present tumor was considered malignant because it showed 2 mitoses per high-power field, vascular invasion, and necrosis. These findings meet the histologic criteria for pediatric malignant adrenocortical neoplasms proposed by Wieneke et al [8] and are also consistent with the pathologic correlates of malignant ovarian steroid cell tumors [7] or malignant testicular Leydig cell tumors [13]. The clinical behavior of endocrine tumors is relatively unpredictable based on histology, and it is not easy to determine the necessity for adjuvant treatment [8,14]. However, systemic
chemotherapy for this patient was definitely indicated because the tumor was unresectable at presentation. SMT in teratoma is known to be resistant to GCTdirected chemotherapy, but it may be susceptible to regimens oriented toward the transformed histology [1]. Multidrug therapy including cisplatin and etoposide has been recommended for adrenocortical carcinomas [15] and malignant gonadal sex cord-stromal tumors [13,14]. These 2 drugs were incidentally included in the malignant GCTtargeted treatment given to our patient, which may explain the significant treatment effect. In summary, we have described the first case of malignant steroidogenic tumor arising from SCT as SMT. This report introduces a novel form of SMT and broadens the histologic spectrum of pediatric SCT.
References [1] Terenziani M, D'Angelo P, Bisogno G, et al. Teratoma with a malignant somatic component in pediatric patients: the Associazione
1572
[2]
[3] [4] [5]
[6]
[7]
[8]
Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 2010;54:532-7. Busse C, Nazeer T, Kanwar VS, et al. Sacrococcygeal immature teratoma with malignant ependymoma component. Pediatr Blood Cancer 2009;53:680-1. Andrews PE, Kelalis PP, Haase GM. Extrarenal Wilms' tumor: results of the National Wilms' Tumor study. J Pediatr Surg 1992;27:1181-4. Smith D, Crotty TB, Murphy JF, et al. A steroid cell tumor outside the ovary is a rare cause of virilization. Fertil Steril 2006;85:227. Seber A, Antoneli CB, Spinola-Castro AM, et al. Leydig cell tumor and mature teratoma: unusual non-ocular tumors associated with sexual pseudo-precocity six years after unilateral retinoblastoma. Med Pediatr Oncol 2002;38:285-7. Busam KJ, Iversen K, Coplan KA, et al. Immunoreactivity for A103, an antibody to melan-A (Mart-1), in adrenocortical and other steroid tumors. Am J Surg Pathol 1998;22:57-63. Hayes MC, Scully RE. Ovarian steroid cell tumors (not otherwise specified). A clinicopathological analysis of 63 cases. Am J Surg Pathol 1987;11:835-45. Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003;27:867-81.
M. Yoshida et al. [9] Jou P, Maclennan GT. Leydig cell tumor of the testis. J Urol 2009;181: 2299-300. [10] Zhao C, Vinh TN, McManus K, et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol 2009;33:354-66. [11] Sangoi AR, McKenney JK. A tissue microarray-based comparative analysis of novel and traditional immunohistochemical markers in the distinction between adrenal cortical lesions and pheochromocytoma. Am J Surg Pathol 2010;34:423-32. [12] Hatano O, Takakusu A, Nomura M, et al. Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1996;1:663-71. [13] Cecchetto G, Alaggio R, Bisogno G, et al. Sex cord-stromal tumors of the testis in children. A clinicopathologic report from the Italian TREP project. J Pediatr Surg 2010;45:1868-73. [14] Colombo N, Parma G, Zanagnolo V, et al. Management of ovarian stromal cell tumors. J Clin Oncol 2007;25:2944-51. [15] Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 2004;22:838-45.
www.elsevier.com/locate/humpath
Case study
Malignant steroidogenic tumor arising from sacrococcygeal mature teratoma☆ Mariko Yoshida MD a,d,⁎, Mio Tanaka MD a , Kiyoshi Gomi MD, PhD a , Youkatsu Ohama MD, PhD b , Hisato Kigasawa MD, PhD c , Tadashi Iwanaka MD, PhD d , Yukichi Tanaka MD, PhD a a
Division of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan Division of Surgery, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan c Division of Oncology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan d Department of Pediatric Surgery, The University of Tokyo, Tokyo 113-8656, Japan b
Received 10 November 2010; revised 13 December 2010; accepted 22 December 2010
Keywords: Sacrococcygeal teratoma; Somatic malignant transformation; Steroidogenic tumor
Summary We report a case of malignant steroidogenic tumor arising from a sacrococcygeal teratoma in a 5-year-old girl. A congenital gluteal mass and a 7-month history of precocious puberty had been noted, and a large estrogen-producing tumor in the sacrococcygeal area was found. After a biopsy, chemotherapy and tumor resection were performed, and no recurrence has been observed. The biopsy specimen showed small clusters of atypical round cells adjacent to a mature teratoma. They had large round nuclei with prominent nucleoli and abundant eosinophilic cytoplasms and were positive for vimentin, steroidogenic factor-1, inhibin α, and melan-A. Increased mitoses, vascular invasion, and necrosis were noted. The tumor was diagnosed as sacrococcygeal mature teratoma, with malignant steroidogenic tumor as somatic malignant transformation. Although several kinds of somatic malignant transformation of sacrococcygeal teratoma have been reported, to the best of our knowledge, this is the first case of malignant steroidogenic tumor arising from sacrococcygeal teratoma. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Sacrococcygeal teratomas (SCTs) are the most common germ cell tumors (GCTs) in infancy and early childhood, occurring with an incidence of one in 20,000 to 40,000 live births, with a significant female predominance. Most SCTs in infants and children are considered ☆
This study received financial support from Kanagawa Prefecture Hospitals' Pediatric Research Fund. ⁎ Corresponding author. Division of Pathology, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan. E-mail address: [email protected] (M. Yoshida). 0046-8177/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2010.12.022
to be benign, and malignancies associated with SCTs occur in approximately 10% of cases. Although most of them have a germ cell origin, such as yolk sac tumor, nongerm-cell malignancies also rarely develop. It is called somatic malignant transformation (SMT), in which a malignancy arises from one of the somatic components of mature or immature teratoma. Previously described SMT in pediatric SCTs included cases taking the form of neuroblastoma [1], adenocarcinoma [1], ependymoma [2], or nephroblastoma [3]. We herein report a case of malignant steroidogenic tumor arising from SCT as SMT, which has never been documented to the best of our knowledge.
Malignant steroidogenic tumor
1569
2. Case report A 5-year-old girl was referred to our hospital for the evaluation of 7-month history of precocious puberty and a congenital sacrococcygeal tumor. The tumor had remained stable in size since her birth. Endocrinologic findings suggested that the tumor produced estradiol. α-Fetoprotein (AFP) and β-human chorionic gonadotropin (βHCG) levels were within the normal limits. Pelvic computed tomographic imaging showed a 9 × 6 × 5-cm well-circumscribed softtissue mass present in the presacral area to the left buttock. After a tumor biopsy, chemotherapy with bleomycin, etoposide, and cisplatin was remarkably effective for tumor shrinkage and resolution of precocious puberty. The tumor was resected 3 months after the biopsy. Adjuvant chemotherapy was continued for another year, and the patient was alive without recurrence at the 13-year follow-up.
3. Pathologic findings 3.1. Macroscopic and microscopic findings The tissue that underwent biopsy showed 2 distinct adjacent elements. The first consisted of small solid clusters of atypical round cells, containing necrosis (Fig. 1A). The nuclei of these cells were large, round, and vesicular, with single prominent nucleoli, and the cytoplasms were abundant and eosinophilic (Fig. 1B). There were no intracytoplasmic structures, such as crystalloids of Reinke. There were as many as 2 mitotic figures per high-power field (Fig. 1B). Focal vascular invasion was observed (Fig. 1A, inset, and Fig. 2A). The other element was a mature teratoma (MT), in which ciliated columnar epithelium, adipose tissue, peripheral nerve tissue, pancreatic islets, and pancreatic acini were observed (Fig. 2A). Some small vacuolated cells were also noted within the MT (Fig. 2B), which appeared similar to benign steroidogenic cells, including adrenocortical cells, ovarian hilus cells, and testicular Leydig cells. The resected specimen was 4.5 × 4.0 × 3.5 cm in size and yellowish in color, containing cartilaginous tissue, musclelike tissue, and variously sized cysts. Microscopically, it consisted of only MT admixed with fibrosis and necrosis. The atypical round cells and the benign-looking small vacuolated cells seen in the tissue that underwent biopsy were not detected in the resected material.
3.2. Immunohistochemical findings The atypical round cells in the tissue that underwent biopsy showed diffuse immunoreactivity for vimentin, CD99, and steroidogenic factor-1 (SF-1) and were focally positive for S-100, inhibin α, and melan-A (Fig. 3, Table 1). They did not stain for cytokeratin (using the clone AE1/AE3 and CAM 5.2), epithelial membrane antigen, placental
Fig. 1 Atypical round cell element in the tissue that underwent biopsy. A, Small solid clusters of atypical round cells containing necrosis are seen. Focal vascular invasion is evident (inset). B, The nuclei of the atypical cells are large, round, and vesicular, with prominent nucleoli. The cytoplasms are eosinophilic, and the cell borders are indistinct. Several mitotic figures are also visible (arrowheads).
alkaline phosphatase, OCT3/4, AFP, HCG, CD30, CD117, or Wilms tumor 1. The MIB-1 labeling index was 5% to 10%. The benign-looking small vacuolated cells in the MT were also positive for SF-1 and inhibin α (Fig. 3, inset). Based on its morphology and immunoprofile, the atypical round cell element was interpreted as a malignant tumor originating from steroidogenic cell lineage, that is, adrenocortical cell, hilus cell, or Leydig cell, and the tumor was considered to be related to the small vacuolated cells in the MT. A diagnosis of sacrococcygeal MT with malignant steroidogenic tumor as SMT was made.
4. Discussion This report describes an extremely rare case of malignant steroidogenic tumor arising from SCT as SMT. As far as we
1570
M. Yoshida et al.
Fig. 2 MT in the tissue that underwent biopsy. A, Ciliated epithelium (arrow), adipose tissue, and pancreatic islets are visible. Atypical round cells are also evident as vascular invasion (arrowhead). B, Benign-looking small vacuolated cells similar to steroidogenic cells (arrowheads) are noted within the MT, adjacent to pancreatic islet cells (P).
are aware, there has been no report of steroidogenic tumor arising from SCT, such as an adrenocortical tumor, steroid cell tumor, or Leydig cell tumor. Adrenocortical tumor has never been reported to occur within a teratoma. Extragonadal sex cord-stromal tumors are very uncommon, either alone [4] or with teratoma [5]. The diagnosis of the present patient was confirmed both morphologically and immunohistochemically. It is virtually impossible to distinguish adrenocortical tumors from steroid cell tumors or Leydig cell tumors purely on histologic grounds [6]. However, their differentiation usually does not pose diagnostic problems because adrenocortical tumors and steroid/Leydig cell tumors each have specific sites of origin: the adrenal glands and the gonads, respectively. These tumors also share common clinical characteristics in that they are relatively rare in young children, and feminization may occur but is less frequent than virilization [7-9]. Microscopically, these tumors often contain sheets, trabec-
Fig. 3 Immunohistochemistry of the tissue that underwent biopsy. Atypical round cells show positive staining for vimentin (A), inhibin α (B), and steroidogenic factor-1 (C). Small vacuolated cells in the MT are also immunoreactive for inhibin α (b, inset) and steroidogenic factor-1 (c, inset).
ulae, or nests of polygonal cells that have large round nuclei with prominent nucleoli and abundant eosinophilic cytoplasms [7-9]. Immunohistochemically, they also display
Malignant steroidogenic tumor Table 1
1571
Immunohistochemistry results for the atypical round cells
Antigen
Antibody source
Dilution/antigen retrieval (buffer pH)
Reactivity
Vimentin Pan-CK a Low-molecular-weight CK b EMA Synaptophysin Chromogranin A S-100 NSE GFAP CD68 CD163 HepPar-1 Placental ALP OCT3/4 AFP HCG CD30 CD99 CD117 Inhibin α Calretinin Steroidogenic factor-1 Melan-A WT1
Dako BD BD Dako Dako Dako Dako Dako Dako Dako Novocastra Dako Dako Santa Cruz Dako Dako Dako Dako Dako AbD Novocastra Perseus Dako Dako
1:100/microwave (pH 6) prediluted/microwave (pH 6) prediluted/microwave (pH 6) 1:50/untreated 1:20/microwave (pH 6) 1:300/microwave (pH 6) 1:400/untreated 1:100/untreated 1:100/untreated 1:50/microwave (pH 6) 1:50/microwave (pH 6) 1:50/microwave (pH 6) 1:100/untreated 1:100/autoclave (pH 9) 1:1000/untreated 1:500/untreated 1:10/proteinase K digestion 1:50/untreated 1:50/microwave (pH 9) 1:100/autoclave (pH 6) 1:100/microwave (pH 6) 1:100/autoclave (pH 6) 1:40/microwave (pH 6) 1:25/proteinase K digestion + autoclave (pH 6)
++ − − − − − + − − − − − − − − − − ++ − + − ++ + −
Abbreviations: CK, cytokeratin; EMA, epithelial membrane antigen; NSE, neuron-specific enolase; GFAP, glial fibrillary acidic protein; ALP, alkaline phosphatase; WT1, Wilms tumor 1. NOTE. Dako, Dako, Glostrup, Denmark; BD, Becton Dickinson, Franklin Lakes, NJ; Novocastra, Novocastra Laboratories, Newcastle-upon-Tyne, United Kingdom; AbD, AbD Serotec, Oxford, United Kingdom; Santa Cruz, Santa Cruz Biotechnology, Santa Cruz, CA; Perseus, Perseus Proteomics, Tokyo, Japan. NOTE. −, negative ; +, focally positive; ++, diffusely positive. a pan-CK are CK 1/3/4/5/6/7/8/10/12/14/15/16 detected by the clone AE1/AE3. b Low-molecular-weight CK are CK 8/18/19 detected by the clone CAM 5.2.
identical features, staining positively for inhibin α, SF-1, and melan-A [6,9-11]. These similarities between adrenocortical tumors and steroid/Leydig cell tumors can be attributed to their common embryonic origin, the adrenogenital primordium [12]. In the present case, some small vacuolated cells resembling benign steroidogenic cells (adrenocortical cells, hilus cells, or Leydig cells) were observed within the teratoma. Their line of differentiation could not be determined because the teratoma lacked both coexisting adrenomedullary tissue and other gonadal components. The present tumor was considered malignant because it showed 2 mitoses per high-power field, vascular invasion, and necrosis. These findings meet the histologic criteria for pediatric malignant adrenocortical neoplasms proposed by Wieneke et al [8] and are also consistent with the pathologic correlates of malignant ovarian steroid cell tumors [7] or malignant testicular Leydig cell tumors [13]. The clinical behavior of endocrine tumors is relatively unpredictable based on histology, and it is not easy to determine the necessity for adjuvant treatment [8,14]. However, systemic
chemotherapy for this patient was definitely indicated because the tumor was unresectable at presentation. SMT in teratoma is known to be resistant to GCTdirected chemotherapy, but it may be susceptible to regimens oriented toward the transformed histology [1]. Multidrug therapy including cisplatin and etoposide has been recommended for adrenocortical carcinomas [15] and malignant gonadal sex cord-stromal tumors [13,14]. These 2 drugs were incidentally included in the malignant GCTtargeted treatment given to our patient, which may explain the significant treatment effect. In summary, we have described the first case of malignant steroidogenic tumor arising from SCT as SMT. This report introduces a novel form of SMT and broadens the histologic spectrum of pediatric SCT.
References [1] Terenziani M, D'Angelo P, Bisogno G, et al. Teratoma with a malignant somatic component in pediatric patients: the Associazione
1572
[2]
[3] [4] [5]
[6]
[7]
[8]
Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 2010;54:532-7. Busse C, Nazeer T, Kanwar VS, et al. Sacrococcygeal immature teratoma with malignant ependymoma component. Pediatr Blood Cancer 2009;53:680-1. Andrews PE, Kelalis PP, Haase GM. Extrarenal Wilms' tumor: results of the National Wilms' Tumor study. J Pediatr Surg 1992;27:1181-4. Smith D, Crotty TB, Murphy JF, et al. A steroid cell tumor outside the ovary is a rare cause of virilization. Fertil Steril 2006;85:227. Seber A, Antoneli CB, Spinola-Castro AM, et al. Leydig cell tumor and mature teratoma: unusual non-ocular tumors associated with sexual pseudo-precocity six years after unilateral retinoblastoma. Med Pediatr Oncol 2002;38:285-7. Busam KJ, Iversen K, Coplan KA, et al. Immunoreactivity for A103, an antibody to melan-A (Mart-1), in adrenocortical and other steroid tumors. Am J Surg Pathol 1998;22:57-63. Hayes MC, Scully RE. Ovarian steroid cell tumors (not otherwise specified). A clinicopathological analysis of 63 cases. Am J Surg Pathol 1987;11:835-45. Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 2003;27:867-81.
M. Yoshida et al. [9] Jou P, Maclennan GT. Leydig cell tumor of the testis. J Urol 2009;181: 2299-300. [10] Zhao C, Vinh TN, McManus K, et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol 2009;33:354-66. [11] Sangoi AR, McKenney JK. A tissue microarray-based comparative analysis of novel and traditional immunohistochemical markers in the distinction between adrenal cortical lesions and pheochromocytoma. Am J Surg Pathol 2010;34:423-32. [12] Hatano O, Takakusu A, Nomura M, et al. Identical origin of adrenal cortex and gonad revealed by expression profiles of Ad4BP/SF-1. Genes Cells 1996;1:663-71. [13] Cecchetto G, Alaggio R, Bisogno G, et al. Sex cord-stromal tumors of the testis in children. A clinicopathologic report from the Italian TREP project. J Pediatr Surg 2010;45:1868-73. [14] Colombo N, Parma G, Zanagnolo V, et al. Management of ovarian stromal cell tumors. J Clin Oncol 2007;25:2944-51. [15] Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol 2004;22:838-45.