Germ Cell Tumors of the Ovary

Genetics

Mature teratomas are diploid, contain a normal 46,XX karyotype, and are homozygous for polymorphic markers, supporting a parthenogenetic origin from a single germ cell. Most mature teratomas show evidence of chromosomal recombination, which indicates that the lesional cells arise from meiotic oocytes or mature postmeiotic ova. Apparently, mature teratomas can originate at various stages of gametogenesis, with most resulting from meiotic errors.

Clinical Presentation

Approximately 20% of patients are asymptomatic at the time of discovery. The most frequent symptom is lower abdominal pain. Acute abdominal pain is uncommon, and 5% to 10% of mature teratomas have been reported to be associated with ovarian torsion. Rupture of ovarian mature teratoma occurs in less than 3% of all cases. Peritoneal lipogranulomas and melanosis have been rarely described in association with ruptured mature teratomas.

Women with ovarian teratomas may rarely develop anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis, which has been recognized as an uncommon but severe neurologic disorder, characterized by psychosis, memory loss, decreased consciousness, seizures, autonomic dysfunction, and hypoventilation. According to the largest study available, in 60% of patients affected by NMDAR encephalitis, tumors were detected following the onset of neurologic symptoms, of which 90% were teratomas; of these, approximately two-thirds were mature teratomas and one-third were immature teratomas. The median age for all patients was 23 years. The condition appears to be a sort of paraneoplastic autoimmunity and has good response to immunosuppressive therapy.

Most ovarian mature teratomas can be diagnosed by ultrasonography and are characterized by echogenic sebaceous material and calcifications. The most common ultrasound appearance is that of an echogenic tubercle, with a cystic echo. Mature teratomas often do not appear cystic on ultrasound, which may lead to the interpretation of a solid neoplasm concerning for malignancy. The diagnosis of mature teratoma is generally made without difficulty by computed tomography (CT) and magnetic resonance imaging (MRI) because both methods are highly sensitive for fat attenuation, which is diagnostic for mature teratoma in the ovary.

Gross Examination

Approximately 10% of benign cystic teratomas are bilateral. Right-sided tumors are slightly more common than left-sided tumors. Multiple mature teratomas in a single ovary have been described in a few patients, and those were almost always also bilateral. The size ranges from 5 to 10 cm in 50% to 60% of mature teratomas, with a median diameter of 6 cm, but up to 10% may be larger than 15 cm.

The gross picture can be typical or extremely variable. The most classic appearance of a mature teratoma is that of a smooth-lined cyst containing a mixture of hair and oily brown to tan sebaceous material ( Fig. 26.2 ). However, the cyst contents may appear hemorrhagic, similar to an endometriotic cyst, or the tumor may be multicystic. A raised protuberance, designated as a Rokitansky tubercle containing adipose tissue, skin appendages, and overlying skin, is often present ( Fig. 26.3 ). This area tends to display the most tissue heterogeneity and often is the only focus at which tissues other than squamous epithelium and skin appendages are found microscopically. As a rule, the more complex the lesion, the more likely other elements will be detected. Teeth are present in a minority of these but are dramatic ( Fig. 26.4 ). A case of a giant mature teratoma has been reported that weighed 10 kg and contained more than 300 teeth.

Some mature teratomas may pose questions at the time of gross examination, as exemplified by the following variants.

Fetiform Teratoma (Homunculus)

A rare variant of mature teratoma, with only about 25 cases reported to date, was found to have the appearance of a malformed fetus on gross examination, termed a homunculus or fetiform teratoma ( Fig. 26.5 ). The caudal portion, including lower extremities with varying degrees of limb formation, is better developed than the cephalic portion, and visceral tissues are rarely encountered. The homunculus should not have a well-developed segmented axial skeleton, which is considered to be too developed for a teratoma.

These tumors may initially be mistaken for ovarian ectopic pregnancies but are recognized by the absence of placental tissue and umbilical cord. The embryo or fetus of an ectopic pregnancy will display less mature tissues than those seen in a fetiform teratoma; these have been reported to be composed of completely mature, adult-like tissues. Another extremely rare entity that may be confused with a fetiform teratoma is termed fetus in fetu , wherein a leftover twin of the patient has been ensconced in the pelvic cavity for years. Because these are not typically in the ovary, they may be easily distinguished.

Diagnostic Criteria

In keeping with the wide diversity of tissues that may be seen grossly, an even wider range of variation can be appreciated on histologic examination of mature teratomas, being limited only by the constraints on human tissue differentiation. Virtually any structure observed in the developing or adult human body may be encountered, as depicted in Figs. 26.6 and 26.7 . The tissues present in a mature teratoma can be categorized based on the corresponding germ layer:

Questionable Immaturity of Neural Tissues

At least three categories of neural tissue may lead the pathologist to consider the possibility of immature teratoma, which includes mature neuroepithelium, differentiating neural tissue, and minor foci of immaturity. Details on the features of these findings are presented later (see “ Differential Diagnosis ”).

Burned-Out Teratoma

Sometimes, rupture of the cyst wall in a teratoma may lead to a prominent inflammatory reaction with abundant histiocytes, not leaving much of the teratomatous tissue behind. This is a process similar to what is more frequently seen in the ovary and termed burned-out endometrioma. Histiocytic giant cells are often seen engulfing keratin ( Fig. 26.8 ). Abundant keratin debris and scattered hair follicles are clues to the diagnosis. Even a careful search may not reveal viable teratomatous cells.

Meningothelial Proliferations

These were once thought to be rare in mature teratomas but have been shown to be more frequent in a recent publication. The histologic appearance is subtle, demonstrating a network of slitlike interanastomosing channels lined with cuboidal cells arranged in dense collagen bundles.

Cerebellum

Although mature neural tissue is a common component of teratomas, the presence of differentiated cerebellum is rare, with fewer than 15 cases reported in the literature to date. It recapitulates the fetal and adult cerebellum, with most being composed of molecular, Purkinje cell, and internal granular layers. One-third of cases also have an external granular layer; this is a progenitor cell layer that decreases after birth and totally disappears by the second postnatal year.

Immunohistochemistry

In general, the diagnosis of mature teratoma is made histologically without difficulty, and the use of routine immunohistochemistry is not necessary. In a small proportion of cases, immunostains may be used in the setting of immature teratoma, monodermal teratomas, and somatic-type malignancies.

Differential Diagnosis

Most ovarian tumors that appear to be mature teratomas by clinical, imaging, and gross features are mature teratomas. However, the pathologist has an essential role in examining these lesions for the presence of associated malignant tumors, malignant germ cell tumors, and somatic-type tumors. Even though both categories combined are seen in association with less than 5% of all mature teratomas, their identification is of paramount importance for management and prognosis.

Proposed Report Wording

• Mature teratoma

• Mature cystic teratoma

Management and Outcome

The management of a mature teratoma is influenced by the risk of malignancy—a function of the age of the patient—and the desire to minimize surgical trauma. Typically, cystectomy is performed to preserve ovarian function; however, follow-up is necessary to exclude recurrence, which occurs in 4% to 5% of cases and, because the latter is typically asymptomatic, periodic ultrasound examination is recommended. Multiple mature teratomas in a single ovary and bilateral teratomas may have a greater risk for recurrence. Laparoscopy is acceptable, provided that strict guidelines are followed that pertain to any ovarian mass. For younger patients, preoperative serologic studies to exclude a malignant germ cell tumor are indicated, and every patient must be made aware of the small risk of malignancy, which would necessitate a second surgical procedure.

Monodermal and Malignant Variants of (Mature) Teratoma

The monodermal variants of mature teratoma include those containing thyroid tissue (e.g., struma ovarii, strumal carcinoid, malignant struma), carcinoid tumors, and other rare proliferations. The great majority of monodermal teratomas are strumas, which correspond to about 2% of all ovarian teratomas and less than 1% of all ovarian neoplasms. Somatic-type malignancy is a rare occurrence in ovarian mature teratoma and occurs in approximately 1% to 2% of tumors. The great majority of these tumors are epithelial and, of these, approximately 65% are squamous cell carcinomas. All tumors in this category are composed of adult-type somatic tissues and arise from proliferation of a teratomatous cell, as has been shown by some molecular studies.

Struma Ovarii

Struma ovarii are monodermal mature teratomas exclusively composed of thyroid tissue or mature teratomas containing a significant representation of thyroid component that can be benign or malignant. To be classified as struma ovarii, the tumor has to meet at least one of the following criteria ( Box 26.2 ) :

• 1.

  Tumor composed exclusively of thyroid tissue

• 2.

  Mature teratoma with greater than 50% thyroid tissue, grossly visible or not

• 3.

  Mature teratoma with less than 50% thyroid tissue, grossly visible

• 4.

  Any mature teratoma with malignant thyroid tissue, independent of extent or gross appearance, specifically termed malignant struma ovarii

Box 26.2

Classification of Struma Ovarii

Benign Struma Ovarii

• Tumor composed exclusively of benign thyroid tissue

• Mature teratoma with >50% benign thyroid tissue, grossly visible or not

• Mature teratoma with <50% benign thyroid tissue that is grossly visible

Malignant Struma Ovarii

• Any mature teratoma with malignant thyroid tissue, independent of extent or gross appearance

• Subtypes:

  • 1.

    Histologically malignant struma ovarii resembling papillary thyroid carcinoma

  • 2.

    Proliferative (malignant) struma ovarii

  • 3.

    Highly differentiated follicular carcinoma of ovarian derivation

  • 4.

    Histologically malignant struma ovarii with high-grade features

The great majority of struma ovarii are composed of conventional benign thyroid tissue. Malignant struma ovarii usually show histologic features of thyroid follicular adenoma or papillary carcinoma and are discussed in the next section.

Approximately 7% of mature teratomas have microscopic thyroid tissue; but less than 2% meet the criteria for struma ovarii. Although struma is the most common of ovarian monodermal teratomas, in two large cohorts of patients with ovarian tumors from single institutions, only 34 of 10,442 (0.3%) and 16 of 1501 (1%) were struma ovarii. Of all struma ovarii, approximately 60% are entirely composed of thyroid and 40% are associated with other teratomatous components.

Tumors other than mature teratomas that have been seen in association with struma ovarii are Brenner tumor, fibrothecoma, and serous and mucinous cystadenoma. These components may be considered as independent epithelial tumors (somatic origin) or as part of the teratoma spectrum (germ cell origin).

Clinical Presentation

Struma ovarii occurs most frequently in the fifth decade, with a median age of about 45 years for benign struma. Extragonadal cases of struma have been reported in the fallopian tube (struma salpingii), uterine cervix (struma uteri), and vaginal wall, and even in the testis.

Unlike most classic mature teratomas, most struma ovarii are not diagnosed preoperatively, inasmuch as the ultrasound appearance is not as specific, depicting it as a heterogeneous solid or cystic mass. Less than 15% of struma ovarii are recognized as such by imaging studies; the remaining are mistaken for other benign processes, such as mature teratomas without struma, endometriomas, or other benign cysts. Almost 30% of strumas in general can show features that may be misleading for malignancy. Clinicians are advised to proceed cautiously if a suspected teratoma contains a complex ultrasonographic picture because a benign struma may be the cause.

At least 40% of strumas are asymptomatic and are recognized as an incidental finding; symptomatic patients most often report lower abdominal pain. Approximately 8% have abnormal vaginal bleeding, which is likely to result from luteinization of surrounding ovarian stromal cells that is sometimes prominent in these neoplasms. Infertility has been rarely reported.

Clinical evidence of hyperthyroidism in benign struma is uncommon. Two case series with 34 and 16 patients have reported no patients with symptoms of hyperthyroidism. Thyroid hormone serology is typically not performed because patients do not report suspicious symptoms. Thyrotoxicosis (Graves' disease) is rare and occurs in benign and malignant struma ovarii.

Patients rarely develop hypothyroidism. Five cases of mature teratoma (with thyroid tissue not qualifying for struma ovarii) and five cases of struma ovarii with features of Hashimoto thyroiditis have been reported in patients who developed hypothyroidism. Most cases were categorized as ectopic Hashimoto thyroiditis due to the association of ectopic thyroid tissue with lymphocytic infiltration and, in three cases where this was lacking, by hypothyroidism, with positive antibodies as measured by blood tests. A single case of hyperemesis gravidarum has been reported in a patient with struma ovarii.

Mildly elevated serum cancer antigen 125 (CA-125) levels are found in up to 30% of patients with struma ovarii in general. However, in the presence of ascites, this level may be in the hundreds to low thousands. This measurement in not useful in the distinction between benign and malignant struma.

The triad of pleural effusion, ascites, and ovarian fibroma defines Meigs syndrome. The same presentation when encountered with other benign ovarian tumors is typically referred to as pseudo-Meigs syndrome. The development of this syndrome has been reported in association with at least 20 patients with struma ovarii. They tended to have significant moderate to marked elevation of serum CA-125 levels. A review of 11 patients has revealed that most are postmenopausal (73%). The average reported size of the tumor was 10 cm, with 9% rate bilaterally, and right-sided predominance. Therefore, strumas associated with pseudo-Meigs syndrome are slightly larger (10 cm vs. 9 cm) and more often bilateral (9% vs. 1%) than strumas in general. One-third of patients had hypothyroidism or hyperthyroidism, a rate also remarkably higher than that of conventional strumas (36% vs. 5%). Interestingly, an additional 10 cases of struma ovarii, with high-volume ascites without hydrothorax (and therefore not qualifying for pseudo-Meigs syndrome), have been reported and had similar features, including frequent postmenopausal status and large size. Unlike regular strumas, patients in both scenarios are almost always symptomatic, and the tumor is almost always suspected to be a malignant tumor preoperatively.

Gross Examination

Like all specialized patterns of differentiation, these tumors are classically unilateral; less than 1% of struma ovarii are reported to be bilateral. The frequency of a contralateral mature teratoma is approximately 7%, slightly lower than teratomas in general. The mean size is 9 cm.

On gross examination, if visible, the thyroid component has the characteristic appearance of normal thyroid. It appears as greenish brown, fleshy slightly gelatinous tissue ( Fig. 26.10 ).

Most struma ovarii are solid or solid-cystic, whether or not associated with a mature teratoma. A small proportion of tumors, approximately 5%, may appear as serous cystadenomas that form a thin-walled multiloculated cyst with serous fluid; these can be referred to as cystic struma ovarii. The material contained in these cysts may be green or brown-tinged, which provides a clue to the diagnosis.

Diagnostic Criteria

The diagnosis of struma ovarii is usually straightforward—that is, macro- and microfollicles contain colloid, closely resembling the thyroid gland ( Fig. 26.11 ). Variations in histologic appearance include inconspicuous pseudotubular and cordlike arrangements and solid patterns lacking colloid ( Fig. 26.12 ). Most cases have scant stroma but in some cases the presence of fibromatous stroma and less conspicuous follicle formation may mimic an adenofibroma or Brenner tumor ( Fig. 26.13 ). Some are associated with abundant edematous stroma. Ovarian stromal luteinization can be seen.

Follicular cells can be flat, cuboidal, or columnar. The cytoplasm is usually pale or eosinophilic. Some cases show abundant eosinophilic cytoplasm, characteristic of Hurthle cells (see Fig. 26.12 ). Clear cell changes can be seen but a predominant clear cell pattern is uncommon. Nuclei are uniform, round to oval, and show evenly distributed chromatin and smooth nuclear membranes. Nucleoli are small. Endocrine-type atypia may be focally present in some cases (see Fig. 26.13 ), characterized primarily by nuclear enlargement, and is not indicative of malignancy ( Fig. 26.14 ). The typical struma ovarii contains rare to a few mitoses.

Benign struma should not have any architectural or cytologic features of papillary thyroid carcinoma or proliferative changes that would resemble follicular adenoma in the thyroid gland, which would be suggestive of malignant struma.

Immunohistochemistry

Struma cells are positive for thyroid transcription factor 1 (TTF-1) and thyroglobulin; the former has great sensitivity and specificity and is sufficient to confirm the diagnosis. Lung tissue is almost never seen in mature teratomas, and the only other lesion that could be positive for TTF-1 in the ovary is metastasis from a lung tumor, excluding rare cases of primary ovarian carcinomas that have shown TTF-1 staining. If cells showing positive nuclear staining for TTF-1 are also positive for neuroendocrine markers, such as chromogranin and synaptophysin, the best interpretation would be strumal carcinoid (discussed later in the chapter).

Differential Diagnosis

The differential diagnosis of struma ovarii includes carcinoid, sex cord–stromal tumors, epithelial tumors, and metastasis, particularly if colloid and typical follicular arrangements are inconspicuous, and the epithelial cells are arranged in tubules, cords, and microfollicles devoid of colloid. Another pitfall is struma ovarii with a predominance of clear cells or cells with abundant eosinophilic cytoplasm. The key to diagnosis is a high index of suspicion, particularly if other components of teratoma are present. In difficult cases, areas with a more characteristic appearance of thyroid tissue are present in most cases. Immunostaining for TTF-1 and thyroglobulin is positive in struma ovarii and strumal carcinoid and negative in other differentials, greatly facilitating the diagnosis. Below is a list of tumors that may have a histologic appearance similar to struma ovarii.

Proposed Report Wording

• 1.

  Monodermal teratomas composed exclusively of benign thyroid tissue—struma ovarii

• 2.

  Mature teratomas containing thyroid tissue that meet criteria for struma ovarii—mature teratoma with struma ovarii or struma ovarii arising in association with mature teratoma

• 3.

  Mature teratomas containing thyroid tissue but that do not meet criteria for struma ovarii—mature teratoma with focal thyroid differentiation

• 4.

  Any struma ovarii that is entirely cystic simulating serous cystadenoma—cystic struma ovarii

Management and Outcome

Struma ovarii is a benign neoplasm in the great majority of cases and by definition does not spread beyond the ovary. If it does, it must be classified as malignant struma, even when it has an innocuous, non-neoplastic appearance. Proliferative strumas are also regarded as potentially malignant, independent of the presence or absence of extraovarian spread. High-risk features in struma ovarii that could correlate with aggressive behavior are large size, abundant adhesions, and ovarian serosal defects.

Struma ovarii associated with high-volume ascites, with or without pseudo-Meigs syndrome, achieve complete remission of ascites, hydrothorax, and elevated CA-125 levels following surgical resection of the ovarian mass. No recurrences have been reported and therefore it appears that associated pseudo-Meigs syndrome does not place struma ovarii in a high-risk category for malignancy. Of note, few cases of pseudo-Meigs syndrome have been associated with malignant struma ovarii.

Clinical Presentation

The median age for patients with malignant struma ovarii does not seem to differ significantly from patients with benign struma, reported to be 41 years for the former and 45 years for the latter.

Struma ovarii is defined as clinically malignant if it meets one of the following criteria, regardless of whether it is histologically benign or malignant :

• 1.

  Thyroid tissue infiltrating ovarian serosa with tumor on the ovarian surface

• 2.

  Extragonadal spread at presentation

• 3.

  Recurrence after initial surgery

Almost 50% of patients with malignant struma present with abdominal swelling, pain, or a mass. In about 40% of cases, malignant struma is an incidental finding. One-third of the patients may have vague signs and symptoms of hyperthyroidism, which is typically not severe enough to prompt clinical and laboratorial investigation prior to tumor diagnosis. Patients with clinical hyperthyroidism have a tendency to have large tumors that are clinically malignant in the absence of malignant histology. Thyrotoxicosis (Graves' disease) is rare and occurs in benign and malignant struma ovarii. Of all patients 7% report abnormal vaginal bleeding. High-volume ascites or hydrothorax are seen in less than 10% and 5% of patients, respectively. Malignant struma presenting with metastatic bone disease and an occult primary has been reported in two case reports and, although very rare, an ovarian origin should be considered when metastatic thyroid carcinoma is detected in the absence of a thyroid tumor.

Gross Examination

The gross appearance of the malignant struma will vary depending on the histologic subtype and extent of the malignant component. Many are undetectable by gross examination showing the characteristic appearance of normal thyroid, seen as a greenish brown, fleshy, slightly gelatinous tissue, with or without associated mature teratoma (see Fig. 26.10 ). Large areas of papillary thyroid-type carcinoma may appear more firm and fibrotic.

Most areas of malignant struma are solid; the average diameter is 12 cm, including any associated teratoma ( Fig. 26.15 ). Of these malignant strumas, 7% are bilateral and an additional 13% have a contralateral teratoma without struma. Almost 50% of malignant strumas are pure and 50% are associated with other teratomatous components.

Any struma ovarii infiltrating the ovarian serosa and involving the ovarian surface is considered malignant; therefore, the ovarian surface should be carefully inked and well sampled in any suspected case of struma ovarii encountered during the gross examination. Surface ovarian adhesions have also been associated with an increased risk for extragonadal spread and recurrence in struma ovarii. They should be documented and sampled, whenever present.

Diagnostic Criteria

Most malignant struma ovarii have histopathologic features of papillary thyroid carcinoma or follicular adenoma; it is not possible to predict which of these will have malignant behavior. Very rarely, struma ovarii with the appearance of normal thyroid tissue spreads to extragonadal locations and is then considered malignant struma. Finally, few cases with histopathologic features of thyroid carcinoma contain high-grade foci; this is the only category that is known consistently to behave aggressively.

Histologically Malignant Struma Ovarii Resembling Papillary Thyroid Carcinoma

This displays typical nuclear features of papillary thyroid carcinoma, including nuclear enlargement, chromatin clearing (referred to as Orphan Annie eyes), nuclear grooves, and nuclear pseudoinclusions ( Figs. 26.16 to 26.18 ). The diagnosis is straightforward when the tumor has a papillary architecture characteristic of the classic variant (see Fig. 26.16A ). Cases with features of a follicular variant of papillary thyroid carcinoma are also encountered and, when considered, should be diagnosed with strict cytologic criteria, which are the same as those applied in thyroid pathology, involving at least 50% of tumor cells (see Figs. 26.17 and 26.18 ). Most cases in this category do not spread beyond the ovary and do not necessarily equate to malignant behavior.

Highly Differentiated Follicular Carcinoma of Ovarian Derivation

Highly differentiated follicular carcinoma of ovarian derivation (HDFCO) are struma ovarii resembling non-neoplastic thyroid tissue that spreads to extragonadal locations, with an innocuous appearance, similar to non-neoplastic eutopic thyroid tissue in ovarian and extraovarian sites ( Fig. 26.19 ). The latter, by definition, must be documented concurrently or following the initial primary as a fundamental criterion for this diagnosis.

Immunohistochemistry and Genetics

Malignant struma ovarii stain positive for thyroglobulin and TTF-1, even when poorly differentiated. Malignant struma ovarii with histologic features of papillary thyroid carcinoma are usually positive for CK19, galectin-3, and HMBE-1, as in the thyroid gland (see Figs. 26.16 to 26.18 ). Likewise, malignant cases may harbor mutations in BRAF , HRAS, and KRAS that are not detected in benign struma. Malignant struma with the histologic appearance of a follicular variant of papillary thyroid carcinoma tend to show RET gene rearrangements. Based on these findings, the development of carcinoma in struma ovary appears to share similar pathogenic mechanisms with the thyroid gland, because most mutations have been shown to occur in both locations, with a few exceptions.

Differential Diagnosis

The main role of the pathologist is to distinguish benign and malignant struma ovarii by recognizing all the histologic patterns that form the spectrum of malignancy in stroma ovarii (as discussed earlier). Otherwise, the differential diagnoses will depend on the histologic appearance of the struma in question. In all the scenarios outlined below, immunostaining for TTF-1 is very helpful because it is positive in any struma ovarii, benign or malignant, and is negative in all other differentials, with the exception of strumal carcinoid and metastatic lung carcinoid.

Because the ovary is a common site for metastases, it is important to search for areas with a more characteristic appearance of thyroid tissue or other teratomatous components to characterize the tumor as primary in the ovary. Of interest, metastases of papillary thyroid carcinoma to the ovary have been rarely reported, and synchronous papillary carcinoma in the thyroid gland and struma ovarii have also been reported. Differentials include those that resemble the following.

Proposed Report Wording

• 1.

  Malignant struma resembling papillary thyroid carcinoma

  • a.

    Malignant struma ovarii (classical papillary thyroid-type carcinoma). See comment.

  • b.

    Malignant struma ovarii (follicular variant of papillary thyroid-type carcinoma). See comment.

• 2.

  Proliferative struma ovarii

  Comment: These neoplasms have a low malignant potential. The biologic behavior cannot be predicted on the basis of histologic examination in the absence of extraovarian disease. Prolonged follow-up is advised as recurrences may occur years after the initial diagnosis.

• 3.

  Highly differentiated follicular carcinoma of ovarian derivation:

  Malignant struma ovarii consistent with highly differentiated follicular carcinoma of ovarian derivation.

  Comment: The diagnosis was based on the presence of ovarian surface involvement and/or extraovarian disease. These neoplasms tend to have an indolent clinical course.

• 4.

  Malignant struma with high-grade features

  • a.

    Malignant struma ovarii with high-grade features (poorly differentiated thyroid-type carcinoma). See comment.

  • b.

    Malignant struma ovarii with high-grade features (anaplastic thyroid-type carcinoma). See comment.

  Comment: These neoplasms tend to behave aggressively similar to the counterparts in the thyroid gland.

In all these, it is important to include the following:

• 1.

  Size of malignant struma component

• 2.

  Presence or absence of benign struma and other teratomatous elements

• 3.

  Percentage of malignant struma component in comparison with benign struma, if present

• 4.

  Presence or absence of ovarian surface involvement or surface adhesions

• 5.

  Presence or absence of lymphovascular invasion

Management and Outcome

Most cases with malignant features by histology do not progress to extraovarian disease, recurrence, or metastasis. ^a

a References .

Likewise, proliferative strumas, and even strumas with non-neoplastic thyroid histology, may present with extraovarian disease or have recurrences. ^b

b References .

No histologic features are predictive of biologic behavior. The only exceptions are struma ovarii with high-grade features, which are exceedingly rare and have been shown consistently to behave in an aggressive fashion.

The size of the struma component is of prognostic significance, regardless of histology. Strumas measuring less than 4 cm do not seem to recur; clinically malignant strumas are larger and have a greater percentage of malignant struma than those that are clinically benign. Surface adhesions or rents are associated with extraovarian spread and recurrences. More than 1 L of ascites has been shown to be an adverse prognostic indicator in one cohort. Remarkably, about 30 case reports have described benign struma ovarii presenting with large-volume ascites, with or without pseudo-Meigs syndrome, and not a single documented case of extraovarian disease or recurrence, which brings into question the significance of large-volume ascites as an adverse sign. Rare reports of pseudo-Meigs syndrome have been associated with malignant struma ovarii.

Approximately 18% of malignant strumas in general have ovarian surface involvement or extraovarian spread at diagnosis, usually in the pelvic and abdominal peritoneum. Distant metastases are rare and tend to involve bone, particularly the spine. Of clinically malignant tumors, 31% were histologically malignant, 65% were histologically proliferative, and 4% were histologically benign, according to the most recent and largest case series. The probability of a malignant clinical course was 30% overall for any histology in another case series by a different group. Overall 10- and 25-year survivals are 89% and 84%, respectively. The initial stage does not affect overall survival. Recurrences tend to be late and average 4 years after initial diagnosis; survival rates are around 85%, even for recurrent tumors. Death also occurs late, with a mean interval from the initial diagnosis of 20 years for stage IA tumors and 10 years for higher stage tumors.

The main exception to these observations are struma ovarii with high-grade features, which are exceedingly rare and have been shown to behave frequently in a malignant fashion. Extraovarian spread is typically present at the time of diagnosis. Death usually occurs months to a few years after the initial diagnosis.

Almost 90% of cases of HDFCO have peritoneal spread at the time of initial diagnosis. About 20% of patients develop distant metastases, usually to liver and bone, and rarely o the lung. Even in the presence of peritoneal and distant spread, the prognosis is excellent, with no documented deaths.

As noted earlier, along with struma ovarii resembling papillary thyroid carcinoma, proliferative strumas have a similarly low but definite possibility of recurrence and therefore would be best regarded as being of low malignant potential. In the future, we may consider classifying struma ovarii akin to epithelial ovarian tumors in three categories—benign, borderline or of low malignant potential (LMP), and malignant. Judging from the evidence provided by recent publications, only malignant struma ovarii with high-grade features have definite clinical characteristics of a malignant process. Therefore, even struma ovarii with histologic features of papillary thyroid carcinoma may be placed in the LMP category in case this classification scheme is ever adopted.

In the past, the presence of small foci of benign-looking thyroid tissue in the peritoneum of patients with struma ovarii was termed strumosis (see Fig. 26.19 ). However, studies have shown that these patients can progress to have multiple recurrences; therefore, this term is to be avoided.

There is no standard management scheme for malignant struma ovarii. It appears that good local control is achieved by surgical removal of the primary ovarian tumor and of pelvic and peritoneal tumor deposits, if present. Late recurrences require long-term follow-up, of at least a 10-year duration. Stage IA tumors may benefit from follow-up with iodine-131 ( ¹³¹ I) body-wide uptake scans. Radioactive iodine therapy may be considered in higher stage tumors, in which case total thyroidectomy may be considered as an adjunct for treatment. Patients with malignant struma ovarii with high-grade features may benefit from chemotherapy and radioactive iodine therapy, independent of stage. Radiotherapy has been used successfully for bone metastasis.

Insular Carcinoids

Background and Clinical Presentation

Insular carcinoids resemble midgut carcinoids and are the most common pattern in the ovary, corresponding to approximately 50% of primary ovarian carcinoid tumors (see Table 26.2 ). Most patients are postmenopausal or perimenopausal. At least one-third to two-fifths are associated with carcinoid syndrome, which occurs more frequently in tumors larger than 7 cm and in patients older than 50 years. Unlike intestinal carcinoids, liver metastases are not a requirement for the development of carcinoid syndrome. Insular carcinoids are not traditionally associated with peptide YY (PPY) production and constipation. However, one case has been described for which this manifestation was associated with a mixed insular and trabecular ovarian carcinoid.

Gross Examination

Tumors are almost invariably unilateral. They present as firm, solid, homogeneous, gray to yellow masses, often in association with mature teratoma or mucinous tumors, that can also be found in the contralateral ovary ( Fig. 26.20 ).

Diagnostic Criteria

Histologically, two distinguishing features characterize insular carcinoids: architecture and cytology. They are composed of large islands, variably sized nests, and small acini or glands set in a fibrous stroma ( Fig. 26.21A ). Islands and nests tend to show an uneven cribriform appearance resulting from the presence of acinar lumens predominately located toward the periphery. Simple tubular glands tend to be arranged in garland-like patterns or small groups, with sharply defined central lumina and, frequently, a surrounding retraction artifact.

The cells are polygonal and uniform and have round monotonous nuclei with so-called salt and pepper chromatin (see Fig. 26.21B ). Mitotic activity is low. The cytoplasm is ample, lightly eosinophilic, and often contains red to brown argentaffin granules polarized toward the base.

Immunohistochemistry and Differential Diagnosis

Carcinoid tumors are positive for pankeratin and neuroendocrine markers. Chromogranin and synaptophysin are more specific and are preferred to CD56. Primary ovarian insular carcinoid tumors are negative for CK7, CK20, and TTF-1 and often positive for CDX2.

The differential diagnosis of insular carcinoid comprises tumors that form nests composed of bland-looking cells. Because of fixation artifacts, the pathologist may not always appreciate the stippled nuclear features of insular carcinoid (see Fig. 26.21C ). Brenner tumor, endometrioid adenocarcinoma, sex cord–stromal tumors, Sertoli cell or granulosa cell tumor, and metastatic adenocarcinomas, particularly gastrointestinal, can look similar to insular carcinoid tumors. Immunostains are helpful because sex cord–stromal tumors are positive for inhibin, calretinin, and SF1, endometrioid adenocarcinomas are positive for PAX8, and Brenner tumors are positive for urothelial markers such as p63, GATA3, and S-100P. The presence of other teratomatous components would render a diagnosis of primary ovarian carcinoid tumor more probable.

If the tumor is bilateral, multilobular, or unaccompanied by a mature teratoma, a metastatic midgut carcinoid must always be considered. Immunostains are not helpful in this distinction.

Management and Outcome

The outcome of insular carcinoids is favorable. Recurrences and metastases are rare.