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Small cell carcinoma of the ovary of hypercalcemic type: a case report
Journal of Pediatric Surgery (2012) 47, 588–592
www.elsevier.com/locate/jpedsurg
Small cell carcinoma of the ovary of hypercalcemic type: a case report J. Matt McDonald a , Rouzan G. Karabakhtsian b , Heather H. Pierce c , Joseph A. Iocono d , Christopher P. DeSimone a , Sherry L. Bayliff e , Frederick R. Ueland a,⁎ a
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA b Department of Pathology and Laboratory Medicine, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA c Clinical Genetic Counseling Program, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA d Division of Pediatric Surgery, Department of Surgery, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA e Division of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA Received 5 August 2011; revised 6 December 2011; accepted 8 December 2011
Key words: Small cell ovarian cancer; Hypercalcemia; SCCOHT
Abstract The authors report a case of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), in a mother and daughter and discuss the possibility of a heritable risk. Both mother and daughter were treated at the same institution for SCCOHT. A 23-year-old woman presented with hypercalcemia 4 months after giving birth to her daughter. She was diagnosed as having SCCOHT. Despite surgery, chemotherapy, and radiation, she died of the disease 11 months after diagnosis. Eleven years later, her daughter presented with a histologically and immunophenotypically identical SCCOHT tumor. She received postoperative chemotherapy and radiation but, eventually, relapsed and died of the disease at 27 months after the initial diagnosis. Small cell carcinoma of the ovary, hypercalcemic type, is an uncommon and aggressive malignancy that occurs in young women, which is associated with a solid ovarian tumor and hypercalcemia. Despite aggressive multimodality treatment, most patients die within 2 years of diagnosis. Genetic counseling, sonographic ovarian surveillance and serum calcium monitoring at early age, and even prophylactic oophorectomy should be considered for surviving at-risk family members. © 2012 Elsevier Inc. All rights reserved.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), was first described in detail in 1979 [1]. This ⁎ Corresponding author. Tel.: +1 859 257 1613; fax: +1 859 323 1018. E-mail addresses: [email protected], [email protected] (F.R. Ueland). 0022-3468/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.12.004
rare malignancy typically affects young women, has an aggressive biologic behavior, and has a poor clinical outcome. Hypercalcemia is present at the time of diagnosis in more than 60% of those with SCCOHT [2,3]. Since the clinical report of Dickersin et al [2] in 1982, there have been scattered cases suggesting a heritable risk. A phenomenon of
Small cell carcinoma of the ovary of hypercalcemic type
589
genetic anticipation has also been suggested [4]. Unfortunately, most patients with SCCOHT rapidly relapse and die despite aggressive, multimodality treatment [5,6]. We present a case of SCCOHT in an 11-year-old girl whose mother died at the age of 23 years of the same disease.
vincristine/doxorubicin/cyclophosphamide and then switched to carboplatin/paclitaxel. After 3 cycles, CT imaging demonstrated disease progression. Her family agreed to radiation therapy, and she received 1710 cGy to the pelvis in 10 fractions. A magnetic resonance imaging demonstrated a significant response in the pelvis, and extended field whole abdominal radiation was prescribed. She received an additional 2000 cGy in 20 fractions to the whole abdomen. Unfortunately, the patient rapidly developed progressive disease, was admitted to a hospice care, and died 5 months after relapse and 27 months after her initial diagnosis.
1. Clinical history A 23-year-old Caucasian woman presented with nausea, lower abdominal pain, and fatigue 4 months after a vaginal delivery. Computed tomography (CT) scan showed a 10-cm solid right ovarian mass and ascites. Her total serum calcium was 19.2 mg/dL (reference range, 8.8-10.2 mg/dL) and serum cancer antigen 125 (CA-125) was 353 U/mL (reference value, b35 U/mL). After electrolyte correction, she underwent right salpingo-oophorectomy, omentectomy, and pelvic and paraaortic lymphadenectomy, peritoneal biopsies, and appendectomy. The surgical findings included 5 L of ascites, a ruptured, solid ovarian tumor, but no visible extraovarian disease. The histopathologic examination revealed a SCCOHT with microscopic metastases to the pelvic peritoneum (FIGO stage IIC). After 6 cycles of cisplatin/paclitaxel, the results of pelvic peritoneal biopsies at reassessment laparotomy were positive for recurrent SCCOHT. The patient received external beam pelvic radiotherapy, with a total dose of 5040 cGy in 28 fractions. Two months after radiation, CT imaging revealed disease progression and salvage chemotherapy was unsuccessful. The patient died of the disease 11 months after her initial diagnosis. At age 11 years, the patient's only daughter presented with left-sided abdominal pain, fatigue, and nausea. Computed tomographic imaging revealed a 10-cm solid left ovarian tumor. Her total serum calcium was 13.6 mg/dL (reference range, 8.8-10.2 mg/dL), and serum CA-125 was 46 U/mL (reference value, b35 U/mL). She underwent a laparoscopic left salpingo-oophorectomy, pelvic lymphadenectomy, omental biopsy, and appendectomy. At surgery, there was operative rupture of the ovarian capsule. On histologic evaluation, the tumor was consistent with a SCCOHT (FIGO stage IC). Postoperative CT imaging showed mesenteric lymphadenopathy and an irregular omentum, prompting a prophylactic laparoscopic contralateral (right) salpingo-oophorectomy with infracolic omentectomy and mesenteric biopsy. All ectopic specimens were negative for malignancy. The patient received 5 cycles of chemotherapy, alternating cisplatin/etoposide with carboplatin/etoposide. Because of the adverse effects, the family declined the sixth cycle of chemotherapy and refused whole abdominal radiation therapy. Approximately 18 months after her chemotherapy, she presented with lethargy and abdominal pain. Her serum calcium was 12.6 mg/dL (reference range, 8.8-10.2 mg/dL), and CT imaging confirmed disease recurrence in the pelvis. At laparotomy, there was a friable, hemorrhagic tumor with extensive carcinomatosis. She received one course of
2. Histologic and immunohistochemical findings Both ovarian tumors occurring in the mother and daughter were histologically identical. They were composed of sheets of anaplastic small cells with associated extensive necrosis
Fig. 1 Anaplastic tumor with associated follicle-like spaces containing eosinophilic fluid: mother (A) and daughter (B) (hematoxylin and eosin, ×100).
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J.M. McDonald et al.
and hemorrhage, exhibiting an increased mitotic rate (15-20 per single high-power field). Extensive hypercellular areas with hyalinized stroma and characteristic follicle-like spaces containing eosinophilic fluid were present (Fig. 1). Both tumors also demonstrated similarity by immunophenotype. The tumor cells showed diffuse and strong immunoreactivity for Wilms tumor-1 (WT-1) protein (Fig. 2); patchy moderate immunostaining for p53, p16, vimentin, and CD99 (Fig. 3); and only focal positivity for epithelial membrane antigen, low-molecular-weight cytokeratin (CAM 5.2), calretinin, and CD10. No immunostaining was observed for α-inhibin, estrogen and progesterone receptors, chromogranin, synaptophysin, and thyroid transcription factor-1. The immunostaining pattern in both tumors supported the morphologic impression of a primary SCCOHT.
3. Genetic risk assessment The family history was obtained by a genetic counselor, as reported by the daughter's paternal grandmother (who was
Fig. 3 Tumor cells showing membranous staining for CD99: mother (A) and daughter (B) (×200).
also the daughter's legal guardian) and maternal great aunt (Fig. 4). The number of family members with cancer suggests a hereditary cancer syndrome. However, the history was not consistent with hereditary breast-ovarian cancer syndrome. Because of the very early age at cancer diagnosis, the family was tested for Li-Fraumeni syndrome. Sequence analysis of the p53 gene on a peripheral blood sample obtained from the daughter identified no mutations. Possible enrollment in gene identification studies was discussed with the daughter's guardian, but ultimately, enrollment was not pursued because of emergent family issues. Based on the family history of early-onset ovarian cancer, potentially atrisk family members including the mother's 2 nieces were offered ovarian cancer surveillance with annual or semiannual transvaginal sonography.
4. Discussion Fig. 2 Tumor cells showing nuclear immunoreactivity for WT-1: mother (A) and daughter (B) (×100).
Small cell carcinoma of the ovary, hypercalcemic type, is a rare and aggressive ovarian tumor that primarily affects
Small cell carcinoma of the ovary of hypercalcemic type
591
Fig. 4 Pedigree showing family history of cancer. Diagnoses with an asterisk (⁎) have been verified by pathology reports. The proband died of SCCOHT at age 24 years, and the proband's daughter died of SCCOHT at age 14 years. Maternal great grandmother reportedly had ovarian cancer at age 40. Family history of cancer otherwise includes a male maternal first cousin with pleomorphic carcinoma of the salivary gland diagnosed at age 32 years, a female maternal first cousin with cancer not otherwise specified, and diagnoses of lung cancer in maternal grandfather, maternal grandmother, and maternal great grandmother. Proband's mother had no personal history of cancer as of age 54 years (age at last contact with family). Proband's paternal family history not available. Paternal family history of the proband's daughter is also shown and includes a great aunt's diagnosis of brain cancer, a great uncle's diagnosis of colon cancer, and another great uncle's diagnosis of cancer not otherwise specified.
young women (mean age, 22 years). Based on immunohistochemical staining and electron microscopy, Young et al [3] suggested an epithelial origin, whereas Ulbright et al [7] believed that the early age at diagnosis made a germ-cell origin more likely. More recent publications suggest that SCCOHT has neither an epithelial nor a germ-cell origin [8,9]. Moreover, SCCOHT is more common than the pulmonary type of ovarian small cell carcinoma (mean age, 62 years), which is of a neuroendocrine origin [10]. In more than 60% of cases, SCCOHT is associated with a paraneoplastic syndrome at presentation [5], thought to be from a parathyroid hormone–like substance [11]. Severe hypercalcemia (N13 mg/dL) may cause serious sequelae, including hypotonia, lethargy, stupor, and coma. Associated cardiac effects include hypertension, dysrhythmias, heart block, and even cardiac asystole. Preoperatively, hypercalcemia can be treated by saline infusion, diuresis, and bisphosphonate therapy. Calcium levels will spontaneously return to normal after tumor removal. Small cell carcinoma of the ovary, hypercalcemic type, is characteristically unilateral (N95%) and is discovered at an early stage in more than 50% of patients. Reporting on 150 patients with SCCOHT, Young et al [3] found stage I disease in 50% of cases; stage II, 5%; stage III, 43%; and stage IV, 1%. Thirty-three percent of patients with stage IA disease
were alive and disease-free at 5 years, whereas only 10% of patients with stage IC disease were long-term survivors. Harrison et al [5] reported on 7 of 10 patients with stage I diseases that were alive and disease-free at a median followup of 40 months, also noting that all long-term survivors received cisplatin and etoposide. Of the 4 patients who received carboplatin and paclitaxel, 2 had disease progression during treatment and 2 progressed within 3 months of completing chemotherapy. Most long-term survivors in the literature received radiotherapy either concurrently or sequentially with chemotherapy [2,3,5]. There are several reports of cases occurring in family members suggesting that SCCOHT can be heritable. Young et al [3] described a case of familial SCCOHT where 3 sisters were similarly diagnosed. In 1995, a mother and a daughter (ages, 40 and 21 years) were diagnosed as having SCCOHT [12]. Longy et al [13] also reported a family of 3 sisters who were diagnosed as having SCCOHT at the ages of 19, 14, and 28 years. In our report of SCCOHT in a mother and a daughter, both tumors were identical by histomorphology and immunohistochemical profile. The presence of diffuse nuclear staining for WT-1 may indicate a müllerian origin for SCCOHT [14], and the immunoreactivity for p53 in familial tumors may imply a p53 mutation [9,15]. The authors speculate that the potential for
592 a germ-line mutation may place some families at an increased risk for SCCOHT. Based on the genetic risk assessment of this family with multiple affected members with a variety of seemingly unrelated cancers (see Fig. 4), the history was suggestive of a potential hereditary cancer syndrome. Furthermore, the history was not consistent with hereditary breast-ovarian cancer syndrome because no mutations in BRCA1 or BRCA2 were identified in the 11-year-old proband from a previous case study of familial SCCOHT [4] and because the observed histology of the ovarian cancers associated with mutations in BRCA1 and BRCA2 has been almost exclusively serous or endometrioid [16]. Because of the very early age at cancer diagnosis in the patient and her daughter, the possibility of Li-Fraumeni syndrome was considered. However, the sequence analysis of the p53 gene on a peripheral blood sample obtained from the patient's daughter identified no p53 mutations. The daughter's diagnosis at a significantly younger age than that of the patient is suggestive of hereditary ovarian cancer predisposition with genetic anticipation, which has been proposed in a previous case study of SCCOHT [4]. The multiple case studies of familial clustering of SCCOHT are suggestive of a heritable predisposition to SCCOHT, but the genetic etiology and pattern of inheritance have yet to be characterized. Further genetic evaluation of familial and sporadic cases of SCCOHT will be necessary to confirm heritability and identify candidate loci. Whenever possible, it is recommended that array CGH be performed on affected individuals to screen for germ-line DNA microrearrangements, with reflex whole-exome sequencing reserved, at the present time, to family trios and families with multiple affected members with variant annotation, filtering, and clinical genotyping of candidate alleles. Clinical wholeexome sequencing with variant interpretation is now available in a commercial basis, and enrollment of families in gene identification research studies is encouraged whenever possible. The rarity of this ovarian neoplasm precludes definitive conclusions concerning optimal care. The early age at onset and rapid progression of this cancer also make establishing a possible pattern of inheritance challenging because many patients die of the disease before reproducing. Women with SCCOHT should be made aware of the potential risk to their female offspring and be offered genetic counseling. Based on this case and others [4], the recommendation to begin surveillance strategies 10 years before the mother's age at diagnosis should be considered. Earlier surveillance can include annual ovarian sonography, serum calcium, and/or
J.M. McDonald et al. biomarker (CA-125) monitoring, with serum calcium monitoring being less intrusive than ovarian sonography at an early age. Given the high mortality of SCCOHT, prophylactic bilateral salpingo-oophorectomy can be discussed. The authors suggest that the occurrence of SCCOHT in mother and daughter should raise awareness of this disease, the importance of surveillance and early detection, and a high suspicion for genetic causation.
References [1] Scully RE. Tumors of the ovary and maldeveloped gonads. Atlas of tumor pathology second series, fascicle 16. Washington, DC: Armed Forces Institute of Pathology; 1979. [2] Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer 1982;49:188-97. [3] Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol 1994;18:1102-16. [4] Martinez-Borges AR, Petty JK, Hurt G, et al. Familial small cell carcinoma of the ovary. Pediatric Blood & Cancer 2009;53:1334-6. [5] Harrison ML, Hoskins P, du Bois A, et al. Small cell of the ovary, hypercalcemic type—analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol 2006;100:233-8. [6] Distelmaier F, Calaminus G, Harms D, et al. Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease. Cancer 2006;107: 2298-306. [7] Ulbright TM, Roth LM, Stehman FB, et al. Poorly differentiated (small cell) carcinoma of the ovary in young women: evidence supporting a germ cell origin. Hum Pathol 1987;18:175-84. [8] Walt H, Hornung R, Fink D, et al. Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line. Anticancer Res 2001;21:3253-9. [9] McCluggage WG, Oliva E, Connolly LE, et al. An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 2004;23:330-6. [10] Eichhorn JH, Young RH, Scully RE. Primary ovarian small cell carcinoma of pulmonary type. A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. Am J Surg Pathol 1992;16: 926-38. [11] Burton PB, Knight DE, Quirke P, et al. Parathyroid hormone related peptide in ovarian carcinoma. J Clin Pathol 1990;43:784. [12] Lamovec J, Bracko M, Cerar O. Familial occurrence of small-cell carcinoma of the ovary. Arch Pathol Lab Med 1995;119:523-7. [13] Longy M, Toulouse C, Mage P, et al. Familial cluster of ovarian small cell carcinoma: a new Mendelian entity? J Med Genet 1998;33:333-5. [14] Carlson JW, Nucci MR, Brodsky J, et al. Biomarker-assisted diagnosis of ovarian, cervical and pulmonary small cell carcinomas; the role of TTF-1, WT-1 and HPV analysis. Histopathology 2007;51:305-12. [15] Seidman JD. Small cell carcinoma of the ovary of the hypercalcemic type: p53 protein accumulation and clinicopathologic features. Gynecol Oncol 1995;59:283-7. [16] Boyd J, Sonoda Y, Federici MG, et al. Clinicopathologic features of BRCA-linked sporadic ovarian cancer. JAMA 2000;283:2260-5.
www.elsevier.com/locate/jpedsurg
Small cell carcinoma of the ovary of hypercalcemic type: a case report J. Matt McDonald a , Rouzan G. Karabakhtsian b , Heather H. Pierce c , Joseph A. Iocono d , Christopher P. DeSimone a , Sherry L. Bayliff e , Frederick R. Ueland a,⁎ a
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA b Department of Pathology and Laboratory Medicine, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA c Clinical Genetic Counseling Program, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA d Division of Pediatric Surgery, Department of Surgery, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA e Division of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Kentucky Chandler Medical Center–Markey Cancer Center, Lexington, KY 40536-0298, USA Received 5 August 2011; revised 6 December 2011; accepted 8 December 2011
Key words: Small cell ovarian cancer; Hypercalcemia; SCCOHT
Abstract The authors report a case of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), in a mother and daughter and discuss the possibility of a heritable risk. Both mother and daughter were treated at the same institution for SCCOHT. A 23-year-old woman presented with hypercalcemia 4 months after giving birth to her daughter. She was diagnosed as having SCCOHT. Despite surgery, chemotherapy, and radiation, she died of the disease 11 months after diagnosis. Eleven years later, her daughter presented with a histologically and immunophenotypically identical SCCOHT tumor. She received postoperative chemotherapy and radiation but, eventually, relapsed and died of the disease at 27 months after the initial diagnosis. Small cell carcinoma of the ovary, hypercalcemic type, is an uncommon and aggressive malignancy that occurs in young women, which is associated with a solid ovarian tumor and hypercalcemia. Despite aggressive multimodality treatment, most patients die within 2 years of diagnosis. Genetic counseling, sonographic ovarian surveillance and serum calcium monitoring at early age, and even prophylactic oophorectomy should be considered for surviving at-risk family members. © 2012 Elsevier Inc. All rights reserved.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), was first described in detail in 1979 [1]. This ⁎ Corresponding author. Tel.: +1 859 257 1613; fax: +1 859 323 1018. E-mail addresses: [email protected], [email protected] (F.R. Ueland). 0022-3468/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.12.004
rare malignancy typically affects young women, has an aggressive biologic behavior, and has a poor clinical outcome. Hypercalcemia is present at the time of diagnosis in more than 60% of those with SCCOHT [2,3]. Since the clinical report of Dickersin et al [2] in 1982, there have been scattered cases suggesting a heritable risk. A phenomenon of
Small cell carcinoma of the ovary of hypercalcemic type
589
genetic anticipation has also been suggested [4]. Unfortunately, most patients with SCCOHT rapidly relapse and die despite aggressive, multimodality treatment [5,6]. We present a case of SCCOHT in an 11-year-old girl whose mother died at the age of 23 years of the same disease.
vincristine/doxorubicin/cyclophosphamide and then switched to carboplatin/paclitaxel. After 3 cycles, CT imaging demonstrated disease progression. Her family agreed to radiation therapy, and she received 1710 cGy to the pelvis in 10 fractions. A magnetic resonance imaging demonstrated a significant response in the pelvis, and extended field whole abdominal radiation was prescribed. She received an additional 2000 cGy in 20 fractions to the whole abdomen. Unfortunately, the patient rapidly developed progressive disease, was admitted to a hospice care, and died 5 months after relapse and 27 months after her initial diagnosis.
1. Clinical history A 23-year-old Caucasian woman presented with nausea, lower abdominal pain, and fatigue 4 months after a vaginal delivery. Computed tomography (CT) scan showed a 10-cm solid right ovarian mass and ascites. Her total serum calcium was 19.2 mg/dL (reference range, 8.8-10.2 mg/dL) and serum cancer antigen 125 (CA-125) was 353 U/mL (reference value, b35 U/mL). After electrolyte correction, she underwent right salpingo-oophorectomy, omentectomy, and pelvic and paraaortic lymphadenectomy, peritoneal biopsies, and appendectomy. The surgical findings included 5 L of ascites, a ruptured, solid ovarian tumor, but no visible extraovarian disease. The histopathologic examination revealed a SCCOHT with microscopic metastases to the pelvic peritoneum (FIGO stage IIC). After 6 cycles of cisplatin/paclitaxel, the results of pelvic peritoneal biopsies at reassessment laparotomy were positive for recurrent SCCOHT. The patient received external beam pelvic radiotherapy, with a total dose of 5040 cGy in 28 fractions. Two months after radiation, CT imaging revealed disease progression and salvage chemotherapy was unsuccessful. The patient died of the disease 11 months after her initial diagnosis. At age 11 years, the patient's only daughter presented with left-sided abdominal pain, fatigue, and nausea. Computed tomographic imaging revealed a 10-cm solid left ovarian tumor. Her total serum calcium was 13.6 mg/dL (reference range, 8.8-10.2 mg/dL), and serum CA-125 was 46 U/mL (reference value, b35 U/mL). She underwent a laparoscopic left salpingo-oophorectomy, pelvic lymphadenectomy, omental biopsy, and appendectomy. At surgery, there was operative rupture of the ovarian capsule. On histologic evaluation, the tumor was consistent with a SCCOHT (FIGO stage IC). Postoperative CT imaging showed mesenteric lymphadenopathy and an irregular omentum, prompting a prophylactic laparoscopic contralateral (right) salpingo-oophorectomy with infracolic omentectomy and mesenteric biopsy. All ectopic specimens were negative for malignancy. The patient received 5 cycles of chemotherapy, alternating cisplatin/etoposide with carboplatin/etoposide. Because of the adverse effects, the family declined the sixth cycle of chemotherapy and refused whole abdominal radiation therapy. Approximately 18 months after her chemotherapy, she presented with lethargy and abdominal pain. Her serum calcium was 12.6 mg/dL (reference range, 8.8-10.2 mg/dL), and CT imaging confirmed disease recurrence in the pelvis. At laparotomy, there was a friable, hemorrhagic tumor with extensive carcinomatosis. She received one course of
2. Histologic and immunohistochemical findings Both ovarian tumors occurring in the mother and daughter were histologically identical. They were composed of sheets of anaplastic small cells with associated extensive necrosis
Fig. 1 Anaplastic tumor with associated follicle-like spaces containing eosinophilic fluid: mother (A) and daughter (B) (hematoxylin and eosin, ×100).
590
J.M. McDonald et al.
and hemorrhage, exhibiting an increased mitotic rate (15-20 per single high-power field). Extensive hypercellular areas with hyalinized stroma and characteristic follicle-like spaces containing eosinophilic fluid were present (Fig. 1). Both tumors also demonstrated similarity by immunophenotype. The tumor cells showed diffuse and strong immunoreactivity for Wilms tumor-1 (WT-1) protein (Fig. 2); patchy moderate immunostaining for p53, p16, vimentin, and CD99 (Fig. 3); and only focal positivity for epithelial membrane antigen, low-molecular-weight cytokeratin (CAM 5.2), calretinin, and CD10. No immunostaining was observed for α-inhibin, estrogen and progesterone receptors, chromogranin, synaptophysin, and thyroid transcription factor-1. The immunostaining pattern in both tumors supported the morphologic impression of a primary SCCOHT.
3. Genetic risk assessment The family history was obtained by a genetic counselor, as reported by the daughter's paternal grandmother (who was
Fig. 3 Tumor cells showing membranous staining for CD99: mother (A) and daughter (B) (×200).
also the daughter's legal guardian) and maternal great aunt (Fig. 4). The number of family members with cancer suggests a hereditary cancer syndrome. However, the history was not consistent with hereditary breast-ovarian cancer syndrome. Because of the very early age at cancer diagnosis, the family was tested for Li-Fraumeni syndrome. Sequence analysis of the p53 gene on a peripheral blood sample obtained from the daughter identified no mutations. Possible enrollment in gene identification studies was discussed with the daughter's guardian, but ultimately, enrollment was not pursued because of emergent family issues. Based on the family history of early-onset ovarian cancer, potentially atrisk family members including the mother's 2 nieces were offered ovarian cancer surveillance with annual or semiannual transvaginal sonography.
4. Discussion Fig. 2 Tumor cells showing nuclear immunoreactivity for WT-1: mother (A) and daughter (B) (×100).
Small cell carcinoma of the ovary, hypercalcemic type, is a rare and aggressive ovarian tumor that primarily affects
Small cell carcinoma of the ovary of hypercalcemic type
591
Fig. 4 Pedigree showing family history of cancer. Diagnoses with an asterisk (⁎) have been verified by pathology reports. The proband died of SCCOHT at age 24 years, and the proband's daughter died of SCCOHT at age 14 years. Maternal great grandmother reportedly had ovarian cancer at age 40. Family history of cancer otherwise includes a male maternal first cousin with pleomorphic carcinoma of the salivary gland diagnosed at age 32 years, a female maternal first cousin with cancer not otherwise specified, and diagnoses of lung cancer in maternal grandfather, maternal grandmother, and maternal great grandmother. Proband's mother had no personal history of cancer as of age 54 years (age at last contact with family). Proband's paternal family history not available. Paternal family history of the proband's daughter is also shown and includes a great aunt's diagnosis of brain cancer, a great uncle's diagnosis of colon cancer, and another great uncle's diagnosis of cancer not otherwise specified.
young women (mean age, 22 years). Based on immunohistochemical staining and electron microscopy, Young et al [3] suggested an epithelial origin, whereas Ulbright et al [7] believed that the early age at diagnosis made a germ-cell origin more likely. More recent publications suggest that SCCOHT has neither an epithelial nor a germ-cell origin [8,9]. Moreover, SCCOHT is more common than the pulmonary type of ovarian small cell carcinoma (mean age, 62 years), which is of a neuroendocrine origin [10]. In more than 60% of cases, SCCOHT is associated with a paraneoplastic syndrome at presentation [5], thought to be from a parathyroid hormone–like substance [11]. Severe hypercalcemia (N13 mg/dL) may cause serious sequelae, including hypotonia, lethargy, stupor, and coma. Associated cardiac effects include hypertension, dysrhythmias, heart block, and even cardiac asystole. Preoperatively, hypercalcemia can be treated by saline infusion, diuresis, and bisphosphonate therapy. Calcium levels will spontaneously return to normal after tumor removal. Small cell carcinoma of the ovary, hypercalcemic type, is characteristically unilateral (N95%) and is discovered at an early stage in more than 50% of patients. Reporting on 150 patients with SCCOHT, Young et al [3] found stage I disease in 50% of cases; stage II, 5%; stage III, 43%; and stage IV, 1%. Thirty-three percent of patients with stage IA disease
were alive and disease-free at 5 years, whereas only 10% of patients with stage IC disease were long-term survivors. Harrison et al [5] reported on 7 of 10 patients with stage I diseases that were alive and disease-free at a median followup of 40 months, also noting that all long-term survivors received cisplatin and etoposide. Of the 4 patients who received carboplatin and paclitaxel, 2 had disease progression during treatment and 2 progressed within 3 months of completing chemotherapy. Most long-term survivors in the literature received radiotherapy either concurrently or sequentially with chemotherapy [2,3,5]. There are several reports of cases occurring in family members suggesting that SCCOHT can be heritable. Young et al [3] described a case of familial SCCOHT where 3 sisters were similarly diagnosed. In 1995, a mother and a daughter (ages, 40 and 21 years) were diagnosed as having SCCOHT [12]. Longy et al [13] also reported a family of 3 sisters who were diagnosed as having SCCOHT at the ages of 19, 14, and 28 years. In our report of SCCOHT in a mother and a daughter, both tumors were identical by histomorphology and immunohistochemical profile. The presence of diffuse nuclear staining for WT-1 may indicate a müllerian origin for SCCOHT [14], and the immunoreactivity for p53 in familial tumors may imply a p53 mutation [9,15]. The authors speculate that the potential for
592 a germ-line mutation may place some families at an increased risk for SCCOHT. Based on the genetic risk assessment of this family with multiple affected members with a variety of seemingly unrelated cancers (see Fig. 4), the history was suggestive of a potential hereditary cancer syndrome. Furthermore, the history was not consistent with hereditary breast-ovarian cancer syndrome because no mutations in BRCA1 or BRCA2 were identified in the 11-year-old proband from a previous case study of familial SCCOHT [4] and because the observed histology of the ovarian cancers associated with mutations in BRCA1 and BRCA2 has been almost exclusively serous or endometrioid [16]. Because of the very early age at cancer diagnosis in the patient and her daughter, the possibility of Li-Fraumeni syndrome was considered. However, the sequence analysis of the p53 gene on a peripheral blood sample obtained from the patient's daughter identified no p53 mutations. The daughter's diagnosis at a significantly younger age than that of the patient is suggestive of hereditary ovarian cancer predisposition with genetic anticipation, which has been proposed in a previous case study of SCCOHT [4]. The multiple case studies of familial clustering of SCCOHT are suggestive of a heritable predisposition to SCCOHT, but the genetic etiology and pattern of inheritance have yet to be characterized. Further genetic evaluation of familial and sporadic cases of SCCOHT will be necessary to confirm heritability and identify candidate loci. Whenever possible, it is recommended that array CGH be performed on affected individuals to screen for germ-line DNA microrearrangements, with reflex whole-exome sequencing reserved, at the present time, to family trios and families with multiple affected members with variant annotation, filtering, and clinical genotyping of candidate alleles. Clinical wholeexome sequencing with variant interpretation is now available in a commercial basis, and enrollment of families in gene identification research studies is encouraged whenever possible. The rarity of this ovarian neoplasm precludes definitive conclusions concerning optimal care. The early age at onset and rapid progression of this cancer also make establishing a possible pattern of inheritance challenging because many patients die of the disease before reproducing. Women with SCCOHT should be made aware of the potential risk to their female offspring and be offered genetic counseling. Based on this case and others [4], the recommendation to begin surveillance strategies 10 years before the mother's age at diagnosis should be considered. Earlier surveillance can include annual ovarian sonography, serum calcium, and/or
J.M. McDonald et al. biomarker (CA-125) monitoring, with serum calcium monitoring being less intrusive than ovarian sonography at an early age. Given the high mortality of SCCOHT, prophylactic bilateral salpingo-oophorectomy can be discussed. The authors suggest that the occurrence of SCCOHT in mother and daughter should raise awareness of this disease, the importance of surveillance and early detection, and a high suspicion for genetic causation.
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