Gyn Flashcards
1
Q
3 features of endometrial polyps?
A
Polypoid shape, altered (often fibrous) stroma, thick-walled blood vessels.
2
Q
Uterine leiomyomas. Threshold mitoses #s to upgrade to a leiomyosarcoma?
A
> 5 if atypical-appearing, >10 for usual-appearing, >15 if secretory phase.
3
Q
Compare and contrast the following characteristics for endocervical microglandular hyperplasia (MGH) and well-differentiated endometrioid adenocarcinoma (EC): age, background, glandular architecture, cytoplasm, nuclei, and mitotic activity.
A
Age is reproductive for MGH and perimenopausal or postmenopausal for EC. Background is endocervix for MGH and benign or hyperplastic endometrium for EC. Glandular architecture is complex for both MGH and EC. Cytoplasm is mucinous with subnuclear vacuoles for MGH and endometrioid and/or mucinous for EC. Nuclei are bland for MGH and atypical for EC. Mitotic activity is absent or rare for MGH and present for EC.
4
Q
Compare and contrast the following characteristics for reactive epithelial atypia of the fallopian tube (REA) and serous carcinoma in situ of the fallopian tube (CIS): associated conditions, type of surgery, nuclear atypia, nuclear/cytoplasmic ratio, cilia, and mitotic activity.
A
Associated conditions are inflammation (sometimes) for REA and BRCA mutation for CIS. Type of surgery is salpingectomy was part of surgery for other reasons for REA and prophylactic salpingo-oophorectomy for CIS. Nuclear atypia is mild to moderate (can be focally severe) for REA and severe for CIS. Nuclear/cytoplasmic ratio is maintained in REA and increased in CIS. Cilia are present in REA and absent in CIS. Mitotic activity is absent in REA and present in CIS.
5
Q
Cytotrophoblasts and syncytiotrophoblasts predominantly produce ___, while intermediate trophoblasts express large amounts of ___.
A
Cytotrophoblasts and syncytiotrophoblasts predominantly produce hCG, while intermediate trophoblasts express large amounts of hPL.
6
Q
Diagnosis of conventional (spindle) leiomyosarcoma of the uterus is established when any 2 of the following 3 criteria are present:
A
- Diffuse moderate to marked cytologic atypia. 2. Mitotic rate of 10 or more mitoses per 10 HPFs. 3. Tumor cell necrosis.
7
Q
Diagnosis of myxoid leiomyosarcoma of the uterus is established when 1 of what 2 criteria are found?
A
- Severe cytologic atypia and/or tumor cell necrosis with any mitotic index, or 2. 2 or more mitoses per 10 HPFs in the absence of atypia or tumor cell necrosis.
8
Q
Diagnosis of epithelioid leiomyosarcoma of the uterus is established when 1 of what 2 criteria are found?
A
- Any degree of cytologic atypia and 5 or more mitoses per 10 HPFs in the absence of tumor cell necrosis, or 2. 5 or more mitoses per 10 HPFs and tumor cell necrosis with any degree of cytologic atypia.
9
Q
Placental mesenchymal dysplasia.
A
~1/4 of cases are associated with Beckwith-Wiedemann syndrome. Can also have a completely normal fetus or a growth-restricted fetus. There is increased maternal serum AFP, and normal to slightly elevated bHCG. Large placenta with dilated and tortuous chorionic plate vessels. Can have chorangiomas and cystic vesicles. Absence of: trophoblastic proliferation, stromal trophoblastic inclusions, scalloping of villous surface. Most cases are diploid.
10
Q
Squamous lesions of the ovary.
A
Squamous elements are most commonly identified in the ovary as part of a mature cystic teratoma (or dermoid cyst). The mature cystic teratoma is both the most common ovarian tumor and the most common benign ovarian tumor. Although the squamous elements in these tumors are benign the vast majority of the time, squamous cell carcinoma can arise from them, and is the most common malignant component arising from a mature teratoma. Although only 1-2% of mature teratomas harbor a malignant component, up to 80% of those will be of squamous derivation. Metaplasia is likely the next most common cause of squamous differentiation in the ovary. The most frequently encountered nonteratomatous primary tumors showing squamous differentiation are ovarian endometrioid adenocarcinoma of the ovary and the Brenner tumor. Metastases are another common source of squamous elements in the ovary; endometrial endometrioid adenocarcinoma and squamous cell carcinoma of the cervix are 2 likely sources of metastatic ovarian squamous components. Vary rarely, squamous elements are identified in the absence of any of the above senarios; there have been a few cases of de novo squamous cell carcinoma of the ovary, some associated with endometriosis, as well as a few cases of pure epidermoid cysts without teratomatous features. In squamous cell carcinomas that are less differentiated, other epithelioid lesions may enter the DDx, such as epithelioid mesothelioma and epithelioid sarcoma.
11
Q
Which are the HPV low risk and high risk genotypes? Which are the most common subtypes found in invasive squamous cell carcinoma and adenocarcinoma of the cervix?
A
Low risk genotypes: 6, 11, 42, 44. High risk genotypes: 16, 18, 31, 33, 45, 58. HPV 16 is the most common subtype found in cervical squamous cell carcinoma. HPV 16 and 18 are detected with equal prevalence in most subtypes of cervical adenocarcinoma (HPV 18 is more common in cervical AIS).
12
Q
What HPV types (in order of frequency) are seen mostly commonly in the following lesions? Plantar wart, common wart, flat (juvenile) wart, oral squamous papilloma, oral focal epithelial hyperplasia (Heck disease), epidermodysplasia verruciformis, laryngeal papillomas, condyloma acuminatum, cervical LSIL, cervical HSIL, cervical AIS and invasive cervical adenocarcinoma.
A
Plantar wart: 1, 2. Common wart: 2, 1, 4, (HPV 7 in fish and meat handlers). Flat (juvenile) wart: 3, 10. Oral squamous papilloma: 6, 11. Oral focal epithelial hyperplasia (Heck disease): 13, 32. Epidermodysplasia verruciformis: 2, 3, 10, 5, 8. Laryngeal papillomas: 6, 11. Condyloma acuminatum: 6, 11. Cervical LSIL: 6, 11. Cervical HSIL: 16, 18, 31, 33, 35. Cervical AIS: 18. Invasive cervical adenocarcinoma: HPV 16 and 18 are detected with equal prevalence in most subtypes of cervical adenocarcinoma.
13
Q
Peritoneal ovarian tumor implants. What types are there?
A
The two major types are noninvasive and invasive. The noninvasive type is further subdivided into epithelial and desmoplastic subtypes. The epithelial noninvasive implants may be exophytic or buried within invaginations beneath the peritoneal surface; they are characterized by a papillary pattern of growth, mild to moderate aypia, and lack of inflammation or stromal reaction. In desmoplastic noninvasive implants, the epithelial component is more irregular, the cells have a more abundant acidophilic cytoplasm, and there is inflammation (oocasionally severe) and a brisk stromal reaction with a granulation tissue-like appearance. Invasive implants show haphazard destructive infiltration of the stroma. As a general rule, psammoma bodies are less numerous than in noninvasive implants. The nuclear atypia is not necessarily more pronounced. Some implants of either noninvasive or invasive types are composed of papillary cores within clear spaces lined by mesothelial cells or tumor cells, resulting in a glomeruloid appearance.
14
Q
Lynch syndrome has mutations in what genes?
A
The hallmark of Lynch syndrome is a genetic mutation in one of the family of DNA mismatch repair (MMR) protein genes (MLH1, MLH3, MSH2, MSH6, PMS2). These proteins function to repair errors in replication of DNA at short repetitive sequences (microsatellites). Lynch syndrome is associated with a high risk of colon and endometrial cancers, as well as increased risk of urothelial, small bowel, hepatobiliary, and pancreatic cancer. Further, 10-15% of sporadic colon, endometrial, and gastric tumors may harbor a somatic, non-germline MMR mutation or loss of expression.
15
Q
Immunostains for endometrial stromal sarcoma.
A
ESS is CD10 positive, but other mesenchymal tumors such as smooth muscle tumors (highly cellular leiomyoma, leiomyosarcoma), adenosarcoma, and MMMT can be CD10 positive. Also, CD10 expression can be reduced in endometrial stromal sarcomas with variant histologic features (fibrosis, myxoid change, etc.). Therefore, CD10 is best used with a panel of other stains. Most of the tumors also express vimentin, ER, PR, WT1 (nuclear), bcl-2, and SMA; some express keratin and KIT. There can be scattered staining for desmin in some cases (in areas besides those of smooth muscle differentiation); so, like CD10, it should be used in a panel. Caldesmon is another smooth muscle marker expected to be negative in most ESS and is often included in diagnostic panels. Areas of sex cord differentiation may express inhibin, calretinin, melan-A, CD56, and CD99. EMA, DOG1, and CD34 should be negative in ESTs.
16
Q
The spectrum of gestational trophoblastic disease (GTD) includes what entities?
A
The spectrum of gestational trophoblastic disease (GTD) includes hydatidiform molar pregnancies (complete hydatidiform mole, partial hydatidiform mole, and invasive mole), as well as non-molar lesions (placental site nodule, epithelioid trophoblastic tumor, placental site trophoblastic tumor and choriocarcinoma).
17
Q
What immunostain is useful to distinguish complete hydatidiform mole from partial hydatidiform mole?
A
Since complete hydatidiform moles are paternally derived, paternally imprinted genes that are normally expressed exclusively from maternally derived chromosomes should be absent. Studies have shown that p57KIP2, a paternally imprinted, maternally expressed gene, is useful in confirming the diagnosis of a complete mole, as the villous mesenchymal cells and villous cytotrophoblast of CHM are negative for this marker. PHM are p57KIP2 positive.
18
Q
Persistent trophoblastic disease occurs in approximately __% of women with a prior complete hydatidiform mole, and in __% of women with a partial hydatidiform mole.
A
Persistent trophoblastic disease occurs in approximately 20% of women with a prior CHM. Persistent trophoblastic disease may represent persistent mole with no myometrial invasion, an invasive mole, or a choriocarcinoma (occurring in approximately 2 – 3% of women with prior CHM). Persistent trophoblastic disease is treated with chemotherapy with a cure rate approaching 100%. PHM are rarely associated with persistent trophoblastic disease.
19
Q
How does a hydropic abortus differ from a complete hydatidiform mole?
A
Hydropic abortus differs from CHM as (1) it typically is not associated with a markedly elevated ß-HCG level, (2) the volume of tissue removed is typically much less than that with CHM, (3) the villi appear swollen but lack true cistern formation, (4) the villi typically have a degenerative appearance in keeping with early embryonic demise, (5) the trophoblastic proliferation has a polar distribution with the formation of trophoblastic columns at one end of the villous and (6) are p57KIP2 positive.
20
Q
Twin-twin transfusion syndrome (TTTS) is a serious condition that affects __% to __% of twin pregnancies with monochorionic diamniotic placentation.
A
Twin-twin transfusion syndrome (TTTS) is a serious condition that affects 10% to 15% of twin pregnancies with monochorionic diamniotic placentation. It occurs due to intrauterine blood transfusion from one twin (donor) to another twin (recipient) through placental vascular anastomoses from shared placental cotyledons. This results in increased fetal and neonatal mortality, premature delivery and neurologic complications in the surviving twin(s).
21
Q
Juvenile granulosa cell tumor comprises __% of granulosa cell tumors as a whole, and represents __% of ovarian tumors in patients younger than 20 years of age. __% of JGCTs present in patients less than 30 years of age, with an average age of __ years at presentation.
A
Juvenile granulosa cell tumor comprises 5-15% of granulosa cell tumors as a whole, and represents 10% of ovarian tumors in patients younger than 20 years of age. 97% of JGCTs present in patients less than 30 years of age, with an average age of 13 years at presentation. These tumors frequently produce estrogen and are associated with isosexual pseudoprecocity in most prepubertal patients. JGCTs presenting after puberty may be detected secondary to abdominal swelling, pain, a pelvis mass or menstrual irregularities.
22
Q
Histologic appearance of juvenile granulosa cell tumor.
A
JGCTs are composed of a nodular to diffuse proliferation of granulosa cells, with a fibrothecomatous stroma that can be myxoid or edematous. Characteristic follicular spaces are found within the nodules or scattered in the solid areas. The folicular spaces vary in shape from round to irregular and in size from small to macrofollicular, but microfollicles (Call-Exner bodies) are rare. Eosinophilic or basophilic fluid is present in the spaces, and the fluid is mucicarmine positive in two-thirds of the cases. The granulosa cells of JGCT are generally larger than those of AGCT and often have luteinized, moderate to abundant, pale or eosinophilic cytoplasm. The nuclei are round or oval and hyperchromatic; grooves are rarely present. Most of the tumors have at least some foci or moderate to marked nuclear atypia. Mitotic activity is variable, ranging from 1 to 32 per 10 HPF, with a median of 6-8 per 10 HPF. Theca cells can be seen in JGCTs. They may surround nodules of granulosa cells or intermix with them in solid areas.
23
Q
Stains for juvenile granulosa cell tumor.
A
Reticulin staining demonstrates fibers around groups and nodules of granulosa cells, and fibers that surround individual theca cells. JGCT is characteristically positive for inhibin and/or calretinin. Vimentin, keratin, and CD56 are positive in most cases, and WT-1 (nuclear) and S-100 are also frequently expressed. In contrast to other sex cord-stromal tumors, focal staining for EMA (<25% of tumor cells in most cases) can be seen in 25-50% of JGCTs. Most cases are positive for SMA, but desmin is negative.
24
Q
What entities are in the differential diagnosis of juvenile granulosa cell tumor, and how can they be distinguished?
A
The diffuse and nodular pattern with follicular spaces, round to oval hyperchromatic nuclei without grooves, and frequent luteinized cells distinguish JGCT from the adult counterpart. Because of the luteinization, JGCTs may be mistaken for thecomas. Thecomas, however, lack the follicular spaces and generally the mitotic activity seen in JGCTs; the reticulin fiber pattern is also different in these tumors. Because of the young age of most patients with JGCT, germ cell tumors, such as yolk sac tumor or dysgerminoma, may be considered. However, follicular spaces and inhibin expression are not features of those tumors. Small cell carcinoma of the hypercalcemic type is also characteristically seen in young patients and has follicle-like spaces, but it lacks the estrogenic manifestations, theca cells, and inhibin expression of JGCT. The luteinized cells with pale to clear cytoplasm in some JGCTs may resemble clear cell carcinoma. But clear cell carcinoma is rare in patients of the age that is typical for JGCT; additionally, clear cell carcinoma lacks inhibin expression and is diffusely positive for EMA.
25
Brenner tumors are neoplasms of urothelial (transitional cell) differentiation that are favored to be derived from ___. They constitute ___% of all ovarian tumors. Patients present in middle age with unilateral slow-growing adnexal masses which are often found incidentally. Brenner tumors may be associated with symptoms of hyperestrinism. Approximately 20% of cases are also associated with other lesions such as ___.
Brenner tumors are neoplasms of urothelial (transitional cell) differentiation that are favored to be derived from ovarian surface epithelium. They constitute 1-2% of all ovarian tumors. Patients present in middle age with unilateral slow-growing adnexal masses which are often found incidentally. Brenner tumors may be associated with symptoms of hyperestrinism. Approximately 20% of cases are also associated with other lesions such as serous of mucinous cystadenomas of the ovary, benign cystic teratoma or struma ovarii, and urothelial carcinoma of the bladder.
26
Under the WHO classification, Brenner tumors are classified into what 3 subtypes?
Benign, borderline, and malignant. Transitional cell carcinomas of the ovary lack a benign or borderline Brenner tumor component.
27
Stains for Brenner tumor vs. transitional cell carcinoma of the ovary?
Brenner tumors are generally positive for keratins, EMA, CEA, CK7, and glycogen. Evidence of urothelial differentiation in Brenner tumors is seen with reactivity for uroplakin III, thrombomodulin, and CK20. Brenner tumors are generally negative for p16 and p53. In contrast, TCC of the ovary rarely expresses the aforementioned urothelial markers. Reactivity for ER, WT-1, CA125, p16, and p53 has been observed in TCC of the ovary.
28
The principal differential diagnosis of mesenchymal dysplasia, both clinically and pathologically, is partial hydatidiform mole due to the similar cystic changes and the admixture of normal and abnormal villi. How can they be distinguished?
Unlike partial hydatidiform mole, mesenchymal dysplasia shows no trophoblast hyperplasia, stromal trophoblastic inclusions, or scalloping of the villous surface. The fetus associated with partial molar pregnancy is often small and malformed, unlike the more normal fetus associated with mesenchymal dysplasia. DNA ploidy may also help in distinguishing these entities, as partial hydatidiform molar pregnancy is typically triploid, whereas mesenchymal dysplasia is typically diploid.
29
Are the lymphocytes seen in seminoma/dysgerminoma B-cells or T-cells?
T-cells.
30
Approximately __% of ovarian clear cell carcinomas have a mixed component of endometrioid carcinoma.
Approximately 20% of ovarian clear cell carcinomas have a mixed component of endometrioid carcinoma, perhaps related to the common association with endometriosis.
31
From the LAST (Lower Anogenital Squamous Terminology Standardization) Project, when is p16 staining recommended?
The LAST Project recognized p16 as a biomarker for E6/E7 oncogene activation in all HPV-related precancerous squamous lesions of the LAT. Briefly, p16 staining is recommended whenever there is: Differential diagnosis between precancer (HSIL) and precancer mimics. Disagreement in interpretation of precancer. High risk for missing precancer (high-risk cytology with negative/LSIL biopsy findings). H&E morphologic pattern of -IN2 (This recommendation has proved to reduce the equivocal and poorly reproducible -IN2 diagnostic category. Positive p16 staining supports classifying -IN2 as definitive HSIL). Staining for p16 is not recommended for biopsies that are negative or show unequivocal LSIL or HSIL (-IN3).
32
Positive p16 staining is defined as ___.
Positive p16 staining is defined as ___.
33
What is the difference between a D&C and a D&E?
Dilation and curettage is performed in the first trimester, as the pregnancy is easily evacuated using mechanical cervical dilation and suction curettage. The resulting specimen is fragmented placental tissue and, depending on the gestational age and indications for the procedure, there may be small portions of the embryo/fetus identified. In the second trimester, dilation and evacuation is performed because the procedure requires greater cervical dilation and advanced surgical skills for removal of tissue (the fetal tissue is larger and bony tissue is more calcified). D&Es begin with 1-2 days of cervical preparation to obtain adequate cervical dilation. The procedure may be performed with any level of anesthesia. The placental and fetal tissue is evacuated using a combination of suction and extraction forceps in multiple passes. The resulting specimen is fragmented placental and fetal tissue. The federal Partial Birth Abortion Act of 2003 bans a procedure known as "intact D&E" or "dilation and extraction," which involves greater cervical dilation, delivery of the fetus to the level of the cranium, and decopression of the cranium to allow passage through the cervix.
34
Undifferentiated endometrial carcinoma.
UEC is a relatively uncommon neoplasm thought to have a higher prevalence than had previously been thought, as many cases of UEC were either reported as endometrioid endometrial carcinoma FIGO grade 3, or as HG sarcomas or carcinosarcomas. UEC, compared to endometrioid adenocarcinoma FIGO grade 3 (the main differential diagnosis), carries a much worse prognosis. Involvement of and origin from the LUS is a frequent finding. Microscopically, it is defined as a tumor composed of medium or large-sized cells with complete absence of glandular differentiation and with absent or minimal (<10-20% of tumor cells.
35
How can undifferentiated/dedifferentiated endometrial carcinoma be distinguished from endometrial adenocarcinoma FIGO grade 3? Comment on mean age at presentation, high stage (stage III/IV) %, growth pattern, glands, cords and trabeculae, cohesive growth, component demarcation, rhabdoid cells, myxoid matrix, IHC for panCK, IHC for EMA, and IHC for ER/PR.
Undifferentiated/dedifferentiated endometrial carcinoma: 55, 45%, diffuse patternless sheets, absent, vague, dyshesive cells, sharp demarcation, may be present, may be present, patchy/focal, patchy/focal, focal in 12% of cases. Endometrial adenocarcinoma FIGO grade 3: 68, 30%, solid and glandular, present (1-49% of tumor area), well demarcated, cohesive squamoidlike, intermingled components, absent, absent, diffuse, diffuse, diffuse in 60% of cases.
36
Why does a normal placenta show heterogeneous maturation?
A normal placenta shows heterogeneous maturation because better-oxygenated centers of cotyledons (placentones) are less mature (larger chorionic villi with less syncytial knots) than are their peripheral parts, where the less-oxygenized blood returns toward the uterus. The accelerated heterogeneous hypermaturity is a sensitive feature of uteroplacental malperfusion. Homogeneous placental maturation is always abnormal, the placentas being either hypomature or hypermature.
37
How can decreased extracellular matrix of chorionic villi be distinguished from villous edema?
The extracellular matrix of chorionic villi can be decreased and the villous cores as pale as the intervillous space. Such a finding has to be distinguished from villous edema, where, in addition, a split artifact between the trophoblastic shell and the villous core is, at least focally, present. An increased extracellular matrix of chorionic villi, produced in excess by villous fibroblasts in response to intravillous hypoxia associated with intervillous hyperoxemia, manifests as intense eosinophilia of villous cores.
38
In what clinical situations are preuterine hypoxic, uterine hypoxic, and postuterine hypoxic patterns of chronic hypoxic placental injury seen, and what are the histologic features?
Preuterine hypoxic pattern is seen in maternal anemia, pregnancy at high altitudes, air pollution, maternal smoking, and multifetal pregnancy. Histologic features are: Homogeneously, diffusely hypomature villi. Diffusely increased (including diffuse or incipient chorangiosis) villous vascularity. Increased (b/c of tangential cutting) nonapoptotic, syncytial knotting; increased villous cytotrophoblasts and Hofbauer cells; and extracellular matrix of chorionic villi are diffusely present. Uterine hypoxic pattern is seen in late onset fetal growth restriction and preeclampsia. Heterogeneously hypermature villi. Same additional histologic patterns as in preuterine hypoxic pattern, but only focally present; lesions associated with increased extravillous trophoblasts; decidual arteriolopathy. Postuterine hypoxic pattern is seen with retained stillbirth and early onset fetal growth restriction and preeclampsia. Homogeneously hypermature villi. Diffusely increased apoptotic (smudgy) syncytial knotting; decreased villous cytotrophoblasts and Hofbauer cells; increased extracellular matrix of chorionic villi (terminal villous hypoplasia).
39
What is the histologic evolution of villous infarction in the placenta?
Agglutination of villi --> vascular congestion --> intravillous hemorrhage --> coagulative necrosis --> acute inflammatory response --> fibrin deposition, fibrosis, calcification. Villous infarction is the most frequently (or readily) diagnosed placental lesion; it starts to develop 2-4 hours to 4 days after an aucte hypoxic event. Once intravillous stromal hemorrhage (red infarction) occurs, the sequence is irreversible. The time frame of these sequential changes in humans has not been determined. Villous infarctions have diagnostic limitations b/c they occur not infrequently in otherwise uncomplicated pregnancies, indicating a substantial placental reserve. Only infarctions in a central/paracentral location and occupying >5-20% of the placental parenchyma are regarded as diagnostically significant.
40
Peutz-Jeghers (hamartomatous) polyps overview.
Peutz-Jeghers polyps (hamartomatous polyps) are supported by broad bands of muscularis mucosa smooth muscle, which is thicker centrally, and resembles a Christmas tree at low power. The polyp has superficial columnar and goblet cells, but Paneth and endocrine cells at its base. Peutz-Jeghers polyps are large, pedunculated polyps of the gut almost always seen in association with Peutz-Jeghers syndrome. This rare autosomal dominant disorder is usually diagnosed at ages 20-30, with hamartomatous polyps in the small bowel (100%), stomach and colon (25%), and associated adenomatous lesions that may give rise to adenocarcinoma of the stomach, large or small bowel; adenoma malignum of the cervix, ovarian mucinous tumors, and carcinoma of the breast, lung and pancreas. The syndrome is also associated with sex-cord tumor with annular tubules (almost all patients) and melanotic pigmentation of the digits, genitalia, lips, oral mucosa, palms and soles. Peutz-Jeghers syndrome is caused by mutations in STK11/LKB1, a serine threonine kinase that may play a role in cell polarity.
41
Steroid cells tumors of the ovary are divided into what 3 groups?
Steroid cell tumors of the ovary, which are composed of hormone producing cells, are divided into three groups: 1) stromal luteoma, 2) Leydig cell tumor and 3) steroid cell tumor, NOS. Steroid cell tumors in general are uncommon, representing only 0.1% of all ovarian neoplasms; however, within this category of tumors, steroid cell tumor, NOS is most frequent, representing approximately 60% of all ovarian steroid cell tumors.
42
Steroid cell tumor, NOS of the ovary overview.
Steroid cell tumor, NOS can occur over a wide age range; however most patients tend to be younger than those with the other types of ovarian steroid cell tumors with an average age of 43 years at presentation. Approximately 50% of patients present with virilization and hirsutism. A minority will present with estrogenic manifestations or occasionally Cushing syndrome due to cortisol production by tumor cells. The vast majority of tumors are unilateral and they are typically well circumscribed, lobulated or multinodular solid yellow to orange to brown tumors that may occasionally exhibit hemorrhage and/or necrosis. These tumors have an average size of 8.4 cm. Histologically, most show a diffuse pattern of growth, but they may also have a clustered or corded growth pattern as evident in this case. There is typically little intervening stroma, but there is often a rich vascular network of thin compressed capillaries. The tumor cells have moderate amounts of granular eosinophilic or vacuolated cytoplasm with distinct cell borders and centrally placed round and regular nuclei with conspicuous nucleoli. Cytologic atypia is uncommon and mitotic activity is usually low (<2 per 10 high power fields). Occasionally, hemorrhage and necrosis can be present. Tumor cells are positive for inhibin and calretinin, but are usually negative for keratin.
43
By definition, the granulosa cells must make up at least 10% of the tumor for a diagnosis of AGCT; otherwise it is classified as a ___.
By definition, the granulosa cells must make up at least 10% of the tumor for a diagnosis of AGCT; otherwise it is classified as a fibroma, or fibrothecoma, with a minor sex cord element.
44
In contrast to distinct reticulum fibers surrounding large groups of granulosa cells in adult granulosa cell tumor, thecomas and fibromas have ___.
In contrast to distinct reticulum fibers surrounding large groups of granulosa cells in AGCT, thecomas and fibromas have small fibers surrounding many individual cells.
45
In the ovary, how do you differentiate a cystic follicle from a follicular cyst, a cystic corpus luteum from a corpus luteum cyst, and a surface epithelial inclusion cyst from a serous cystadenoma?
Cystic follicle is a cyst smaller than 3 cm lined by an inner layer of granulosa cells and an outer layer of theca interna cells; if 3 cm or larger then it is called a follicular cyst. If the lining granulosa and theca cells show extensive luteinization, it is called a cystic corpus luteum when smaller than 3 cm or corpus luteum cyst when 3 cm or larger. A surface epithelial inclusion is a cyst smaller than 1 cm lined by a single layer of ovarian surface epithelium; if 1 cm or larger then it is called a serous cystadenoma.
46
How can pregnancy affect the Lewis phenotype Le (a-b+)?
Some Le (a−b+) women can transiently become phenotypically Le (b−), with the development of anti-Leb, during pregnancy.
47
In women with Lynch syndrome, is the incidence of endometrial cancer or colorectal cancer greater?
Endometrial cancer. Lynch syndrome accounts for ~2-3% of CRC and 2.3% of EC, with an overall risk of developing CRC of 68% and EC of 62% in Lynch patients. However, when looking at the two genders separately, the risk of CRC for men is 83% versus 48% for women. Therefore, women with Lynch syndrome are at a substantially greater risk of developing EC than CRC.
48
What are the most common benign and most common malignant vulvar adnexal lesions?
Most common benign: hidradenoma papilliferum. Most common malignant: extramammary Paget disease.
49
What are some epithelial cysts that can be seen in the vulva?
Vulvar epithelial cysts are derived from a variety of resident structures. Those thought to arise from remnants of urogenital sinus include urogenital sinus cysts, major (Bartholin gland) and minor vestibular gland cysts, paraurethral (Skene gland) cysts, Wolffian-like duct cyst, and cysts of canal of Nuck. Cysts derived from the overlying epidermis, hair follicles, and apocrine glands include epidermoid cysts, pilar or trichilemmal cysts, dermoid cysts, and hidrocystomas. Less-common entities include steatocystomas and cysts of anogenital mammary-like glands (previously reported as milk cysts of the supernumerary mammary glands).
50
What is extrauterine deciduosis?
Extra-uterine deciduosis (EUD) is a benign condition which can be mistaken macroscopically for malignancy and resembles peritoneal carcinomatosis. EUD can be discovered accidentally in pregnancy during caesarean sections and during pelvic surgery in women taking oral contraceptives. Deposits are found mainly on the ovary and cervix, but also on abdominal serosal surfaces of the fallopian tubes, bowel, peritoneum and vagina, as well as lungs, pleura, retroperitoneal lymph nodes and rarely skin. The decidual proliferation will be PR and vimentin positive. Most lesions do not require further treatment and spontaneously involute within 4-6 weeks of delivery.
51
What component of the virus is in the HPV vaccines?
The major HPV capsid protein L1.
52
Villin IHC stain. What is the target? In what normal and disease states is there positivity? What are some uses of the stain?
Villin is an actin binding protein present in cytoskeleton of intestinal microvilli; has critical role in maintaining brush border organization. It is relatively specific for GI epithelium with brush border microvilli or adenocarcinomas derived from them. Positive staining (normal): Digestive tract epithelium, proximal renal tubules, hepatic bile ducts. Positive staining (disease): Colonic adenocarcinoma, renal cell carcinoma, pulmonary adenocarcinomas. Negative staining: Renal distal tubules, bronchiolar epithelium, pulmonary alveolar cells, bronchial gland cells. Uses: Primary bladder adenocarcinoma (villin-, CDX2-) vs. colorectal carcinoma to bladder. Ovarian adenocarcinoma (villin-) vs. colorectal adenocarcinoma.
53
What is the PTEN gene? In what tumors is it often mutated?
Phosphatase and tensin homolog (PTEN) gene is on chromosome band 10q23.31. In addition to its role as a tumor suppressor, it has important roles in embryogenesis and maintenance of physiologic functions in many organ systems and is constitutively expressed in normal tissues. It is one of the most frequently inactivated genes in sporadic cancer. Sporadic mutations of PTEN occur frequently in many tumors such as glioblastoma, breast carcinoma, endometrial carcinoma, thyroid neoplasms, skin neoplasms, and advanced prostate cancer.
54
Primary vulvar adenocarcinomas are classified into what 3 entities?
Primary vulvar adenocarcinomas are rare, with a poorly understood histogenesis. They are classified into (a) extramammary Paget disease, (b) sweat gland carcinoma, and (c) breast-like adenocarcinoma, and are distinguished from adenocarcinoma originating in the Bartholin glands. Extramamamary Paget disease has large pale staining tumor cells, usually in the lower epidermis, in nests, glandular spaces or continuously along the basement membrane. It may be associated with urothelial carcinoma or anorectal carcinoma. Sweat gland carcinoma derives from native apocrine sweat glands, is usually ER-, PR-, and composed of glandular or papillary cords and tubules, with variable pagetoid components. Breast-like adenocarcinoma may originate from anogenital ER+, PR+ mammary like glands in the interlabial sulci, and is often accompanied by these native glands.
55
What are UTROSCTs?
Uterine Tumors Resembling Ovarian Sex Cord Tumors. Rare neoplasm of unknown etiology occuring usually in middle-aged women. In line with its controversial origin, the current WHO classification placed UTROSCTs in the "miscellaneous" category of tumors of the uterine corpus. A multitude of architectural patterns are described, including plexiform cords, anastomosing trabeculae, watered silk, microfollicle, macrofollicle, tubules, retiform, solid cellular islands, and diffuse pattern. Mitotic figures are infrequent and necrosis is mostly absent. This tumor has a diverse IHC profile with expression of sex cord, epithelial, and smooth muscle markers. Immunoexpression of calretinin and at least for one of the other sex cord markers is required to establish a diagnosis. Most have benign behavior, but some recur, so should be considered a tumor of low malignant potential.
56
Does aggressive angiomyxoma occur only in women?
No. Aggressive angiomyxoma typically occurs in the genital and pelvic regions of women of reproductive age and rarely occurs in the inguinal region, along the spermatic cord and in the scrotum of men. This neoplasm typically has infiltrating borders and shows scattered spindled and stellate shaped cells with thin and thick-walled blood vessels in a myxoid background. The spindled cells are generally positive for actins and desmin and consistently express both estrogen and progesterone receptors, but are negative for S-100.
57
In conjugated hyperbilirubinemia... If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are ___. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is ___.
In conjugated hyperbilirubinemia... If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are Dubin-Johnson syndrome, hepatitis, endotoxin (sepsis), pregnancy (estrogen), and drugs such as estrogen and cyclosporine. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is mechanical obstruction such as from PBC, PSC, tumor, stricture, or stone.
58
List non-pancreatic causes of hyperamylasemia.
Diabetic ketoacidosis, peptic ulcer disease, acute cholecystitis, ectopic pregnancy, salpingitis, bowel ischemia, intestinal obstruction, renal insufficiency, salivary gland pathology, and macroamylasemia. Amylase may also be raised somewhat by the administration of opioid analgesics, due presumably to contracture of the sphincter of Oddi.
59
MSI testing is performed by extracting DNA from paraffin-embedded neoplastic and nonneoplastic tissue. PCR is used to amplify 5 specific microsatellite regions: ___, ___, ___, ___, ___. These regions from the tumor are compared to those from nonneoplastic tissue to assess for differences in length, indicative of MSI.
MSI testing is performed by extracting DNA from paraffin-embedded neoplastic and nonneoplastic tissue. PCR is used to amplify 5 specific microsatellite regions: BAT25, BAT26 (both of which are regions of mononucleotide repeats), D2S123, D5S346, and D17S250 (regions of dinucleotide repeats). These regions from the tumor are compared to those from nonneoplastic tissue to assess for differences in length, indicative of MSI.
60
What tumors are seen in patients with vHL disease?
Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.
61
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
62
What are uncomplicated and complicated UTIs?
Uncomplicated UTI often refers to cases of cystitis in healthy young adult nonpregnant females without anatomic genitourinary anomalies. Some authors also include pyelonephritis in healthy young adult females, cystitis in young adult males, and cystitis in healthy postmenopausal women, Complicated UTI often refers to one arising in association with pregnancy, diabetes, stone, structural genitourinary anomalies, spinal injury, children, and males.
63
For the following clinical syndrome(s), give the causative agent(s) (list most common first): uterine infections following septic abortion.
C. perfringens.
64
CDKN1C (p57) is a paternally imprinted, maternally expressed gene, and as complete moles contain only paternal genes, they have reduced expression of the p57 protein. But what cells exactly do stain and do not stain?
The villous cytotrophoblasts and stromal cells in complete mole are negative or have only focal nuclear staining, while there is diffuse positivity in partial mole and hydropic abortus. Syncytiotrophoblastic cells are also negative for p57. It should be noted, however, that intervillous intermediate trophoblasts and decidual cells in complete mole do stain for p57.
65
What are causes of increased or decreased serum ceruloplasmin levels?
A falsely normal or increased ceruloplasmin may be seen in inflammatory states (ceruloplasmin is an acute phase reactant) or pregnancy. Decreased ceruloplasmin is seen with Wilson disease, hepatic failure, malnutrition, and Menke syndrome.
66
In what conditions/situations is transferrin increased?
Chronic inflammatory state, iron deficiency, pregnancy, estrogen therapy.
67
What is congenital varicella vs. perinatal varicella?
Congenital varicella is diagnosed when there is evidence of maternal varicella infection during pregnancy, skin lesions on the newborn that have a dermatomal distribution, and serologic evidence of infection in the newborn (either IgM or persistent IgG beyond 7 months). Perinatal varicella arises when maternal infection occurs within a few days of delivery
68
The incidence and severity of congenital varicella depend upon the timing of maternal infection. Discuss.
When a woman is infected during pregnancy, the overall incidence of congenital varicella is 1-5%. The incidence is lowest when maternal infection occurs in the 1st trimester and highest in the 3rd. In contrast, the likelihood of perinatal varicella is 50-60%.
69
What ovarian tumors are associated with paraendocrine hypercalcemia?
Small cell carcinoma (60%). Clear cell carcinoma (20%). Serous carcinoma, squamous cell carcinoma arising in a dermoid cyst, and dysgerminoma account for 10%.
70
What are the 3 most common malignant ovarian germ cell tumors?
Dysgerminoma (50%). Yolk sac tumor (20%). Immature teratoma (15-20%).
71
__% of choriocarcinomas are associated with a preceding molar pregnancy, compared to __% for other malignant tumors of trophoblast (such as placental site trophoblastic tumor and epithelioid trophoblastic tumor).
50% of choriocarcinomas are associated with a preceding molar pregnancy, compared to 5-8% for other malignant tumors of trophoblast (such as placental site trophoblastic tumor and epithelioid trophoblastic tumor).
72
Adenomatoid tumor is a benign mesothelial tumor seen most commonly in male and female genital organs. Can malignant change occur in adenomatoid tumor?
No.
73
What are common gene mutations seen in serous, mucinous, and endometrioid ovarian carcinomas?
Mucinous tumors have a high prevalence of KRAS mutations. Serous tumors commonly have TP53 gene mutations. CTNNB1 (beta-catenin) gene mutations and PTEN mutations are common in endometrioid adenocarcinomas.
74
Metastatic tumors to the breast comprise ~1% of all tumors encountered in the breast. In adult women, what are the top 3 most common metastases to the breast?
Malignant melanoma, followed by lung and gynecologic cancers.
75
There are three major mechanisms by which hypercalcemia of malignancy can occur: osteolytic metastases with local release of cytokines (including osteoclast activating factors); tumor secretion of parathyroid hormone-related protein (PTHrP) (humoral hypercalcemia); and tumor production of 1,25-dihydroxyvitamin D (calcitriol). Additionally, some tumors cause ectopic secretion of PTH. List some malignancies that cause each of the three main types.
Osteolytic metastases: breast cancer, multiple myeloma, lymphoma, leukemia. Humoral hypercalcemia (PTHrP): squamous cell carcinoma, RCC, breast cancer, bladder carcinoma, ovarian carcinoma, non-Hodgkin lymphoma, CML, leukemia, lymphoma. Tumor production of calcitriol: lymphoma (Hodgkin, non-Hodgkin, lymphomatosis/granulomatosis), ovarian dysgerminoma.
76
What features can be used to help differentiate endocervical vs endometrial adenocarcinoma on Pap smears?
Endocervical lesions will typically present more cells. Endocervical adenoCA cells and nuclei are typically larger. Nucleoli are more common and larger in endocervical adenoCA. Endocervical AIS and adenoCA cells typically retain their columnar configuration, consistent with direct sampling, whereas endometrial groups tend to round up, consistent with spontaneous exfoliation. As endometrial adenoCAs become higher grade, differential features are less helpful in rendering a definitive distinction.
77
What features can be used to help differentiate endocervical vs endometrial adenocarcinoma on Pap smears?
Endocervical lesions will typically present more cells. Endocervical adenoCA cells and nuclei are typically larger. Nucleoli are more common and larger in endocervical adenoCA. Endocervical AIS and adenoCA cells typically retain their columnar configuration, consistent with direct sampling, whereas endometrial groups tend to round up, consistent with spontaneous exfoliation. As endometrial adenoCAs become higher grade, differential features are less helpful in rendering a definitive distinction.
78
What features can be used to help differentiate endocervical vs endometrial adenocarcinoma on Pap smears?
Endocervical lesions will typically present more cells. Endocervical adenoCA cells and nuclei are typically larger. Nucleoli are more common and larger in endocervical adenoCA. Endocervical AIS and adenoCA cells typically retain their columnar configuration, consistent with direct sampling, whereas endometrial groups tend to round up, consistent with spontaneous exfoliation. As endometrial adenoCAs become higher grade, differential features are less helpful in rendering a definitive distinction.
79
What is hCG? What are its subunits and which is measured in immunoassays? What units is hCG concentration expressed in?
hCG is a glycoprotein heterodimer composed of an alpha and a beta chain. The alpha subunit is identical to that found in TSH, FSH, and LH. The predominant methodologies involve immunoassay directed against the beta subunit. The concentration is expressed in mIU/mL and ng/mL (100 mIU = 8 ng).
80
When can false negative and false positive hCG measurements occur, and what can be done to remedy them?
False negative hCG can occur with urine testing, especially if the urine is dilute. When there is high suspicion, the negative urine hCG is confirmed with a serum hCG test. False positive hCG can occur due to heterophile antibody interference. The measurement can be repeated on a different analyzer, pretreat sample with a heterophile binding reagent, or run serial dilutions.
81
What is "phantom" hCG?
A false-positive hCG result that is a consequence of interference of heterophil antibodies with standard assays for hCG. A diagnosis of “phantom” hCG should be
suspected in patients with a negative urine and a positive serum hCG. Apart from pregnancy, heterophil bridging antibodies in immunometric hCG assays can cause falsely elevated levels in patients with gestational trophoblastic diseases, choriocarcinoma, testicular germ cell tumors
and IgA deficiencies.
82
What is the pattern of hCG levels in a normal gestation, from conception to postpartum?
hCG becomes detectable 6-8 days following conception (about the time of implantation), when levels are 10-50 mIU/mL. The hCG level doubles every 2 days until 1200 mIU/mL at 10 weeks. The level doubles every 3 days between 1200 to 6000 mIU/mL. The level doubles every 4 days above 6000 until it peaks near the end of the first trimester around 10,000 (800 ng/mL). After delivery, hCG normally remains detectable for 2 weeks.
83
When does hCG first become detectable in a normal gestation?
hCG becomes detectable 6-8 days following conception (about the time of implantation), when levels are 10-50 mIU/mL.
84
For how long after delivery is hCG detectable?
After delivery, hCG normally remains detectable for 2 weeks. The disappearance of hCG after term pregnancy is best viewed as triphasic, with rapid, medium, and slow half-lives of 3.6 hrs, 18 hrs, and 53 hrs.
85
What is the most common cause of maternal death in the 1st trimester?
Ectopic pregnancy.
86
In what location do most ectopic pregnancies occur?
>95% occur in the fallopian tube. The remainder occur in the ovary, abdomen, or cornu.
87
Heterotopic pregnancy, in which there is simultaneous intrauterine and ectopic implantation, is rare, but in those treated with fertility-enhancing agents the incidence is __%.
Heterotopic pregnancy, in which there is simultaneous intrauterine and ectopic implantation, is rare, but in those treated with fertility-enhancing agents the incidence is 1%.
88
If a normal hCG dynamic is not seen, this suggests an abnormal pregnancy. Specifically, if serum hCG does not rise at least 66% in 48 hrs, or if the hCG falls during this time, this suggests an ectopic pregnancy or nonviable IUP. However, a normal rate of rise can be seen in __% of ectopics, and an abnormal rate of rise can be seen in __% of normal IUP.
If a normal hCG dynamic is not seen, this suggests an abnormal pregnancy. Specifically, if serum hCG does not rise at least 66% in 48 hrs, or if the hCG falls during this time, this suggests an ectopic pregnancy or nonviable IUP. However, a normal rate of rise can be seen in 15% of ectopics, and an abnormal rate of rise can be seen in 15% of normal IUP.
89
What are some causes of abnormally elevated hCG in pregnancy?
Multiple gestations, polyhydramnios, eclampsia, erythroblastosis fetalis.
90
With transabdominal US, a gestational sac should be detectable when the hCG >__ mIU/mL. When the hCG is >__ mIU/mL, the absence of an IUP detectable by transvaginal US is 90% specific for an ectopic.
With transabdominal US, a gestational sac should be detectable when the hCG >6000 mIU/mL. When the hCG is >1400 mIU/mL, the absence of an IUP detectable by transvaginal US is 90% specific for an ectopic.
91
A serum progesterone level >__ ng/mL virtually assures an IUP. Levels <__ ng/mL are strongly (almost 100%) predictive of an abnormal pregnancy.
A serum progesterone level >25 ng/mL virtually assures an IUP. Levels <5 ng/mL are strongly (almost 100%) predictive of an abnormal pregnancy. However, most patients fall somewhere in between these thresholds.
92
For how long after a normal delivery is hCG detectable? For how long after removal of an ectopic pregnancy is hCG detectable? For how long after spontaneous abortion is hCG detectable? For how long after evacuation of an uncomplicated molar pregnancy is hCG detectable?
2 weeks. 4 weeks. 4-6 weeks. Up to 10 weeks.
93
What is the risk of malignancy for partial moles and for complete moles?
<5% for partial, 20% for complete.
94
After evacuation of a molar pregnancy, hCG levels must be monitored weekly until undetectable for __. It is then measured monthly for __.
After evacuation of a molar pregnancy, hCG levels must be monitored weekly until undetectable for 3 consecutive weeks. It is then measured monthly for 1 year.
95
Uterine choriocarcinomas. __% of cases follow a normal term pregnancy. __% of cases follow a histologically normal spontaneous abortion. __% of cases derive from molar pregnancy.
Uterine choriocarcinomas. 50% of cases follow a normal term pregnancy. 25% of cases follow a histologically normal spontaneous abortion. 25% of cases derive from molar pregnancy.
96
What are the sensitivities of the following for Down syndrome? Triple screen, quad test, integrated screen (and then the addition of US nuchal fold thickness).
Triple screen - 70%, Quad test - 80%. Integrated screen - 85%. Integrated screen combined with US nuchal fold thickness - >90%.
97
What are the components of the following prenatal screening panels? Triple screen. Quad test. Integrated screen.
Triple screen: hCG, AFP, unconjugated estriol. Quad test: the components of the triple screen plus dimeric inhibin A. Integrated screen: PAPP-A and hCG are measured in the 1st trimester; AFP, unconjugated estriol, and dimeric inhibin A are measured in the 2nd trimester; then the data are combined.
98
What is the main reason for better performance of the Quad test over the triple screen for prenatal screening?
The improved performance of the Quad test comes mainly from amelioration of the effects of inaccurate gestational age which plague the triple screen.
99
How do diabetes and smoking affect the values of the prenatal triple screen?
In diabetic mothers, unconjugated estriol and hCG are mildly decreased. In mothers who smoke, unconjugated estriol and hCG are decreased, while AFP is increased.
100
Trisomy 18 (Edwards syndrome) usually shows a characteristic pattern on prenatal triple screen. What is it?
All 3 components (uE, hCG, AFP) are decreased.
101
Trisomy 21 (Down syndrome) shows a characteristic pattern on prenatal triple screen. What is it?
hCG increased, AFP and uE decreased. Also, dimeric inhibin A is increased.
102
Neural tube defects show a characteristic pattern on prenatal triple screen. What is it?
AFP increased, uE decreased, hCG normal. With increased AFP, if an US confirms gestational age and excludes overt anatomic abnormalities, multiple gestations, or fetal demise, then amniocentesis is performed to obtain amniotic fluid for AFP and AChE.
103
2-3% of maternal serum AFPs are elevated on prenatal screening; of these, __% are due to an actual NTD. The sensitivity of MSAFP screening is __%.
2-3% of maternal serum AFPs are elevated on prenatal screening; of these, 10% are due to an actual NTD. The sensitivity of MSAFP screening is 90% - the sensitivity is worse for multiple gestations (30%).
104
AFP is the principal plasma protein in the fetus. It is a fetal specific globulin, synthesized by the fetal yolk sac, gastrointestinal tract, and liver. What factors affect MSAFP level interpretation?
MSAFP rises progressively during the 1st and 2nd trimesters. Adjustments to the MSAFP interpretation are made for maternal weight, race, number of fetuses, and maternal diabetes. Increased maternal weight can have a dilutional effect on the AFP, providing a falsely low value. Levels are much higher in multiple gestations, and much lower in maternal diabetes.
105
MSAFP is >2.5 MOM in >80% of NTDs. How many MOM are considered abnormal in maternal diabetes, and in twin gestations?
>2.0 MOM is considered abnormal in maternal diabetes, and >4.5 MOM is considered abnormal in twin gestations.
106
What conditions are associated with increased MSAFP?
NTDs. Omphalocele and gastroschisis. Renal anomalies. Sacrococcygeal teratoma. Cystic hygroma. Hydrops fetalis. Turner syndrome. Bowel obstruction. Twins. Wrong gestational age. Fetal demise. Fetal-maternal hemorrhage.
107
Maternal serum hCG is ~__x higher than normal in Down syndrome.
Maternal serum hCG is ~2x higher than normal in Down syndrome.
108
Unconjugated estriol is weakly sensitive to Down syndrome, but is a very good indicator of what other 3 conditions?
Trisomy 18 (Edward syndrome). Smith-Lemli-Optiz syndrome. Inherited (fetal) deficiencies of steroid sulfatase.
109
Dimeric inhibin A is a glycoprotein produced by the placenta. In a Down syndrome fetus, DIA is increased to an average of ___ MOM.
Dimeric inhibin A is a glycoprotein produced by the placenta. In a Down syndrome fetus, DIA is increased to an average of 1.9 MOM.
110
How is preterm labor defined?
Regular contractions with associated cervical change prior to 37 weeks.
111
What is fetal fibronectin? Where is it found? How can it be used to determine preterm labor?
Fetal fibronectin is a protein found normally at the placental fetomaternal interface. Cervicovaginal fluid contains fetal fibronectin briefly during early gestation, after which time it is absent until just before labor. The absence of fetal fibronectin has very high NPV and can exclude impending preterm birth. A positive result suggests the onset of preterm labor, but the overall PPV is low.
112
What changes are seen in the following lab values in pregnancy: albumin, total calcium, creatinine, fibrinogen, albumin, BUN, urine protein, amylase, hct, hgb?
Albumin: dec 1 g/dL. Total calcium: dec 10%. Creatinine: dec 0.3 mg/dL. Fibrinogen: inc 1-2 g/L. Albumin: dec 0.5-1 g/dL. BUN: dec 50%. Urine protein: inc to approximately double. Amylase: inc 50-100%. Hct: dec 4-7%. Hgb: dec 1.5-2 g/dL.
113
Out of the following lab values which are the only ones that increase in pregnancy: albumin, total calcium, creatinine, fibrinogen, albumin, BUN, urine protein, amylase, hct, hgb?
Fibrinogen: inc 1-2 g/L. Urine protein: inc to approximately double. Amylase: inc 50-100%.
114
What happens with levels of circulating fatty acids and serum triglycerides in pregnancy?
There are increased circulating fatty acids and serum triglycerides are increased by about 40%. Also, a low-level ketosis is often seen.
115
By what mechanisms are the following lab results seen in pregnancy: Decreased albumin and total protein. Increased transport proteins such as TBG. Increased GFR. Increased insulin resistance.
Decreased albumin and total protein result from hemodilution. Increased transport proteins such as TBG result from increased estrogen. Increased GFR is due to increased blood volume and is reflected in decreased BUN, Cr, and urate. Increased insulin resistance is due to hPL, which has anti-insulin effects similar to GH.
116
When in pregnancy does insulin resistance develop, and what is the cause?
Until the mid-2nd trimester, glucose tolerance actually improves. After that, however, relative insulin resistance emerges, reflected in prolonged elevations in postprandial serum glucose. The most important cause of this is hPL, which has anti-insulin effects similar to GH.
117
How are levels of sodium, potassium, and calcium changed in pregnancy?
Sodium and potassium remain relatively constant throughout pregnancy. Calcium falls slightly throughout pregnancy.
118
What are incidences of antepartum DVT and postpartum DVT in pregnant women?
Antepartum DVT: 1/2000. Postpartum DVT: 1/700. And the incidence of PE is about 1/2500.
119
Which autoimmune conditions are palliated by pregnancy, which are exacerbated by pregnancy, and which have postpartum exacerbations?
RA and Graves disease seem to be palliated by pregnancy. SLE is exacerbated by pregnancy. Graves disease and myasthenia gravis are notorious for postpartum exacerbations.
120
Pregnancy increases the likelihood of SLE flares. The risk is highest in early pregnancy and during puerperium, with relative quiescence in the latter half of pregnancy. A lupus flare may be difficult to distinguish from pregnancy-induced HTN, as the features of HTN, edema, and proteinuria are shared. What lab value can help with this distinction?
Complement levels are low in SLE flare and normal in PIH.
121
Mortality is increased in pregnancy women with SLE, with most deaths occuring as a result of ___.
Mortality is increased in pregnancy women with SLE, with most deaths occuring as a result of pulmonary hemorrhage due to lupus pneumonitis and other complications (transverse myelitis, stroke, corticosteroid complications).
122
In addition to an increased incidence of IUGR and preterm labor, neonates born to mothers with SLE have a risk of congenital heart block. Why?
Antibodies to SS-A and SS-B (Ro and La) are thought to mediate this complication.
123
Is hypothyroidism or hyperthyroidism more common in pregnancy?
Hypothyroidism. In pregnancy there is increased demand placed upon the thyroid due to an estrogen-driven increase in TBG and the TSH-like stimulatory effect of hCG. Patients with borderline thyroid function or those with borderline availability of iodine will be unable to meet these demands.
124
What is the most common cause of hyperthyroidism in pregnancy?
Transient hyperthyroidism of hyperemesis gravidarum, due to high levels of hCG.
125
Acute fatty liver of pregnancy is a rare but serious condition - a medical emergency usually complicated by ___. What is the incidence per 10,000 pregnancies? In which trimester does it usually present? What is the treatment?
Acute fatty liver of pregnancy is a rare but serious condition - a medical emergency usually complicated by DIC. It affects about 1 in 10,000 pregnancies but has a 30% case fatality rate. It usually presents in the third trimester. Immediate delivery is the treatment of choice.
126
What is seen histologically in acute fatty liver of pregnancy?
Widespread microvesicular steatosis, accentuated paracentrally (zone 3), with a paucity of inflammatory activity or hepatocellular necrosis. An oil red O stain on frozen tissue highlights microvesicles.
127
Intrahepatic cholestasis of pregnancy presents with mild jaundice and severe pruritis, usually in the third trimester. What is the most characteristic laboratory finding in this condition?
Serum bile acids (chenodeoxycholic acid, deoxycholic acid, and cholic acid) are increased, often to levels 10x the upper limit of normal.
128
What laboratory investigations are often undertaken following two or more spontaneous abortions?
Parental karyotyping (karyotyping of an abortus is often indicated as well). Endometrial bxs may be obtained to exclude luteal phase defect (endometrial histology that is 2 or more days discrepant with dates). Endometrial culture may be obtained to exclude subclinical infection with U. urealyticum or C. trachomatis. Thyroid function tests. Tests for lupus anticoagulants.
129
What is a normal LAP score in adults? What conditions cause low or high LAP scores?
Normal adults score in the range of 40-120. Low LAP scores are seen in PNH, some MDSs, congenital hypophosphatasia, CML (LAP score is 0-15), and neonatal septicemia (LAP paradoxically decreased). Elevated levels (>180) are seen in leukemoid reactions, non-CML MPDs, glucocorticoid administration and 3rd trimester of pregnancy.
130
What is OCT3/4?
OCT3/4, also known as POU5F1, is a nuclear transcription factor interacting with other
nuclear factors, such as NANOG, SOX2, SALL4, and KLF4, that maintain pluripotency in primordial germ and stem cells. It is expressed very early during embryogenesis
and has an essential role in blastocyst differentiation.
131
How can OCT3/4 be helpful in diagnosis of ovarian germ cell tumors?
OCT3/4 regularly shows positivity in dysgerminoma but can also be expressed in embryonal carcinoma and in some immature neural elements of ovarian teratoma. However, considering that EC is exceptionally rare in the ovary, OCT3/4 can be considered as a selective marker of ovarian dysgerminoma. OCT3/4 is particularly useful in demonstrating the primitive germ cell identity of poorly fixed tissue or microcystic cases, helping to differentiate them from small cell tumors and even struma ovarii. It
also identifies isolated dysgerminoma cells masked by fibrosis or inflammation. Furthermore, it is particularly useful in the identification of the primary tumor in distant metastases.
132
What is SALL4?
SALL4 is a nuclear factor and a member of the family of SALL genes, which are involved in totipotency and are expressed at an early stage of embryogenesis.
133
How can SALL4 be used for malignant ovarian germ cell tumors?
SALL4 is a pluripotency marker strongly expressed by dysgerminomas, embryonal carcinoma, yolk sac (primitive endodermal) tumor, and primitive areas of immature teratoma; consequently, it represents a good, broad marker for MOGCTs. Nevertheless, its expression has also been shown in myeloid leukemia and in some gastric carcinomas.
134
Why is ovarian embryonal carcinoma so rare compared to testicular embryonal carcinoma?
This preference for a testicular location reflects the different histogenesis of testicular and ovarian germ cell tumors, the former originating from primitive germ cells with a malignant character, while the latter mostly have a parthenogenetic origin from postmeiotic or meiotic cells. For these reasons, the presence of EC in the ovary is extremely rare. Hence, although equating ovarian and testicular germ cell tumors may not be totally correct biologically, their morphology and diagnostic IHC are practically similar.
135
What is the most frequent autoimmune disorder associated with ovarian teratomas?
Autoimmune encephalitis due to antibodies against the N-methyl-D-aspartate receptor (anti-NMDAR), a condition that frequently involves temporal lobes and hippocampus.
Its recognition is important, as removal of the ovarian tumor and early immunosuppressive therapy will often improve the outcome, with full recovery or only a residual mild neurologic deficit.
136
Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS) are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. In what populations/conditions is it seen?
Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. They are also seen in neonates, pregnant women, and renal failure.
137
___ testing is performed on all amniotic fluids having elevated AFP concentrations.
AChE testing is performed on all amniotic fluids having elevated AFP concentrations. The odds of having a fetus with a NTD are considerably greater if both the AFP is elevated and the AChE is positive.
138
The incubation period for human papillomavirus after primary exposure is ___.
The incubation period for human papillomavirus after primary exposure is 2-4 months.
139
In benign lesions, HPV DNA is episomal (extra-chromosomal); whereas, in malignant lesions, it is integrated into the host cell DNA. Which 2 viral genes are crucial for subsequent oncogenesis?
E6 and E7 genes.
140
What is Bowenoid papulosis?
A condition caused by HPV 16 that presents in younger males (but can occur in females) as multiple small pearly papules on the anogenital skin. Histologically, it resembles SCCIS, but rarely results in invasive carcinoma. While histologically difficult to distinguish from true SCCIS (Bowen disease and erythroplasia of Queyrat), it is usually easily distinguished clinically.
141
What is a Buschke-Lowenstein tumor?
AKA giant condyloma (accuminatum) of Buschke and Lowenstein. Is a slow-growing, locally destructive verrucous plaque that typically appears on the penis but may occur elsewhere in the anogenital region. M:F = 3.5:1. It most commonly is considered to be a regional variant of verrucous carcinoma, together with oral florid papillomatosis and epithelioma cuniculatum. It is commonly associated with HPV 6 or 11.
142
HEV has a __% fatality rate in pregnancy.
HEV has a 20-30% fatality rate in pregnancy.
143
What hormone is responsible for the relative glucose intolerance of pregnancy?
Human placental lactogen, also called somatomammotropin, has anti-insulin effects and is responsible for the relative glucose intolerance of pregnancy.
144
What is the process for screening for/diagnosing gestational diabetes?
Screening can be performed at the first prenatal visit for high-risk women, where a FPG of 126 mg/dL or random plasma glucose of 200 mg/dL is diagnostic of GDM. In the absence of early screening/testing or if early screening/testing is negative, universal screening is performed at 24 to 28 weeks of gestation. There are numerous approaches from numerous organizations: one step vs. two steps, 75g vs 100g oral glucose load, 2 hr test vs 3 hr test.
145
Women who have been diagnosed with gestational diabetes mellitus should be tested for nongestational diabetes at what time postpartum?
6-12 wks postpartum.
146
What age group is typical for endocervical adenocarcinoma in situ?
Women in their 4th decade, which is 10 to 15 yrs earlier than invasive adenocarcinoma.
147
Endocervical AIS usually involves both endocervical glands and surface epithelium; however, it may be limited to endocervical glands (__%), being a potential source of sampling error, or infrequently, to the surface epithelium (__%).
Endocervical AIS usually involves both endocervical glands and surface epithelium; however, it may be limited to endocervical glands (33%), being a potential source of sampling error, or infrequently, to the surface epithelium (3%).
148
What are subtypes of endocervical AIS?
The 3 most frequent are: endocervical (usual), intestinal, and endometrioid. Others, including tubal, stratified mucin-producing intraepithelial lesion (SMILE), and adenosquamous subtypes are uncommon to rare.
149
Endocervical (usual) AIS is the most frequent subtype of endocervical AIS. It can be pure (__%), or admixed with intestinal (__%) or endometrioid (__%) AIS.
Endocervical (usual) AIS is the most frequent subtype of endocervical AIS. It can be pure (58%), or admixed with intestinal (29%) or endometrioid (16%) AIS.
150
Which has has been associated with a higher rate of progression to invasive endocervical adenocarcinoma, usual (endocervical) subtype of AIS, or intestinal subtype of AIS?
Intestinal AIS.
151
Stratified mucin-producing intraepithelial lesion (SMILE) is an infrequent and relatively recently described variant of endocervical AIS. What are architectural and cytologic features?
Architectural features: stratified epithelium resembling squamous dysplasia at low power; rounded borders at the epithelial-stromal interface; absence of gland formation. Cytologic features: polyhedral to columnar cells; abundant clear or vacuolated cytoplasm throughout the thickness of the epithelium, often showing intracellular mucin creating even spacing of nuclei in middle and lower layers; nuclear hyperchromasia.
152
What are benign glandular lesions of the cervix that can be confused with endocervical AIS?
Reactive/reparative glandular atypia. Mitotically active endocervical glands. Tubal/tuboendometrioid metaplasia. Endometriosis. Mesonephric remnants. Intestinal metaplasia. Arias-Stella reaction. Atypical oxyphilic metaplasia.
153
How can vimentin be useful in the distinction of endocervical tuboendometrioid metaplasia from AIS?
TEM typically exhibits diffuse cytoplasmic staining, while AIS is negative with rare exceptions. Of note, normal endocervical glands may show minimal vimentin expression confined to the basal cytoplasm along with delicate lateral staining of the cell borders.
154
Most cervical adenocarcinomas are HPV related. HPV 16 and 18 are detected with equal prevalence in most subtypes, except in ___ and ___ where HPV 16 is the predominant types, and ___ and ___ which seem to be HPV unrelated.
Most cervical adenocarcinomas are HPV related. HPV 16 and 18 are detected with equal prevalence in most subtypes, except in endometrioid and well-differentiated villoglandular adenocarcinoma where HPV 16 is the predominant types, and minimal deviation adenocarcinoma and mutinous adenocarcinoma with gastric phenotype which seem to be HPV unrelated.
155
What are the 5 histologic criteria for the diagnosis of endometrial intraepithelial neoplasia?
The diagnosis of EIN must meet these 5 criteria in a single fragment: architectural gland crowding, altered cytology relative to background glands, minimum size of 1 mm in a single linear extent, exclusion of adenocarcinoma, exclusion of mimics. The most common benign mimics include reparative endometrium, metaplasia, endometrial breakdown, secretory endometrium, the effects of unopposed estrogen, and polyps.
156
Follicular cervicitis, AKA lymphofollicular cervicitis, pseudolymphoma, or chronic cervicitis. What is seen on Pap smear? What usually causes it?
Variably sized lymphocytes, mature and immature, tingible body macrophages and plasma cells are seen on Pap smear, with Thin-Prep often showing clumps. Follicular cervicitis suggests, but is not pathognomonic of, chlamydial cervicitis (50-75% are associated with Chlamydia). Follicular cervicitis can also occur with noninfectious cervicitis.
157
Biopsy will reveal a high grade lesion in __ to __% of patients with LSIL.
Biopsy will reveal a high grade lesion in 20 to 30% of patients with LSIL.
158
What is the % risk of the following people developing anti-D if exposed: pregnant patient not given RhIG, pregnant patient given RhIG, immunocompromised or trauma patient, healthy patient?
Pregnant patient not given RhIG: 16%. Pregnant patient given RhIG: 0.1%. Immunocompromised or trauma patient: 25-30%. Healthy patient: 85%.
159
The rosette test is performed post-delivery with an Rh neg mother and an Rh pos fetus. How is the test performed?
Maternal sample (potentially containing fetal RBCs) is incubated with anti-D, then washed to remove unbound anti-D. Indicator RBCs (ficin-treated R2R2 cells) are added, which form agglutinates (rosettes) around fetal D-pos cells if they are present.
160
The rosette test is performed post-delivery with an Rh neg mother and an Rh pos fetus. How is the test interpreted?
If ficin-treated R2R2 indicator cells are used, up to 1 rosette in 3 microscopic fields is negative. If untreated indicator cells and an enhancing medium is used, up to 6 rosettes per 5 microscopic fields is negative.
161
The rosette test is performed post-delivery with an Rh neg mother and an Rh pos fetus. What is done if the test is negative or positive?
If the rosette test is negative, one standard dose of RhIG is given. If the rosette test is positive, the Kleihauer-Betke test (or flow cytometry) is performed to determine the volume of fetal cells and the dose of RhIG needed.
162
The G antigen is an antigen present on any RBC that carries either D or C antigen. Should pregnant patients with anti-G receive RhIG prophylaxis?
Patients with anti-G do not have anti-D and should receive RhIG prophylaxis if pregnant to prevent immunization to D when indicated.
163
The G antigen is an antigen present on any RBC that carries either D or C antigen. In what 2 situations can the presence of an anti-G antibody cause clinical confusion?
It can give the appearance of an Rh-negative person having anti-D after being transfused with D-C+ blood. It can give the appearance of an Rh-negative mother developing anti-D after delivering a D-C+ child.
164
In Pap smears, what is the appearance of tumors derived from endometrium or endocervix vs. tumors derived from fallopian tube or ovary?
Tumors cells derived from fallopian tube, ovary, and rarely, other intra-abdominal sites can occasionally be detected in cervicovaginal cytology specimens. These cells appear as atypical or neoplastic glandular cells in a clean background. They usually present as three-dimensional tubular, spherical, or papillary groups. One symptom that is quite characteristic of fallopian tube tumors is watery discharge. In contrast, tumors derived from endometrium or endocervix typically show greater numbers of neoplastic cells in a bloody or necrotic background, and evidence of a co-existing SIL may be present.
165
Pseudokoilocytes are squamous cells with perinuclear halos that are small and do not have sharply defined dense edges, and with normal nuclei. In what conditions are pseudokoilocytes seen in Pap smears?
Pseudokoilocytes can be seen in conditions such as inflammation (Trichomonas and Chlamydia), pregnancy (navicular cells), androgenic effect, and immature squamous metaplasia.
166
DDx of hyperchromatic crowded groups of small cells on Pap smears.
HCGs may represent benign epithelial cells such as endometrial cells, endocervical cells, tubal metaplastic cells, or basal cells of severe atrophy. However, malignant lesions such as carcinoma in situ, invasive squamous cell carcinoma, and invasive or in situ adenocarcinoma may also shed HCGs.
167
The corpus luteum of pregnancy and the placenta produce progesterone, resulting in a predominance of intermediate squamous cells seen on Pap smears. Navicular cells are boat-shaped intermediate cells containing abundant glycogen. Cytolysis may be marked during pregnancy. What clinical situations result in: a maturation shift towards mature squamous cells, a maturation shift towards a lower maturation, i.e., an atrophic pattern, and the presence of anucleated squames?
A maturation shift towards mature squamous cells may indicate fetal distress. A maturation shift towards a lower maturation, i.e., an atrophic pattern suggests progesterone deficiency and may indicate intrauterine fetal demise. The presence of anucleated squames may indicate rupture of fetal membranes.
168
Postpartum Pap smears show a predominantly atrophic pattern in __% of lactating and __% of nonlactating women.
Postpartum Pap smears show a predominantly atrophic pattern in 66% of lactating and 33% of nonlactating women.
169
What are the mutation rates of MSH2, MSH6, MLH1, PMS2, and EPCAM in Lynch syndrome?
MSH2 - 40%. MSH6 - 7-10%. MLH1 - 50%. PMS2 - less than 5%. EPCAM - 1-3%.
170
What is the typical IHC staining pattern for MSH2, MSH6, MLH1, and PMS2 with gene mutation/silencing of EPCAM?
MSH2-, MSH6-, MLH1+, PMS2+.
171
What 4 hormones have the same alpha subunit?
TSH, FSH, LH, and hCG. The first 3 are synthesized by the anterior pituitary, while hCG is synthesized by placental trophoblastic cells during pregnancy. The unique beta subunit of all four protein hormones provides biological specificity. The beta subunit of hCG is closely related to the beta subunit of LH, and both hormones bind to the LH receptor, which reflects the physiologic role of both hormones
172
Activating mutations of the ___ oncogene are
seen in approximately 50% of invasive mucinous
ovarian cancers, but they are relatively rare in high grade
serous, clear cell, and endometrioid ovarian cancers.
Activating mutations of the KRAS oncogene are
seen in approximately 50% of invasive mucinous
ovarian cancers, but they are relatively rare in high grade
serous, clear cell, and endometrioid ovarian cancers. Missense mutations are commonly seen in codons 12, 13, and 61. In addition, most mucinous tumors of low malignant potential also harbor KRAS mutations, suggesting a possible common pathway of tumorigenesis.
173
What is MUTYH-associated polyposis AKA MYH-associated polyposis AKA MAP?
A condition caused by biallelic pathogenic germline variants in MUTYH characterized by a greatly increased lifetime risk of colorectal cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals in the absence of polyposis. The colonic phenotype is similar to AFAP but the terminology "FAP/AFAP caused by MYH mutations" is not correct. Extracolonic manifestations include duodenal adenomas/carcinomas, ovarian CA, bladder CA, skin CA.
