Uterine Corpus (Pure Mesenchymal and Mixed Epithelial-Mesenchymal Lesions)

4.1 ATYPICAL LEIOMYOMA VS. LEIOMYOSARCOMA

	Atypical Leiomyoma	Leiomyosarcoma
Age	43-45 years (mean)	Usually, >50 years
Location	Uterus	Uterus
Symptoms	Asymptomatic, menorrhagia, or pelvic pain/pressure	Abnormal vaginal bleeding and/or pelvic pain; clinical features can overlap with those of leiomyoma
Signs	May have enlarged uterus on clinical exam; gross mass within the myometrium	Pelvic mass; gross mass within the myometrium; clinical features can overlap with those of leiomyoma
Etiology	Pathogenesis unclear; rare cases can have germline fumarate hydratase mutations associated with the hereditary leiomyomatosis and renal cell carcinoma syndrome	Pathogenesis unclear but probably arises de novo rather than from malignant transformation of leiomyoma
Histology	1. Spindle cell neoplasm with fascicular architecture	1. Spindle cell neoplasm with fascicular architecture
	2. Significant (moderate or severe) atypia evident at low- or intermediate-power magnification (Fig. 4.1.1); may include symplastic/bizarre nuclei (enlarged with smudgy chromatin, +/- intranuclear inclusions) (Figs. 4.1.2 and 4.1.3)	2. Significant (moderate or severe) atypia evident at low- or intermediate-power magnification; usually lacks symplastic/bizarre nuclei (enlarged with smudgy chromatin, +/- intranuclear inclusions) although occasionally can be present; some cases may have deceptively homogeneous (rather than pleomorphic) pattern of moderate atypia at low- or intermediate-power magnification (evaluation at high-power magnification can be helpful in such cases) (Figs. 4.1.5 and 4.1.6)
	3. Variable mitotic index (<10 mitotic figures/10 high-power fields)	3. Elevated mitotic index (usually, ≥10 mitotic figures/10 high-power fields) (Figs. 4.1.5 and 4.1.6)
	4. May have infarct-type/hyaline necrosis (intervening band of hyalinization or granulation tissue between necrosis and viable tumor; acute infarct may be indistinguishable from coagulative tumor cell necrosis, but the latter designation is generally reserved for leiomyosarcoma) (Fig. 4.1.4)	4. May have coagulative tumor cell necrosis (sharp interface between necrosis and viable tumor); infarct-type/hyaline necrosis can also be present, but the latter is not used as a diagnostic criterion for leiomyosarcoma (Figs. 4.1.7 4.1.8, 4.1.9)
	5. Criteria for atypical leiomyoma: lacks two of three criteria necessary for diagnosis of leiomyosarcoma	5. Criteria for leiomyosarcoma: ≥2 of 3 criteria present (significant atypia, mitotic index ≥10 mitotic figures/10 high-power fields, coagulative tumor cell necrosis)
Special studies	Immunohistochemistry of no help (exact role of p53, p16, and Ki-67 for this differential diagnosis unclear)	Immunohistochemistry of no help (exact role of p53, p16, and Ki-67 for this differential diagnosis unclear)
Treatment	Myomectomy or hysterectomy	Hysterectomy, +/- bilateral salpingo-oophorectomy; further management is stage dependent but can include observation or chemotherapy and/or radiation therapy
Prognosis	Risk of recurrence low (≤2%)	Stage dependent; 5-year survival: 15%-25%; tumors are not graded as they are conventionally considered high grade

Figure 4.1.1 Atypical leiomyoma with significant nuclear atypia evident at intermediate-power magnification.

Figure 4.1.2 Atypical leiomyoma with bizarre nuclei and smudgy chromatin.

Figure 4.1.3 Atypical leiomyoma with bizarre nuclei and intranuclear inclusions.

Figure 4.1.4 Atypical leiomyoma with hyaline-type necrosis. Necrotic tumor is at the left with viable tumor at the right. In the middle, a vertical intervening band of granulation tissue/hyalinization is present.

Figure 4.1.5 Leiomyosarcoma with significant nuclear atypia and mitotic activity (arrow).

Figure 4.1.6 Leiomyosarcoma with significant nuclear atypia and atypical mitotic figures. The morphologic features of the atypical nuclei in this case overlap with those of bizarre/symplastic leiomyomas.

Figure 4.1.7 Leiomyosarcoma with coagulative tumor cell necrosis. Note the abrupt transition between viable tumor and necrosis.

Figure 4.1.8 Leiomyosarcoma with coagulative tumor cell necrosis. Note the preserved atypical nuclei within zones of necrosis.

Figure 4.1.9 Leiomyosarcoma with coagulative tumor cell necrosis. Viable tumor cells are present around large thick-walled vessels (“peritheliomatous pattern”).

4.2 INFARCTED CELLULAR LEIOMYOMA VS. SMOOTH MUSCLE TUMOR OF UNCERTAIN MALIGNANT POTENTIAL (STUMP)

	Infarcted Cellular Leiomyoma	STUMP
Age	Most common in pre- or perimenopausal women	Pre-, peri-, or postmenopausal
Location	Uterus	Uterus
Symptoms	Asymptomatic, menorrhagia, or pelvic pain/pressure	Asymptomatic, menorrhagia, or pelvic pain/pressure
Signs	May have enlarged uterus on clinical exam; gross mass within the myometrium	May have enlarged uterus on clinical exam; gross mass within the myometrium
Etiology	Acute infarction within a cellular leiomyoma, which can create histologic concern for leiomyosarcoma; may be related to progestin therapy	STUMP has been variably defined; however, herein, it is considered a smooth muscle neoplasm with features concerning for leiomyosarcoma but that the ambiguous histologic findings preclude further classification (typically due to inability to determine the level of atypia, mitotic index, or type of necrosis)
Histology	1. Cellular tumor with spindle cell differentiation	1. Spindle cell tumor with variable cellularity (Fig. 4.2.6)
	2. Infarct-type/hyaline necrosis, often with hemorrhage (intervening band of hyalinization or granulation tissue between necrosis and viable tumor; acute infarct may be indistinguishable from coagulative tumor cell necrosis, but the latter designation is generally reserved for leiomyosarcoma) (Figs. 4.2.1 and 4.2.2)	2. Infarct-type/hyaline necrosis can be present; pattern of necrosis may be of indeterminate type, in which distinction between infarct-type/hyaline necrosis vs. coagulative tumor cell necrosis (sharp interface between necrosis and viable tumor) may not be possible (Fig. 4.2.7)
	3. No significant atypia (Fig. 4.2.3)	3. No, insignificant (mild), or significant (moderate or severe) atypia may be present; due to ambiguous morphologic features, determining insignificant vs. significant atypia may not be possible (Fig. 4.2.8)
	4. Mitotic index usually not elevated (mitotically active cellular leiomyomas may have mitotic index ≥5 mitotic figures/10 high-power fields) (Figs. 4.2.4 and 4.2.5)	4. Variable mitotic index; in cases with significant atypia or coagulative tumor cell necrosis, the mitotic index may approach the level of 10 mitotic figures/10 high-power fields, but due to ambiguous morphologic features, determining the exact level of mitotic activity may not be possible (Fig. 4.2.9)
	5. Does not fulfill criteria for leiomyosarcoma; caution should be exercised when diagnosing leiomyosarcoma based only on the mitotic index and necrosis in cases lacking atypia since mitotically active leiomyomas can have infarct-type necrosis indistinguishable from coagulative tumor cell necrosis	5. Does not fulfill criteria for leiomyosarcoma (lacks ≥2 of 3 criteria: significant atypia, mitotic index ≥10 mitotic figures/10 high-power fields, coagulative tumor cell necrosis)
Special studies	Immunohistochemistry of no help for this differential diagnosis	Immunohistochemistry of no help for this differential diagnosis
Treatment	Myomectomy or hysterectomy	Hysterectomy
Prognosis	Benign	Uncertain behavior (this is a heterogeneous category that likely includes morphologically problematic leiomyomas and leiomyosarcomas that cannot be distinguished from one another because of ambiguous histologic features)

Figure 4.2.1 Cellular leiomyoma with acute infarct simulating coagulative tumor cell necrosis of leiomyosarcoma.

Figure 4.2.2 Infarcted cellular leiomyoma with hemorrhage.

Figure 4.2.3 Region of viable tumor from infarcted cellular leiomyoma. Note the absence of atypia.

Figure 4.2.4 Pyknotic nuclei simulating mitotic figures at edge of infarct in cellular leiomyoma.

Figure 4.2.5 Pyknotic nuclei simulating mitotic figures at edge of infarct in cellular leiomyoma (same case as Fig. 4.2.4).

Figure 4.2.6 Smooth muscle tumor of uncertain malignant potential with increased cellularity and spindle cell differentiation.

Figure 4.2.7 Smooth muscle tumor of uncertain malignant potential with necrosis of uncertain type.

Figure 4.2.8 Smooth muscle tumor of uncertain malignant potential with level of atypia equivocal for mild (insignificant) vs. moderate (significant).

Figure 4.2.9 Smooth muscle tumor of uncertain malignant potential with mitotic activity (arrow).

4.3 LEIOMYOMAS WITH VARIANT GROWTH PATTERNS (DISSECTING LEIOMYOMA/INTRAVENOUS LEIOMYOMATOSIS) VS. LEIOMYOSARCOMA

	Leiomyomas with Variant Growth Patterns (Dissecting Leiomyoma/Intravenous Leiomyomatosis)	Leiomyosarcoma
Age	Most common in pre- or perimenopausal women	Usually, >50 years
Location	Uterus	Uterus
Symptoms	Asymptomatic, menorrhagia, or pelvic pain/pressure	Abnormal vaginal bleeding and/or pelvic pain; clinical features can overlap with those of leiomyoma
Signs	May have enlarged uterus on clinical exam; gross mass within the myometrium, including nodular/worm-like growth within the myometrium or broad ligament; cotyledonoid dissecting leiomyoma (the “Sternberg tumor”) may grossly resemble placental tissue within broad ligament	Pelvic mass; gross mass within the myometrium; clinical features can overlap with those of leiomyoma
Etiology	Variant growth patterns of leiomyomas that may create concern for leiomyosarcoma because of permeation into the myometrium or broad ligament	Pathogenesis unclear but probably arises de novo rather than from malignant degeneration of leiomyoma
Histology	1. Dissecting leiomyoma contains bundles of leiomyoma extending between preexisting myometrium; may extend into broad ligament (Figs. 4.3.1 and 4.3.2)	1. Frequently has pushing border, but infiltrative patterns may be seen (Fig. 4.3.7)
	2. Intravenous leiomyomatosis contains extension of leiomyoma into vascular spaces beyond confines of leiomyoma; may extend into broad ligament; histologic variants have been described, including cellular, atypical, epithelioid, and lipoleiomyomatous types (Figs. 4.3.3 4.3.4, 4.3.5)	2. Lymphovascular space invasion may be seen (Fig. 4.3.8)
	3. Lacks histologic criteria for leiomyosarcoma (Fig. 4.3.6)	3. Criteria for leiomyosarcoma: ≥2 of 3 criteria present (significant atypia [Figs. 4.3.9 and 4.3.10], mitotic index ≥10 mitotic figures/10 high-power fields, coagulative tumor cell necrosis); significant (moderate or severe) atypia evident at low- or intermediate-power magnification (Fig. 4.3.9); some cases may have deceptively homogeneous (rather than pleomorphic) pattern of moderate atypia at low- or intermediate-power magnification (evaluation at high-power magnification can be helpful in such cases); may have coagulative tumor cell necrosis (abrupt transition between necrosis and viable tumor); infarct-type/hyaline necrosis can also be present
Special studies	Immunohistochemistry of no help (exact role of p53, p16, and Ki-67 for this differential diagnosis unclear)	Immunohistochemistry of no help (exact role of p53, p16, and Ki-67 for this differential diagnosis unclear)
Treatment	Hysterectomy	Hysterectomy, +/- bilateral salpingo-oophorectomy; further management is stage dependent but can include observation or chemotherapy and/or radiation therapy
Prognosis	Benign; intravenous leiomyomatosis can recur (<5%), sometimes many years later, with sites of recurrence including the pelvis, vena cava, lung, and heart	Stage dependent; 5-year survival: 15%-25%; tumors are not graded as they are conventionally considered high grade

Figure 4.3.1 Dissecting leiomyoma with tumor present in between preexisting nonneoplastic myometrial bundles of smooth muscle.

Figure 4.3.2 Dissecting leiomyoma.

Figure 4.3.3 Intravenous leiomyomatosis. At low-power magnification, this appearance can create concern for either leiomyosarcoma with lymphovascular space invasion or low-grade endometrial stromal sarcoma.

Figure 4.3.4 Intravenous leiomyomatosis.

Figure 4.3.5 Intravenous leiomyomatosis with hyalinization and areas of increased cellularity.

Figure 4.3.6 Intravenous leiomyomatosis. Note absence of atypia.

Figure 4.3.7 Leiomyosarcoma with infiltrating border.

Figure 4.3.8 Leiomyosarcoma exhibiting lymphovascular space invasion. This appearance at low-power magnification can mimic cellular intravenous leiomyomatosis or low-grade endometrial stromal sarcoma.

Figure 4.3.9 Leiomyosarcoma showing significant atypia detectable at intermediate-power magnification.

Figure 4.3.10 Leiomyosarcoma with significant nuclear atypia.

4.4 EPITHELIOID LEIOMYOMA VS. EPITHELIOID LEIOMYOSARCOMA

	Epithelioid Leiomyoma	Epithelioid Leiomyosarcoma
Age	Most common in pre- or perimenopausal women	Pre-, peri-, or postmenopausal
Location	Uterus	Uterus
Symptoms	Asymptomatic, menorrhagia, or pelvic pain/pressure	Abnormal vaginal bleeding and/or pelvic pain; clinical features can overlap with those of leiomyoma
Signs	May have enlarged uterus on clinical exam; gross mass within the myometrium	Pelvic mass; gross mass within the myometrium; clinical features can overlap with those of leiomyoma
Etiology	Pathogenesis unclear	Pathogenesis unclear
Histology	1. Usually sheets of tumor cells with occasional corded, trabecular, and/or nested patterns (Figs. 4.4.1 and 4.4.2)	1. Usually sheets of tumor cells with occasional corded, trabecular, and/or nested patterns (Figs. 4.4.5 4.4.6, 4.4.7)
	2. Polygonal to round cells with eosinophilic to pale cytoplasm	2. Polygonal to round cells with eosinophilic to pale cytoplasm
	3. Necrosis is absent in most cases	3. Coagulative tumor cell necrosis may be present (Fig. 4.4.8)
	4. Mild atypia can be present (Fig. 4.4.3)	4. Atypia can be variable from mild-moderate to severe; in general, level of atypia is less than in conventional/spindle cell leiomyosarcomas (Figs. 4.4.9 and 4.4.10)
	5. Mitotic index typically low (<3 mitotic figures/10 high-power fields)	5. Mitotic index usually low but often >3 mitotic figures/10 high-power fields (Fig. 4.4.7); in general, level of mitotic activity is less than in conventional/spindle cell leiomyosarcomas
	6. No lymphovascular space invasion	6. Lymphovascular space invasion may be present
	7. No infiltrating patterns	7. Borders are often pushing but may be infiltrative
	8. Criteria for malignancy: criteria are ill defined and based on limited data for uterine epithelioid smooth muscle neoplasms; however, most epithelioid leiomyomas lack significant atypia, mitotic activity, and/or necrosis; cases that have ambiguous features in between epithelioid leiomyoma and epithelioid leiomyosarcoma may be classified as smooth muscle tumor of uncertain malignant potential (Fig. 4.4.4)	8. Criteria for malignancy: criteria are ill defined and based on limited data for uterine epithelioid smooth muscle neoplasms; however, most epithelioid leiomyosarcomas have some degree of atypia, mitotic activity (see above), and/or necrosis; tumors that have ≥5 mitotic figures/10 high-power fields should be considered malignant; neoplasms that have ambiguous features in between epithelioid leiomyoma and epithelioid leiomyosarcoma may be classified as smooth muscle tumor of uncertain malignant potential
Special studies	Immunohistochemistry of no help for this differential diagnosis	Immunohistochemistry of no help for this differential diagnosis
Treatment	Myomectomy or hysterectomy; however, insufficient data for the level of risk associated with performing only myomectomy (see Prognosis below)	Hysterectomy, +/- bilateral salpingo-oophorectomy; further management is stage dependent but can include observation or chemotherapy and/or radiation therapy
Prognosis	Benign; however, rare cases without significant mitotic activity or atypia can recur	Stage dependent; limited survival data for epithelioid types (for conventional/spindle cell types, 5-year survival: 15%-25%); tumors are not graded as they are conventionally considered high grade

Figure 4.4.1 Epithelioid leiomyoma with diffuse sheets of tumor cells.

Figure 4.4.2 Epithelioid leiomyoma with corded pattern.

Figure 4.4.3 Epithelioid leiomyoma exhibiting abundant eosinophilic cytoplasm and lack of significant atypia.

Figure 4.4.4 Atypical epithelioid smooth muscle tumor with other features too equivocal for definitive classification as leiomyoma or leiomyosarcoma (i.e., best classified as smooth muscle tumor of uncertain malignant potential).

Figure 4.4.5 Epithelioid leiomyosarcoma with diffuse cellular pattern and significant atypia seen at intermediate-power magnification.

Figure 4.4.6 Epithelioid leiomyosarcoma with corded growth pattern.

Figure 4.4.7 Epithelioid leiomyosarcoma with vaguely nested pattern and mitotic activity (arrows).

Figure 4.4.8 Epithelioid leiomyosarcoma with necrosis.

Figure 4.4.9 Epithelioid leiomyosarcoma showing uniform pattern of moderate (significant) atypia.

Figure 4.4.10 Epithelioid leiomyosarcoma demonstrating severe atypia.

4.5 CELLULAR LEIOMYOMA VS. ENDOMETRIAL STROMAL NODULE

	Cellular Leiomyoma	Endometrial Stromal Nodule
Age	Most common in pre- or perimenopausal women	53 years (mean)
Location	Uterus	Uterus
Symptoms	Asymptomatic, menorrhagia, or pelvic pain/pressure	Abnormal vaginal bleeding or abdominal pain
Signs	May have enlarged uterus on clinical exam; gross mass within the myometrium	Uterus may be enlarged, or a pelvic mass may be present; gross mass within the myometrium; cut surface of tumor often yellow
Etiology	MED12 mutation common	Substantial proportion of cases has a translocation of chromosomes 7 and 17 with JAZF1 rearrangement
Histology	1. Increased cellularity	1. Increased cellularity (Fig. 4.5.6)
	2. Spindle cell differentiation with organization into fascicles (Figs. 4.5.1 and 4.5.2); some spindle cells can have abundant eosinophilic cytoplasm, but many cells have scant cytoplasm with high nuclear-to-cytoplasmic ratios; nuclei are elongated; fascicles tangentially oriented may simulate the cytology of an endometrial stromal tumor (Fig. 4.5.3)	2. No spindle cell differentiation or fascicular architecture (occasional cases may have smooth muscle differentiation with some degree of spindle cell/fascicle formation [Fig. 4.5.7]); tumor cells are round to oval with scant cytoplasm, have high nuclear-to-cytoplasmic ratios, and resemble proliferative phase endometrial stroma; nuclei are round to oval (Fig. 4.5.8)
	3. Large thick-walled vessels (Fig. 4.5.4)	3. Large thick-walled vessels typically absent; spiral arteriolar or fine branching vasculature pattern usually present (Fig. 4.5.8); cells may appear to circumferentially swirl around spiral arterioles
	4. Interface between tumor and myometrium may have cleft-like spaces (Fig. 4.5.5)	4. Cleft-like spaces at interface between tumor and myometrium typically absent
	5. Usually lack hyaline bands/plaques	5. Hyaline bands/plaques may be present (Fig. 4.5.9)
	6. Foam cells often not present	6. Foam cells may be present (Fig. 4.5.10)
Special studies	• Smooth muscle actin/desmin: positive (usually diffuse pattern)	• Smooth muscle actin/desmin: typically negative; may occasionally have some smooth muscle actin expression but usually not diffuse; cases with smooth muscle differentiation can have smooth muscle actin/desmin expression in the latter component
	• CD10: often negative; occasionally may have focal to patchy expression but not diffuse in most cases (a subset of cellular leiomyomas can have diffuse CD10 staining)	• CD10: usually diffuse expression
Treatment	Myomectomy or hysterectomy	Hysterectomy (for an endometrial biopsy/curettage or a myomectomy specimen, distinction between a cellular leiomyoma and an endometrial stromal lesion is clinically important because distinguishing an endometrial stromal nodule from a low-grade endometrial stromal sarcoma in the aforementioned specimens usually requires a hysterectomy, which is not necessary for all leiomyomas)
Prognosis	Benign	Benign

Figure 4.5.1 Cellular leiomyoma showing fascicular architecture.

Figure 4.5.2 Cellular leiomyoma with spindle cell differentiation.

Figure 4.5.3 Cellular leiomyoma with fascicles oriented perpendicular to the plane of section simulating an endometrial stromal neoplasm.

Figure 4.5.4 Cellular leiomyoma with large thick-walled vessels.

Figure 4.5.5 Cellular leiomyoma containing clefts at the periphery of the tumor.

Figure 4.5.6 Endometrial stromal nodule with diffuse sheets of increased cellularity.

Figure 4.5.7 Endometrial stromal nodule with smooth muscle differentiation. The latter is identified by the nodular, corded, and hyalinized foci, while the area lacking these features in the lower-left quadrant exhibits endometrial stromal differentiation.

Figure 4.5.8 Endometrial stromal nodule with typical cytologic and vascular features.

Figure 4.5.9 Endometrial stromal nodule with hyaline bands/plaques.

Figure 4.5.10 Endometrial stromal nodule with foam cells.

4.6 ENDOMETRIAL STROMAL NODULE WITH IRREGULAR MARGINS VS. LOW-GRADE ENDOMETRIAL STROMAL SARCOMA

	Endometrial Stromal Nodule with Irregular Margins	Low-Grade Endometrial Stromal Sarcoma
Age	53 years (mean)	52 years (mean)
Location	Uterus	Uterus
Symptoms	Abnormal vaginal bleeding or abdominal pain	Abnormal vaginal bleeding or abdominal pain
Signs	Uterus may be enlarged, or a pelvic mass may be present; gross circumscribed mass within the myometrium or endometrial cavity; cut surface of tumor often yellow	Uterus may be enlarged, or a pelvic mass may be present; gross mass within the myometrium or endometrial cavity (may exhibit tongue-like growth pattern); cut surface of tumor often yellow
Etiology	Substantial proportion of cases has a translocation of chromosomes 7 and 17 with JAZF1 rearrangement	Substantial proportion of cases has a translocation of chromosomes 7 and 17 with JAZF1 rearrangement
Histology	1. Mostly circumscribed border (Fig. 4.6.1), but focal projections extend <3 mm beyond tumor-myometrial interface (Figs. 4.6.2 and 4.6.3) (rare cases with extension >3 mm beyond tumor-myometrial interface but lacking the overt tongue-like growth pattern of low-grade endometrial stromal sarcoma have been designated “endometrial stromal tumor with limited infiltration”—follow-up data on such cases are limited)	1. Tongue-like pattern of growth: multiple round to oval nodules of varying size permeate throughout the myometrial wall (Figs. 4.6.4 and 4.6.5)
	2. No lymph-vascular space invasion	2. Lymph-vascular space invasion may be present
	3. Tumor cells are round to oval with scant cytoplasm, have high nuclear-to-cytoplasmic ratios, and resemble proliferative phase endometrial stroma; nuclei are round to oval	3. Same cytologic features as in endometrial stromal nodule (Fig. 4.6.6)
	4. Spiral arteriolar or fine branching vasculature pattern usually present; cells may appear to circumferentially swirl around spiral arterioles	4. Same type of vasculature as in endometrial stromal nodule (Fig. 4.6.7)
	5. Hyaline bands/plaques may be present	5. Hyaline bands/plaques may be present
	6. Foam cells may be present	6. Foam cells may be present
	7. Smooth muscle, sex cord, glandular, fibromyxoid, and epithelioid differentiation can occur	7. Same histologic variants as in endometrial stromal nodule
Special studies	Immunohistochemistry of no help for this differential diagnosis	Immunohistochemistry of no help for this differential diagnosis
Treatment	Hysterectomy (for an endometrial biopsy/curettage or a myomectomy specimen, distinction of endometrial stromal nodule from low-grade endometrial stromal sarcoma usually requires a hysterectomy)	Dependent on stage; hysterectomy (+/- bilateral salpingo-oophorectomy); may include observation, hormonal therapy, and/or radiation therapy
Prognosis	Benign	Stage dependent; 5-year survival: 90% for stages I-II vs. 50% for stages III-IV

Figure 4.6.1 Typical tumor-myometrial interface of endometrial stromal nodule with smooth border.

Figure 4.6.2 Endometrial stromal nodule with irregular tumor-myometrial interface.

Figure 4.6.3 Endometrial stromal nodule with a more irregular tumor-myometrial interface than in Figure 4.6.2.

Figure 4.6.4 Low-grade endometrial stromal sarcoma with characteristic tongue-like pattern of invasion.

Figure 4.6.5 Invasive area from low-grade endometrial stromal sarcoma.

Figure 4.6.6 Low-grade endometrial stromal sarcoma showing cytologic features similar to those of endometrial stromal nodule.

Figure 4.6.7 Low-grade endometrial stromal sarcoma with fine branching vascular pattern, which is also identical to that of endometrial stromal nodule.

4.7 LOW-GRADE ENDOMETRIAL STROMAL SARCOMA WITH GLANDULAR DIFFERENTIATION VS. ADENOSARCOMA

	Low-Grade Endometrial Stromal Sarcoma with Glandular Differentiation	Adenosarcoma
Age	52 years (mean)	Usually postmenopausal
Location	Uterus	Uterus
Symptoms	Abnormal vaginal bleeding or abdominal pain	Abnormal vaginal bleeding
Signs	Uterus may be enlarged, or a pelvic mass may be present; gross mass within the myometrium or endometrial cavity (may exhibit tongue-like growth pattern); cut surface of tumor often yellow	Pelvic mass may be present; gross mass within the endometrial cavity; cut surface may have a cystic component
Etiology	Substantial proportion of cases has a translocation of chromosomes 7 and 17 with JAZF1 rearrangement	Pathogenesis unclear
Histology	1. Tongue-like pattern of growth: multiple round to oval nodules of varying size permeate throughout myometrial wall (Figs. 4.7.1 and 4.7.2)	1. No tongue-like growth pattern
	2. Small- to medium-sized, round, benign, and endometrial-type glands; however, areas of classic low-grade endometrial stromal sarcoma should be present elsewhere (Fig. 4.7.3) and could potentially mimic areas of sarcomatous overgrowth in adenosarcoma	2. Benign glandular component (variable in size and shape); may have metaplastic-type changes
	3. No intraglandular polypoid projections with leaf-like or phyllodes-type architecture	3. Intraglandular polypoid projections with leaf-like or phyllodes-type architecture (Figs. 4.7.5 and 4.7.6)
	4. No periglandular or subepithelial stromal condensation	4. Periglandular or subepithelial stromal condensation (Figs. 4.7.6 4.7.7, 4.7.8)
	5. Tumor cells are round to oval with scant cytoplasm, have high nuclear-to-cytoplasmic ratios, and resemble proliferative phase endometrial stroma; nuclei are low-grade and round to oval (Fig. 4.7.4)	5. Cells may resemble those of low-grade endometrial stromal sarcoma or have fibroblastic-type morphology (Fig. 4.7.9)
	6. Spiral arteriolar or fine branching vasculature pattern usually present; cells may appear to circumferentially swirl around spiral arterioles	6. Vasculature as seen in low-grade endometrial stromal sarcoma can be seen but not characteristic
	7. Smooth muscle, sex cord, fibromyxoid, and epithelioid differentiation can occur	7. Variant patterns of stromal differentiation as seen in low-grade endometrial stromal sarcoma can occur; heterologous elements may be seen in some cases
Special studies	Immunohistochemistry of no help for this differential diagnosis	Immunohistochemistry of no help for this differential diagnosis
Treatment	Dependent on stage; hysterectomy (+/- bilateral salpingo-oophorectomy); may include observation, hormonal therapy, and/or radiation therapy	Hysterectomy and bilateral salpingo-oophorectomy
Prognosis	Stage dependent; 5-year survival: 90% for stages I-II vs. 50% for stages III-IV	Dependent on stage and other risk factors; 5-year survival: ˜80%

Figure 4.7.1 Typical tongue-like pattern of invasion in low-grade endometrial stromal sarcoma with glandular differentiation (glandular differentiation not present in this field).

Figure 4.7.2 Typical tongue-like pattern of invasion in low-grade endometrial stromal sarcoma with glandular differentiation (glandular differentiation not present in this focus).

Figure 4.7.3 Low-grade endometrial stromal sarcoma with glandular differentiation. Areas such as the one shown in this case can be potentially confused with periglandular stromal condensation of adenosarcoma. This can also simulate adenomyosis (see Section 4.8).

Figure 4.7.4 Low-grade endometrial stromal sarcoma with glandular differentiation showing typical cytologic features (glandular differentiation not present in this focus).

Figure 4.7.5 Adenosarcoma with phyllodes growth pattern.

Figure 4.7.6 Adenosarcoma containing intraglandular polypoid projections and subepithelial condensation.

Figure 4.7.7 Adenosarcoma with periglandular stromal condensation. The vague multinodular pattern in this case has the potential to mimic the tongue-like pattern of invasion in low-grade endometrial stromal sarcoma with glandular differentiation.

Figure 4.7.8 Adenosarcoma (higher-power magnification of Fig. 4.7.7).

Figure 4.7.9 Adenosarcoma exhibiting fibromatous differentiation.

4.8 LOW-GRADE ENDOMETRIAL STROMAL SARCOMA WITH GLANDULAR DIFFERENTIATION VS. ADENOMYOSIS/ENDOMETRIOSIS

	Low-Grade Endometrial Stromal Sarcoma with Glandular Differentiation	Adenomyosis/Endometriosis
Age	52 years (mean)	Usually pre- or perimenopausal
Location	Uterus or extrauterine sites	Uterus (adenomyosis); extrauterine sites, including ovaries, uterine ligaments, rectovaginal septum, cul-de-sac, and peritoneum (endometriosis)
Symptoms	Abnormal vaginal bleeding or abdominal pain	Dysmenorrhea, abdominal/pelvic pain, dyspareunia, abnormal vaginal bleeding, and/or infertility
Signs	Uterus may be enlarged, or a pelvic mass may be present; gross mass within the myometrium or endometrial cavity (may exhibit tongue-like growth pattern on gross examination); cut surface of tumor often yellow	Uterus may be enlarged, and myometrium can be thickened with hemorrhagic foci (adenomyosis); although adenomyosis may be nodular, a mass should not be present; tender nodules in the cul-de-sac and uterosacral ligaments, and nonpigmented or pigmented lesions involving the peritoneum (endometriosis)
Etiology	Substantial proportion of cases has a translocation of chromosomes 7 and 17 with JAZF1 rearrangement	Endometrial diverticula containing glands and endometrial stroma extend into myometrium (adenomyosis); ectopic extrauterine endometrial tissue with glands and stroma (endometriosis); most cases of endometriosis believed to be a result of retrograde menstruation
Histology	1. Tongue-like pattern of growth: multiple round nodules of varying size permeate throughout the myometrial wall or extrauterine sites (Figs. 4.8.1 4.8.2, 4.8.3)	1. No tongue-like pattern of growth; extent of proliferation, degree of crowding of foci, and size of foci in adenomyosis (Figs. 4.8.7 4.8.8, 4.8.9)/endometriosis (Fig. 4.8.10) not as great as in low-grade endometrial stromal sarcoma; foci are typically small; occasionally, endometriosis may produce a mass (polypoid endometriosis); foci of adenomyosis or endometriosis can be gland-poor mimicking low-grade endometrial stromal sarcoma (see Section 4.9); adenomyosis can be surrounded by smooth muscle hyperplasia
	2. Small- to medium-sized, round, benign, and endometrial-type glands; however, areas of classic low-grade endometrial stromal sarcoma should be present elsewhere; extent of glandular differentiation is variable (Figs. 4.8.3 4.8.4, 4.8.5, 4.8.6)	2. Appearance of glands similar to that in low-grade endometrial stromal sarcoma with glandular differentiation
	3. Stromal tumor cells are round to oval with scant cytoplasm, have high nuclear-to-cytoplasmic ratios, and resemble proliferative phase endometrial stroma; nuclei are low grade and round to oval	3. Cytologic features of endometrial stroma similar to that in low-grade endometrial stromal sarcoma with glandular differentiation
	4. Spiral arteriolar or fine branching vasculature pattern usually present; cells may appear to circumferentially swirl around spiral arterioles	4. Vascular pattern similar to that in low-grade endometrial stromal sarcoma with glandular differentiation
	5. Smooth muscle, sex cord, fibromyxoid, and epithelioid differentiation can occur	5. Histologic variants that occur in low-grade endometrial stromal sarcoma not seen
Special studies	Immunohistochemistry of no help for this differential diagnosis	Immunohistochemistry of no help for this differential diagnosis
Treatment	Dependent on stage; hysterectomy (+/- bilateral salpingo-oophorectomy); may include observation, hormonal therapy, and/or radiation therapy	Surgical or hormonal/medical therapy
Prognosis	Stage dependent; 5-year survival: 90% for stages I-II vs. 50% for stages III-IV	Benign

Figure 4.8.1 Nodular pattern of invasion in low-grade endometrial stromal sarcoma with glandular differentiation involving the peritoneum (glandular differentiation not present in this field).

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