36. Gestational Trophoblastic Disease.pdf

GESTATIONAL TROPHOBLASTIC DISEASE. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1033-1035. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2...

GESTATIONAL TROPHOBLASTIC DISEASE. Arben Santo, David Stephen. LEARNING OBJECTIVES. See the pathology syllabi for learning objectives. REFERENCES. 1. Kumar V, Abbas AK, Aster JC. Pathologic Basis of Disease, 10e, Elsevier, 2020, pages 1033-1035. 2. Goljan EF. Rapid Review Pathology, 5e, Elsevier, 2018, pages 650-651. CASE PRESENTATION: ABIGAIL PUTMAN. A 29-year-old woman at 18 weeks of gestation presented to the emergency room complaining of vaginal bleeding. Additional history revealed two previous pregnancies, both of which ended in spontaneous abortions. On physical examination, her uterine size was more consistent with a 24-week pregnancy. Pelvic examination noted loose discharge of blood, clots and a large amount of brown-colored grapelike material protruding from the cervical os. Ultrasound examination revealed a snowstorm appearance, no fetus was identified. Laboratory studies revealed a serum β-hCG of 500,000 mIU/mL (normal: <5 mIU/mL). Dilation and curettage were productive of abundant bloody, grape-like vesicles. Pathological examination confirmed the diagnosis of a “complete hydatidiform mole”. The patient did well after the curettage, was discharged two days later, and was lost to follow-up. However, four months following the discharge, she had a grand mal seizure and was rushed to the emergency room, where she begun to cough up blood. A chest x-ray revealed multiple pulmonary nodules bilaterally and massive right pleural effusion. Chest and brain CT scans confirmed the plain x-ray findings and also demonstrated a cystic mass, 4 × 3 × 2 mm in size, in the right parietal lobe of the brain. Her serum β-hCG was 600,000 mIU/mL, 1 while other tumor markers were all within the normal ranges. Transvaginal ultrasonography was unremarkable. A transbronchial biopsy of a pulmonary lesion was performed. Histopathologic examination revealed solid sheets of atypical syncytiotrophoblast and cytotrophoblast in a background of necrosis and hemorrhage. A diagnosis of gestational choriocarcinoma with pulmonary and cerebral metastases was made. DEFINITIONS. “Gestational trophoblastic disease” (GTD) is a group of rare neoplastic conditions derived from placenta and characterized by proliferation of placental tissue, either villous or trophoblastic. The lesions include hydatidiform mole (complete and partial), invasive mole, and the frankly malignant choriocarcinoma and placental-site trophoblastic tumor. • The term “gestational trophoblastic neoplasia” (GTN) refers specifically to the GTD forms that have the potential for tissue invasion and metastasis. The GTN group includes invasive mole, placental-site trophoblastic tumor, and choriocarcinoma. All these closely related neoplasms develop in the placenta. All of them arise from trophoblastic cells. The clinical markers that help in the identification of GTDs are beta subunit of human chorionic gonadotropin (β-hCG) or human placental lactogen (hPL). Moles have characteristic chromosomal abnormalities. EPIDEMIOLOGY. GTD is an uncommon condition. The incidence is estimated at 1-3 cases per 1,000 pregnancies for complete hydatidiform mole and 3 cases per 1,000 pregnancies for partial hydatidiform mole, respectively. The incidence of choriocarcinoma in the United States is 1 in 30,000 pregnancies. Placental site trophoblastic tumor is very rare. PATHOGENESIS. Although hydatidiform moles are not classed as true gestational trophoblastic neoplasia, postmolar GTD can be seen in many patients with hydatidiform moles, especially complete moles. This finding indicates that hydatidiform moles are the precursor lesions of some GTDs. • It is believed that all GTDs arise from the neoplastic transformation of trophoblastic stem cells, presumably cytotrophoblast stem cells. The choriocarcinoma and placental-site trophoblastic tumor recapitulate normal trophoblast differentiation seen in early developing placentas. After neoplastic transformation of cytotrophoblast stem cells, specific differentiation programs dictate the type of trophoblastic tumor that develops. Choriocarcinoma is the most primitive trophoblastic tumor whereas placental-site trophoblastic tumor is relatively more differentiated: the neoplastic cytotrophoblast differentiates into extravillous (intermediate) trophoblastic cells in an implantation site. DEFINITION. The complete hydatidiform mole (CHM) is an abnormal pregnancy, characterized by placental overgrowth, while the embryonic development is severely abnormal or absent. CHMs result from abnormalities in fertilization. 2 Although CHMs are usually considered benign, they are premalignant and do have the potential to transform into choriocarcinoma and placental-site trophoblastic tumor. EPIDEMIOLOGY. The incidence of CHM in North America is 1 per 1200 pregnancies. All women who develop a CHM are in the reproductive years. This condition is more common at the extremes of reproductive age. Women in their early teenage or perimenopausal years are most at risk. Women older than 40 years experience a 5- to 10-fold increase in risk compared to younger women. Parity does not affect the risk. PATHOGENESIS. CHMs arise when an empty ovum without maternal chromosomes is fertilized by one sperm, which then duplicates its DNA, resulting in a 46, XX androgenic karyotype in which all the chromosomes are paternally derived. An empty ovum is an egg cell, which failed to receive its share of chromosomes at cell division. Even though the egg has no maternal nuclear DNA, it still contains maternally transmitted cytoplasmic mitochondrial DNA. • In 80% of cases the complete moles form by fertilization of an empty ovum by a single sperm, which then reduplicates its own DNA resulting in 46, XX chromosomes, all paternally derived. • In 20% of cases CHMs arise by fertilization of an empty ovum by two separate spermatozoa resulting in a conceptus that may be 46,XX or 46,XY, all paternally derived. • The excess of paternal DNA causes exaggerated a placental overgrowth, i.e., trophoblastic hyperplasia. • No embryo/fetus forms due to a lack of maternal nuclear DNA. PATHOLOGY. 1. Gross findings. The uterus is markedly enlarged and filled with a high number of edematous trophoblastic villi that have become fluid-filled and balloon-like. These large villi, called hydropic villi, form large, grape-like clusters with fuzzy surfaces. Multiple containers, even buckets, of markedly hydropic villi admixed with blood are delivered to the surgical pathologist. • There is no normal placenta, and no fetus or fetal parts are found. 3 2. Microscopic findings. Histologically, all the hydropic villi are distended, edematous and often show large central cavitation (cistern). Fetal vessels are generally absent. The hydropic villi are covered by extensive trophoblast proliferation that often involves the entire circumference of the villi and shows cytologic atypia. Mitoses are common. CLINICAL PRESENTATION. Because of pelvic ultrasonography, CHMs are now diagnosed in the first trimester before the onset of the clinical manifestations. Women with CHM feel as if they are pregnant. But because hydatidiform moles grow much faster than a fetus, the abdomen becomes larger much faster than it does in a normal pregnancy. Severe nausea and vomiting and vaginal bleeding, pelvic pressure or pain due to enlarged uterus, and hyperemesis gravidarum are common. LABORATORY STUDIES. Laboratory studies will show very high levels of β-hCG. Normal plasma levels of β-hCG in nonpregnant women are 0-5 mIU/mL. Very elevated levels of β-hCG indicate exuberant trophoblastic growth and raise suspicion for a molar pregnancy. DNA FLOW CYTOMETRY. DNA flow cytometry is a method of measuring the amount of DNA in cells. Complete moles are diploid or tetraploid, whereas partial hydatidiform moles are triploid. DNA flow cytometry provides a major clue as to the appropriate diagnosis. IMAGING STUDIES. Sonographic features suggestive of a complete mole include: (i) absence of an embryo or fetus, (ii) absence of amniotic fluid, (iii) an intrauterine heterogeneous mass with numerous discrete anechoic spaces, that has been called "snowstorm” or “Swiss cheese pattern”. The small cystic areas correspond to the hydropic villi. NATURAL HISTORY. Most CHMs show a benign course. The outcome after treatment is usually excellent but close follow-up is essential. CHMs should be regarded as premalignant lesions, 15-20% of them undergo malignant transformation. CHMs develop into invasive moles in 15% of cases and into choriocarcinoma in 2-3% of cases. PRINCIPLES OF TREATMENT. Suction curettage is the preferred method of evacuation in patients who desire to preserve fertility. Total abdominal hysterectomy is a reasonable option for patients who do not wish to preserve their fertility. DEFINITION. A partial hydatidiform mole (PHM) is a completely independent condition to complete hydatidiform mole. PHM presents as a mixture of normal placental tissue, with large amounts of hydropic villi, and some fetal fragments, without an intact fetus. 4 EPIDEMIOLOGY. The incidence of PHM in North America is 3: 1000 pregnancies. All women are in the reproductive years. PATHOLOGY. 1. Gross findings. CHM and PHM are different entities. On gross examination, partial molar specimens consist of normal appearing placental tissue, admixed with hydropic villi, and with an identifiable embryo/fetus or gestational sac. 2. Microscopic findings. Microscopic examination of PHM demonstrates two populations of villi: (i) small, normal-appearing villi, and (ii) large hydropic villi with central cavitation. The villous outlines are markedly irregular, with geographic scalloped borders (resembling ‘islands’ on map) (or fjord-like). Trophoblast hyperplasia is usually focal and mild, predominantly involving syncytiotrophoblast. • In addition, histologic evidence of fetal development is common, including chorionic plate, amnion, umbilical cord, and fetal tissues. CLINICAL PRESENTATION. Patients with partial mole do not have the same clinical features as those with complete mole. These patients usually present with signs and symptoms consistent with an incomplete or missed abortion, including cramps of the lower abdomen, vaginal bleeding during pregnancy, and absence of fetal heart tones. The uterus is often large for gestational age. LABORATORY STUDIES. Abnormally high levels of serum beta-HCG are characteristic but they are lower than in women with complete hydatidiform mole. DNA FLOW CYTOMETRY. Partial moles result from fertilization of an egg with two sperm. In partial hydatidiform moles, the karyotype is triploid. Partial moles have 69 chromosomes, including 23 of maternal origin and 46 of paternal origin (e.g., 69,XXY). 5 IMAGING STUDIES. Partial moles are often indistinguishable from complete moles on ultrasound. However, demonstration of fetal parts favors the diagnosis of a partial mole. The following appearances are more characteristic for partial mole: enlarged and thickened placenta relative to the size of the uterus, multiple cystic spaces within the placenta, and a dead growth retarded fetus or feral parts. NATURAL HISTORY. Natural history of PHM is much more benign than that of CHM as only 1-5% of women develop into invasive mole. Choriocarcinoma develops very rarely. DEFINITION. Invasive mole is a subtype of gestational trophoblastic neoplasms (GTNs) that usually develops from the malignant transformation of trophoblastic tissue after evacuation of a complete or partial hydatidiform mole. Invasive moles mostly occur in women of reproductive age. The GTN group includes invasive hydatidiform mole, placental site trophoblastic tumor and choriocarcinoma. • It occurs in 15–20% of complete hydatidiform moles and <1–5% of partial moles. PATHOLOGY. An invasive mole is a hydatidiform mole characterized by invasion of the myometrium by hydropic chorionic villi, accompanied by proliferation of both cytotrophoblast and syncytiotrophoblast. • Choriocarcinoma is characterized by marked proliferation of cytotrophoblast and syncytiotrophoblast, but no chorionic villi are present. • Both invasive moles and choriocarcinoma may show invasion of the uterine vasculature and the production of secondary metastatic lesions, particularly involving the vagina and lungs. Invasive moles do not often resolve spontaneously. • Histologic confirmation of the clinical diagnosis is usually not pursued. Invasion can be difficult to diagnose by curettage, as myometrium is often not present. Thus, it is usually only diagnosed histologically if a hysterectomy has been performed. CLINICAL PRESENTATION. The clinical presentation of IHM consists of vaginal bleeding, enlarged uterus, and high urinary or serum β-hCG levels, typically after the evacuation of a molar pregnancy. The interval from an antecedent molar pregnancy is usually less than 6 months. 6 • Management of an invasive mole includes treatment with chemotherapy as well as continued monitoring of β-hCG. With methotrexate, complete remission is achieved in most non-metastatic and low risk cases. Even in the presence of disseminated disease, most of the cases are amenable to treatment with almost 100% survival. DEFINITION. Placental site trophoblastic tumor (PSTT) is a rare form of gestational trophoblastic neoplasia (GTN), in which the neoplastic cytotrophoblast stem cell differentiates into extravillous (intermediate) trophoblastic cells in an implantation site. EPIDEMIOLOGY. PSTT is an extremely rare form of gestational trophoblastic disease. The disease is usually seen in young women, the mean age at diagnosis is 30 years. PATHOLOGY. The extravillous (intermediate) trophoblast is a subpopulation of trophoblastic cells that differentiate from the outer layer of the trophoblastic shell, migrate in large numbers away from placenta into the wall of the uterus, reaching as far as the inner third of the myometrium. The invasion is associated with remodeling of the maternal spiral arteries. As a result, the spiral arteries dilate, and remodeling ensures a constant high volume, low velocity maternal blood flow to the placenta. • The intermediate trophoblast cells are medium-sized spindled or polyhedral mononuclear cells with abundant cytoplasm. They produce human placental lactogen (hPL) and have a high mitotic activity. They are characterized by diploid DNA content. There are no cytotrophoblast and syncytiotrophoblast cells and no chorionic villi. These cells are programmed to invade, but not destroy, the host tissues. • Grossly, PSTTs form a mass with indistinct margins infiltrating the myometrium. • Microscopically, a monomorphic population of large polyhedral cells with irregular hyperchromatic nuclei infiltrate deep myometrium, splitting apart the muscle fibers, and extending to serosa. A few cells also have multiple nuclei. Nuclear atypia is quite variable. Vascular invasion is prominent. • Immunohistochemical staining for human placental lactogen (hPL) is strongly positive. CLINICAL PRESENTATION. PSTTs most commonly develop after a term gestation, but also occur after a molar pregnancy in 8% of cases. The mean interval from the last pregnancy and diagnosis of PSTT can vary from several weeks up to 15 years. 7 Most of women with PSTT present with abnormal vaginal bleeding and/or amenorrhea. Uterine enlargement has been found in only 25% of affected women. This tumor produces human placental lactogen (hPL) and β-hCG. PSTT patients have lower β-hCG levels than those seen in choriocarcinoma (<500 mU/mL). These low levels reflect the scant amount of syncytiotrophoblast in this tumor. In 70% of cases PSTT act in a benign manner, i.e., remains confined to uterus at the time of diagnosis. In 30% of cases PSTTs demonstrate malignant behavior with recurrences and metastases into the ovaries and lungs. All cases of metastasis result in mortality despite all forms of treatment. PRINCIPLES OF TREATMENT. For patients with localized disease, total abdominal hysterectomy is the mainstay of therapy. Unlike other types of GTN, PSTT is relatively unresponsive to chemotherapy. DEFINITION. Gestational choriocarcinoma is a malignant trophoblastic neoplasm usually arising from placenta. Choriocarcinoma derives from admixed proliferating cytotrophoblast, intermediate trophoblast and syncytiotrophoblast. Choriocarcinoma may also arise in the testis and ovary, and in these cases is classified as a germ cell tumor. EPIDEMIOLOGY. Choriocarcinoma is a very rare tumor that occurs in around 1 in 50,000 pregnancies. Choriocarcinoma most frequently follows a previous complete hydatidiform mole (50% of choriocarcinoma cases), though it occurs following normal pregnancy (25% of cases) or spontaneous abortion (25% of cases). The ages of women with choriocarcinoma range from 17 to 51 years. The incidence of choriocarcinoma is 10 times higher in women 40 years and older than in younger women. PATHOLOGY. Choriocarcinoma is a highly invasive tumor consisting of markedly anaplastic trophoblasts totally lacking in chorionic villi. Grossly, choriocarcinoma is a dark red, solid, friable tumor with areas of hemorrhage and necrosis. The most common location is the interface between endometrium and myometrium. • Microscopically, choriocarcinoma consists of a biphasic tumor of mononuclear cells (cytotrophoblast and intermediate trophoblast) with patchy, small foci of multi-nucleated syncytiotrophoblast. Large bands of hemorrhage and necrosis generally are found between zones of viable tumor. 8 • The syncytiotrophoblast is easily recognized by its abundant, darkly stained (violaceous) cytoplasm and small-to-intermediate sized nuclei with eosinophilic nucleoli. • The cytotrophoblast is composed of variably sized cells with moderate amounts of lightly stained eosinophilic cytoplasm. The nuclei of cytotrophoblast cells are larger and more atypical than those of the syncytiotrophoblast. Large, eosinophilic nucleoli with coarse chromatin are common. Vascular invasion occurs early in tumor development and usually is extensive. • Choriocarcinoma spread by hematogenous dissemination, resulting in vaginal and pulmonary metastases. From pulmonary nodules, hematogenous dissemination can occur via the systemic circulation. Brain, liver, gastrointestinal tract and kidneys are the distant organs most often affected. CLINICAL PRESENTATION. Most cases of choriocarcinoma are diagnosed when the serum hCG levels plateau or rise in patients being observed after the diagnosis of complete hydatidiform mole. The most common presenting maternal sign is vaginal bleeding. If metastases are present, signs and symptoms associated with the metastatic disease, such as hemoptysis, abdominal pain, hematuria, and neurologic symptoms, may be present. MOLECULAR GENETICS. A homeobox gene designated NECC1 (not expressed in choriocarcinoma clone 1) has been identified, that might be involved in the development of choriocarcinoma. The expression of NECC1 is lost in all choriocarcinoma tissues, but healthy adult tissues, including trophoblastic cells in healthy placentas, express abundant NECC1. Various experiments have shown that engineered expression of NECC1 in choriocarcinoma cell lines suppresses tumorigenicity and induces terminal differentiation. NECC1 is believed to induce terminal differentiation of trophoblastic cells. Loss of NECC1 expression is involved in malignant conversion of placental trophoblasts. PROGNOSIS. Before the mid-1950s the prognosis for choriocarcinoma was dismal. Since then, a considerable amount of knowledge and experience has been gained; choriocarcinoma is recognized today as the most curable gynecologic malignancy. Several reasons are apparent for this: (i) quantitative assays for β-hCG levels allowed it to become the prototype for tumor markers; the amount of hormone present in serum or urine is proportional to the number of viable tumor cells; and (ii) this malignancy is extremely sensitive to chemotherapy with cure rates exceeding 95% even in the face of widespread metastases. 9