Educational Case: Ovarian neoplasms: A series of educational cases to review malignancies of epithelial, stromal, and germ cell origin.

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An 18-year-old woman presents to the emergency department with right-sided abdominal pain. The pain started 3 weeks ago and has been getting progressively worse and more frequent. She has had nausea, vomiting, and some vaginal bleeding. She is otherwise healthy, takes no medications, and has never had surgery. There is no history of any gynecologic or gastrointestinal cancers in her family. She is sexually active with one male partner and cannot remember the date of her last menstrual period. Physical exam findings include abdominal tenderness in the RLQ with voluntary guarding and fullness in the right adnexa on bimanual exam. An initial differential diagnosis for this patient should include intermittent ovarian torsion, acute appendicitis, ruptured ectopic pregnancy, ruptured tubo-ovarian abscess or ovarian cyst, and acute pelvic inflammatory disease. Initial testing should include a CBC, BMP, lactate, serum quantitative beta-HCG, urinalysis and urine culture, a focused bedside abdominal ultrasound, and TVUS with Doppler studies.

Objective FO1.2: Causes of Ovarian Neoplasm: Describe the risk factors, genetic associations, and molecular basis, including hereditary cancer syndromes, for ovarian neoplasms, including those derived from epithelium, sex-cord stromal as well as germ cell neoplasms. Competency 2: Organ System Pathology; Topic FO: Female Reproductive— Ovary; Learning Goal 1: Ovarian Neoplasia

• Cancer can arise from any cell type in the ovary. The three main categories of primary ovarian cancer are epithelial, sex cord-stromal, and germ cell ( Fig. 16 ). Fig. 16 Depiction of the cell origins of primary ovarian malignancies. Fig. 16 • In the United States, ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death. One in 78 women in the United States will have ovarian cancer in her lifetime. • Currently, no reliable screening tools exist for ovarian cancer, and most women will present with advanced stage disease (Stage III or IV) with no or nonspecific symptoms. • High-grade serous epithelial ovarian carcinoma (HGSC) is the most common epithelial ovarian carcinoma and is most often seen in women in the 4th–6th decades of life. To treat HGSC, surgery and full clinical staging at the minimum is performed, and unless extremely early stage and low-grade tumors, they will also require chemotherapy. • Granulosa cell tumors are the most common sex cord stromal tumors, though they are still rare. They are more likely to be diagnosed in postmenopausal women who present with signs of hyperestrogenism (abnormal uterine bleeding, breast tenderness) or hyperandrogenism (abnormal hair growth, weight gain). These tumors generally have a favorable prognosis after treatment but frequently recur later in life. • Adult subtype granulosa cell tumors are associated with FOXL2 mutations. • Dysgerminomas are the most common malignant germ cell tumor, and mature teratomas are the most common benign germ cell tumor. They are usually diagnosed in children or young women and tend to occur as bilateral ovarian masses. They can be distinguished from other germ cell tumors by levels of serum LDH, PLAP, AFP, and beta-HCG. • Yolk sac tumors are rare germ cell tumors that can occur in women of any age. Most commonly they present in young women with acute symptoms of abdominal or pelvic pain. They will require chemotherapy in order to have a good survival rate. • It is important to obtain a thorough family history for every patient and consider genetic testing when appropriate. • A strong family history of endometrial, colon, and/or ovarian cancer is suggestive of Lynch syndrome, marked by MSH2, MLH1, PMS1, PMS2 , and MSH6 mutations. • A strong family history of breast and ovarian cancer is suggestive of hereditary breast and ovarian cancer syndrome, marked by BRCA1 /2 mutations. • When constructing a differential diagnosis, it is important to take into account the patient's clinical presentation as well as imaging and laboratory results. One must consider the most acute pathologies, those most likely to result in patient mortality, and those most likely in general given the baseline risk in the population. With each piece of new information, the differential diagnosis should start to narrow. • Immunohistochemical (IHC) staining can help determine the diagnosis and prognosis of various ovarian malignancies ( Table 1 ). Table 1 Special stains and other testing for ovarian cancers. Table 1 HGSC (epithelial) Granulosa (stromal) Yolk sac (germ cell) Diagnostic IHC stains CK7: positive CK20: negative Inhibin or Calretinin: diffusely positive AFP: diffusely positive Glypican-3: positive Cytokeratin AE1/AE3: diffusely positive Additional IHC stains P53: diffusely positive Reticulin: surrounds islands of cells, rather than around individual cells P53: patchy (wild type) Serum markers CA-125: elevated Inhibin/AMH: elevated AFP: elevated Genetic/molecular testing BRCA1/2 mutation FOXL2 mutation None IHC: immunohistochemistry; HGSC: high grade serous epithelial ovarian carcinoma; CK: cytokeratin; AFP: alpha fetoprotein; AMH: anti-müllerian hormone; BRCA1/2: breast cancer gene 1 or 2. • For HGSC, look for CK7 positive and CK20 negative staining or diffusely positive P53 staining. • Granulosa cell tumors stain diffusely positive for inhibin and calretinin. • Yolk sac tumors stain positive for AFP, Glypican-3, and Cytokeratin AE1/AE3. Cancer can arise from any cell type in the ovary. The three main categories of primary ovarian cancer are epithelial, sex cord-stromal, and germ cell ( Fig. 16 ). Fig. 16 Depiction of the cell origins of primary ovarian malignancies. Fig. 16 Depiction of the cell origins of primary ovarian malignancies. In the United States, ovarian cancer is the second most common gynecologic malignancy and the most common cause of gynecologic cancer death. One in 78 women in the United States will have ovarian cancer in her lifetime. Currently, no reliable screening tools exist for ovarian cancer, and most women will present with advanced stage disease (Stage III or IV) with no or nonspecific symptoms. High-grade serous epithelial ovarian carcinoma (HGSC) is the most common epithelial ovarian carcinoma and is most often seen in women in the 4th–6th decades of life. To treat HGSC, surgery and full clinical staging at the minimum is performed, and unless extremely early stage and low-grade tumors, they will also require chemotherapy. Granulosa cell tumors are the most common sex cord stromal tumors, though they are still rare. They are more likely to be diagnosed in postmenopausal women who present with signs of hyperestrogenism (abnormal uterine bleeding, breast tenderness) or hyperandrogenism (abnormal hair growth, weight gain). These tumors generally have a favorable prognosis after treatment but frequently recur later in life. Adult subtype granulosa cell tumors are associated with FOXL2 mutations. Dysgerminomas are the most common malignant germ cell tumor, and mature teratomas are the most common benign germ cell tumor. They are usually diagnosed in children or young women and tend to occur as bilateral ovarian masses. They can be distinguished from other germ cell tumors by levels of serum LDH, PLAP, AFP, and beta-HCG. Yolk sac tumors are rare germ cell tumors that can occur in women of any age. Most commonly they present in young women with acute symptoms of abdominal or pelvic pain. They will require chemotherapy in order to have a good survival rate. It is important to obtain a thorough family history for every patient and consider genetic testing when appropriate. A strong family history of endometrial, colon, and/or ovarian cancer is suggestive of Lynch syndrome, marked by MSH2, MLH1, PMS1, PMS2 , and MSH6 mutations. A strong family history of breast and ovarian cancer is suggestive of hereditary breast and ovarian cancer syndrome, marked by BRCA1 /2 mutations. When constructing a differential diagnosis, it is important to take into account the patient's clinical presentation as well as imaging and laboratory results. One must consider the most acute pathologies, those most likely to result in patient mortality, and those most likely in general given the baseline risk in the population. With each piece of new information, the differential diagnosis should start to narrow. Immunohistochemical (IHC) staining can help determine the diagnosis and prognosis of various ovarian malignancies ( Table 1 ). Table 1 Special stains and other testing for ovarian cancers. Table 1 HGSC (epithelial) Granulosa (stromal) Yolk sac (germ cell) Diagnostic IHC stains CK7: positive CK20: negative Inhibin or Calretinin: diffusely positive AFP: diffusely positive Glypican-3: positive Cytokeratin AE1/AE3: diffusely positive Additional IHC stains P53: diffusely positive Reticulin: surrounds islands of cells, rather than around individual cells P53: patchy (wild type) Serum markers CA-125: elevated Inhibin/AMH: elevated AFP: elevated Genetic/molecular testing BRCA1/2 mutation FOXL2 mutation None IHC: immunohistochemistry; HGSC: high grade serous epithelial ovarian carcinoma; CK: cytokeratin; AFP: alpha fetoprotein; AMH: anti-müllerian hormone; BRCA1/2: breast cancer gene 1 or 2. Special stains and other testing for ovarian cancers. IHC: immunohistochemistry; HGSC: high grade serous epithelial ovarian carcinoma; CK: cytokeratin; AFP: alpha fetoprotein; AMH: anti-müllerian hormone; BRCA1/2: breast cancer gene 1 or 2. For HGSC, look for CK7 positive and CK20 negative staining or diffusely positive P53 staining. Granulosa cell tumors stain diffusely positive for inhibin and calretinin. Yolk sac tumors stain positive for AFP, Glypican-3, and Cytokeratin AE1/AE3.

Objective SP1.2: Differential Diagnosis: List the major differential diagnoses for each type of cytology or surgical pathology specimen derived from a lesion or mass and describe appropriate further studies, both special stains and immunohistochemistry. Competency 3: Diagnostic Medicine and Therapeutic Pathology; Topic SP: Surgical Pathology; Learning Goal 1: Role in Diagnosis Objective SP1.3: Special Studies: After looking at slides of a tissue lesion or mass, the pathologist makes a diagnosis. List options for surgical and nonsurgical treatment and describe prognostic and therapy-guiding tests that may be performed on the tissue. Competency 3: Diagnostic Medicine and Therapeutic Pathology; Topic SP: Surgical Pathology; Learning Goal 1: Role in Diagnosis

The patient is admitted overnight for pain control and continued monitoring and workup. In the morning, she is taken to the operating room for diagnostic laparoscopy, pelvic washings, and right salpingo-oophorectomy with the gynecology oncology team. The right ovary with mass and right fallopian tube are sent to the pathology department for frozen section. The specimen is evaluated in the lab. Grossly, the mass is 13 cm in diameter and soft with a firm capsule surrounding it. There are several distinct areas of hemorrhage and necrosis. Images of the frozen H&E slides of the tumor tissue are seen in Fig. 11 , Fig. 12 . Fig. 11 Low power view of the tumor's glandular proliferation with associated necrosis (black stars) (H&E 10×). Fig. 11 Fig. 12 High power view of tumor cells surrounding a blood vessel defined as a “Schiller-Duval Body” (black arrow) (H&E 40×). Fig. 12 Low power view of the tumor's glandular proliferation with associated necrosis (black stars) (H&E 10×). High power view of tumor cells surrounding a blood vessel defined as a “Schiller-Duval Body” (black arrow) (H&E 40×). These images show groups of atypical cells forming glandular and tubular structures adjacent to areas of necrosis (indicated by stars). The figure with the arrow shows those same atypical cells surrounding a small blood vessel. This patient has a yolk sac tumor. Yolk sac tumors, previously called endodermal sinus tumors, are the third most common malignant ovarian germ cell tumor, after dysgerminomas and immature teratomas, respectively. In general, germ cell tumors account for 20–25% of all ovarian tumors, and about 5% are malignant. Derived from the primitive germ cells of the embryonic gonad, yolk sac tumors tend to be unilateral and occur in young women (median age of 18 years). Classically, they exhibit rapid growth, spreading quickly to intra-abdominal viscera, and produce severe, acute abdominal pain. When they occur in younger patients, they can cause precocious puberty. 4 On histology, yolk sac tumors have several architectural patterns including reticular, solid, glandular, and hepatoid. The most common is the reticular pattern, recognizable by scattered tubules lined by single layers of flattened cuboidal cells, loose reticular stroma, and abundant para-aminosalicylic (PAS)-positive globules. Schiller-Duval bodies, which are invaginated papillary structures surrounding a central blood vessel, are pathognomonic for yolk sac tumors 3 , 22 ( Fig. 12 ). Yolk sac tumors stain positive for proteins secreted by normal yolk sac tissue, which include AFP, glypican-3, cytokeratin AE1/AE3, SALL4, and LIN28. 23 These immunohistochemical stains are helpful as they are specific to tumors that grow from the yolk sac. Of these stains, AFP is the most specific. Occasionally, other rare tumors stain for AFP, such as teratomas with hepatic or enteral tissues, ovarian hepatoid carcinoma, metastatic hepatocellular carcinoma, embryonal carcinoma, and Sertoli-Leydig cell tumors with heterologous hepatocytic differentiation. Yolk sac tumors are also generally patchily positive for P53 (wild type) 3 , 24 ( Fig. 13 , Fig. 14 , Fig. 15 ). Fig. 13 Diffuse alpha fetoprotein (AFP) staining (AFP 10×). Fig. 13 Fig. 14 Diffuse cytokeratin staining (AE1-AE3 10×). Fig. 14 Fig. 15 Wild-type p53 staining pattern (p53 10×). Fig. 15 Diffuse alpha fetoprotein (AFP) staining (AFP 10×). Diffuse cytokeratin staining (AE1-AE3 10×). Wild-type p53 staining pattern (p53 10×).

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

There is no known role for genetics in the development or detection of yolk sac tumors or any germ cell tumor. 3 The gold standard of treatment for yolk sac tumors is surgery with adjuvant multi-agent chemotherapy. For surgery, a unilateral salpingo-oophorectomy supplemented by surgical staging is sufficient. Staging is especially important given the age group in which these tumors tend to occur. While these tumors show minimal to no response to radiation therapy, they respond very well to chemotherapy, especially cisplatin-based agents, unless associated with a somatic neoplasm. 3 , 21 Diagnosis of germ cell tumors at an earlier stage is associated with better prognosis. Factors associated with a worse prognosis include having higher volumes of ascites and more residual tumor after treatment. With the advances made in multiagent chemotherapy for germ cell tumors, overall prognosis has improved dramatically. Without treatment, these tumors historically had an abysmal 5-year survival rate; retrospective studies have shown that only 25% of patients with Stage I yolk sac tumors survived 2 years after diagnosis. Now, with the recommended treatment, the 5-year survival can be closer to 60–70%. 4 , 25