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Hematologic Neoplasms and Selected Tumor-Like Lesions Involving the Female Reproductive Organs

  • Judith A. FerryEmail author
Living reference work entry

Abstract

A variety of hematologic neoplasms involves the female reproductive organs, including a number of different types of lymphomas and lymphoid leukemias, myeloid sarcomas and myeloid leukemias, and rarely histiocytic neoplasms. When the female reproductive organs are affected by one of these disorders in the setting of widespread disease, the diagnosis is usually straightforward, but in the uncommon instance in which the female genital tract is the presenting site of a hematologic neoplasm, diagnosis may be problematic, and special problems in differential diagnosis may arise.

A variety of hematologic neoplasms involves the female reproductive organs, including a number of different types of lymphomas and lymphoid leukemias, myeloid sarcomas and myeloid leukemias, and rarely histiocytic neoplasms. When the female reproductive organs are affected by one of these disorders in the setting of widespread disease, the diagnosis is usually straightforward, but in the uncommon instance in which the female genital tract is the presenting site of a hematologic neoplasm, diagnosis may be problematic, and special problems in differential diagnosis may arise.

Lymphoid Neoplasms of the Female Reproductive Organs

Lymphoma rarely presents with involvement of the female reproductive organs. When it does, the ovaries are most commonly affected, followed by the uterine cervix, uterine corpus, vagina, vulva, and fallopian tubes (Nasioudis et al. 2017). Nearly all cases are non-Hodgkin’s lymphoma of B lineage, with diffuse large B-cell lymphoma being the most common type throughout the female reproductive organs (Nasioudis et al. 2017). T-cell lymphoma is very uncommon, and natural killer (NK)-cell lymphoma and Hodgkin’s lymphoma are exceptional (Ferry and Young 1997; Kosari et al. 2005; Nasioudis et al. 2017). Rare cases of lymphoma arising in the setting of HIV infection or iatrogenic immunosuppression (Kaplan et al. 1993; Nagarsheth et al. 2005; Lanjewar and Dongaonkar 2006) and a few cases of women with a family history of hematologic neoplasia have been described (Frey et al. 2006). When lymphoma develops during pregnancy, involvement of reproductive organs is common; it is especially frequent in cases of Burkitt lymphoma (Horowitz et al. 2013).

Ovarian Lymphoma

Primary Ovarian Lymphoma

Overall fewer than 1% of lymphomas present with ovarian involvement (Freeman et al. 1972; Dimopoulos et al. 1997; Ferry and Young 1997), and fewer than 1.5% of neoplasms arising in the ovary are lymphomas. In countries where Burkitt lymphoma is endemic, however, the most common malignant ovarian neoplasm among children and adolescents is Burkitt lymphoma (Scully 1979; Akakpo et al. 2017).

Clinical Features

Patients’ ages range from early childhood to advanced age (Ferry and Young 1997), with a peak incidence in the 30s or 40s (Dimopoulos et al. 1997; Ferry and Young 1997; Vang et al. 2001a). Occasionally lymphoma develops during pregnancy (Ferry and Young 1997; Magloire et al. 2006). Rare patients have been HIV+ (Lanjewar and Dongaonkar 2006). The presenting complaints are generally non-specific symptoms related to the presence of a mass (abdominal pain or distension) (Dimopoulos et al. 1997; Neuhauser et al. 2000; Vang et al. 2001a; Sun et al. 2015). A minority have fatigue, weight loss, fever, or abnormal vaginal bleeding (Dimopoulos et al. 1997). Rarely the lymphoma is an incidental finding (Vang et al. 2001a; Shigematsu et al. 2016). Serum lactate dehydrogenase (LDH) is usually elevated; CA-125 is also often elevated (Miyazaki et al. 2013; Sun et al. 2015; Guvvala et al. 2017).

Pathologic Features

Primary ovarian lymphomas are more often unilateral than bilateral (Sun et al. 2015). They range from microscopic (Vang et al. 2001a) to large masses up to 25 cm in diameter with an average size of 8–14 cm (Ferry and Young 1997; Vang et al. 2001a; Sun et al. 2015). The external surfaces are usually intact and may be smooth or nodular. On sectioning the tumors are soft and fleshy or firm and rubbery, depending on the degree of cellularity and associated sclerosis. They are usually white, yellow, tan, or gray-pink. Some have cystic degeneration, hemorrhage, or necrosis (Ferry and Young 1997; Sun et al. 2015). Very rare cases of lymphoma in association with, possibly arising from, a teratoma have been described (McKelvey et al. 2003; Valli et al. 2014; Maguire et al. 2015).

The most common lymphoma is diffuse large B-cell type, followed by Burkitt lymphoma and follicular lymphoma (Dimopoulos et al. 1997; Nasioudis et al. 2017). Adolescents and children almost always have diffuse, aggressive lymphomas, including Burkitt lymphoma and diffuse large B-cell lymphoma (Kosari et al. 2005), while adults may have indolent or aggressive lymphomas. Ovarian lymphoma may preferentially spare corpora lutea, corpora albicantia, follicles, and a peripheral rim of cortical tissue but otherwise typically obliterates normal ovarian parenchyma. Lymphoma is rarely associated with hyperplasia and luteinization of the adjacent stroma (Ferry and Young 1997).

Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma in the ovary, as in other sites, is composed of centroblasts, immunoblasts, multilobated cells, or a mixture of these. In the ovary, associated sclerosis is common, and tumor cells may grow in cords and nests, simulating carcinoma (Scully 1979), or be elongate and grow in a storiform pattern, mimicking a sarcoma (Fig. 1a–c). A few diffuse large B-cell lymphomas have a component of follicular lymphoma (Neuhauser et al. 2000; Vang et al. 2001a). Neoplastic cells express B-cell markers including CD20+. In most cases, ovarian diffuse large B-cell lymphoma has a germinal center B-cell immunophenotype (CD10+ or CD10-, BCL6+, MUM1-) (Hans et al. 2004). Expression of BCL2 is variable. Proliferation index is usually >50% (Vang et al. 2001a; Maguire et al. 2015; Sun et al. 2015). The lymphomas are typically negative for Epstein-Barr virus (Sun et al. 2015). Immunoglobulin genes are clonally rearranged. In a small minority of cases, FISH shows rearrangement of MYC, BCL2, or BCL6. A case of “double-hit” ovarian lymphoma with concurrent rearrangement of MYC and BCL2 is reported (Sun et al. 2015).
Fig. 1

Ovary, diffuse large B-cell lymphoma with neoplastic spindle cells. (a) Low power shows a thin layer of uninvolved tissue at the surface of the ovary. The neoplastic cells grow in a storiform pattern. (b) High power shows atypical cells with elongate, usually blunt-ended nuclei admixed with cells with round or lobated nuclei; there is interstitial sclerosis. The neoplastic proliferation spares a small epithelial inclusion gland. (c) Neoplastic cells are CD20+ confirming B lineage; they also expressed CD45, the leukocyte common antigen (not shown) (immunoperoxidase technique on a paraffin section)

Burkitt Lymphoma

Ovarian Burkitt lymphoma is most commonly encountered among girls and young adult women (Kosari et al. 2005; Miyazaki et al. 2013; Lee and Chui 2015). Burkitt lymphoma is more often bilateral than other ovarian lymphomas (Lagoo and Robboy 2006; Lee and Chui 2015; Sun et al. 2015; Akakpo et al. 2017). It is hypothesized that Burkitt lymphoma occurring in pregnancy has a tendency to involve hormonally stimulated organs, such as the ovary (Magloire et al. 2006).

Burkitt lymphoma occurs in one of three clinical forms: sporadic, endemic, and immunodeficiency-associated (Leoncini et al. 2017). Both sporadic and endemic Burkitt lymphoma may present with ovarian involvement (Leoncini et al. 2017), and ovarian involvement in the setting of immunodeficiency (HIV infection) has been described (Lanjewar and Dongaonkar 2006). The histologic features are the same as those found in other sites. There is a diffuse proliferation of medium-sized, fairly uniform cells with round nuclei containing stippled chromatin and several small nucleoli in each nucleus. A moderate quantity of cytoplasm which is deep blue with Giemsa or Wright stain is present. Mitoses are numerous. Many scattered pale tingible body macrophages in a background of dark neoplastic cells impart a starry sky pattern at low power (Fig. 2a, b). In some cases, there is plasmacytoid differentiation (Leoncini et al. 2017). Burkitt lymphoma with plasmacytoid differentiation is usually found in the setting of immunodeficiency. As in other sites, the characteristic immunophenotype is monotypic IgM+, CD20+, CD10+, CD5-, BCL6+, BCL2-, and Ki67 ~ 100% +, and the neoplastic cells harbor a translocation involving MYC (Kosari et al. 2005; Chishima et al. 2006; Leoncini et al. 2017; Sun et al. 2015). Endemic Burkitt lymphoma typically contains Epstein-Barr virus (EBV), while a minority of cases of sporadic Burkitt lymphoma and immunodeficiency-associated Burkitt lymphoma are positive for EBV (Leoncini et al. 2017).
Fig. 2

Ovary, Burkitt lymphoma. (a) Low power shows scattered pale tingible body macrophages in a background of dark neoplastic cells, creating a “starry sky” pattern. (b) High power shows fairly uniform, medium-sized lymphoid cells with round nuclei, stippled chromatin, and numerous mitoses; the appearance is typical of Burkitt lymphoma

Follicular Lymphoma
Ovarian follicular lymphomas affect middle-aged and older patients. They may be entirely follicular or may have conspicuous diffuse areas. They are composed of a variable admixture of centrocytes (small cleaved cells) and centroblasts (large non-cleaved cells). Follicular lymphomas of all three grades (grade 1, 0–5 centroblasts/average high power field (HPF); grade 2, 6–15 centroblasts/average HPF; grade 3, >15 centroblasts/average HPF) occur in the ovary (Fig. 3a–d) (Vang et al. 2001a; Lagoo and Robboy 2006). In one study, follicular lymphomas involving the ovary could be divided into two groups. In the first group, BCL2 was negative or weakly expressed, IGH/BCL2 fusion was absent, the lymphomas were grade 2 or grade 3A, and when stage was known, the lymphomas were confined to one ovary. In the second group, all lymphomas were low-grade, BCL2 was strongly expressed, IGH/BCL2 fusion was present, and most had widespread disease. Patients from the first group had a more favorable outcome than those in the second group (Ozsan et al. 2011).
Fig. 3

Ovary, follicular lymphoma. (a) The ovary is replaced by a vaguely nodular-appearing proliferation of atypical lymphoid cells. (b) The atypical cells are mostly small with irregular nuclei; very few large cells are present. (c) The atypical cells are B cells (CD20+); they also expressed the follicle center-associated antigen BCL6 (not shown). (d) CD21 highlights follicular dendritic meshworks; the follicular architecture is more readily appreciated than on routinely stained sections (c, d, immunoperoxidase technique on paraffin sections)

Rare Lymphomas

Rare cases of plasmablastic lymphoma (Guvvala et al. 2017), anaplastic large cell lymphoma, B- and T-lymphoblastic lymphoma (Vang et al. 2001a; Iyengar and Deodhare 2004; Kosari et al. 2005; Sakurai et al. 2008; Yadav et al. 2013), and ALK+ diffuse large B-cell lymphoma (Sellami-Dhouib et al. 2013) presenting with ovarian involvement have been reported. Lymphoblastic lymphomas with ovarian involvement typically also show bone marrow involvement (Cunningham 2013). Extranodal marginal zone lymphoma arising in association with severe endometriosis and involving the ovaries and fallopian tubes has been reported (Nezhat et al. 2013).

Staging, Treatment, and Outcome

Staging discloses extraovarian spread in most cases, often involving pelvic or para-aortic lymph nodes and occasionally the peritoneum, other genital organs, or distant sites (Dimopoulos et al. 1997; Ferry and Young 1997; Sun et al. 2015). Ovarian lymphoma has traditionally been considered an aggressive tumor with a poor outcome, but improvements in therapy in recent years appear to be associated with a prognosis similar to that of lymph nodal lymphomas of comparable stage and histologic type (Dimopoulos et al. 1997; Mansouri et al. 2000; Vang et al. 2001a).

Secondary Ovarian Lymphoma

Among patients with disseminated lymphoma and lymphoid leukemias, the ovary is a relatively common site of involvement, although it may be asymptomatic. Seven to twenty-five percent of women dying with lymphoma have ovarian involvement (Barcos et al. 1987; Ferry and Young 1997). Nearly any type of lymphoma may spread to the ovary, but mediastinal large B-cell lymphoma has a distinct tendency to involve the ovary (Fig. 4a, b) (de Leval et al. 2001; Zinzani et al. 2002; Shulman et al. 2008). Acute lymphoblastic leukemia, usually B lineage, relapsing in the ovaries, with and without involvement of bone marrow and of other sites (peritoneum, omentum, fallopian tubes, lymph nodes, and central nervous system) has been reported (Cecalupo et al. 1982; Wyld and Lilleyman 1983; Cunningham 2013; Nunes et al. 2015).
Fig. 4

Ovarian involvement by mediastinal large B-cell lymphoma. (a) Gross examination of the bisected ovarian tumor shows fleshy white tissue. (b) High power shows discohesive neoplastic cells with round or irregular nuclei and scant cytoplasm. A few cells are multilobated and rare cells are multinucleated

Differential Diagnosis

The differential diagnosis of ovarian lymphoma is broad; it includes dysgerminoma, metastatic carcinoma, primary small cell carcinoma of hypercalcemic and pulmonary types, adult granulosa cell tumor (Neuhauser et al. 2000), spindle cell sarcoma, undifferentiated carcinoma, and myeloid sarcoma (Ferry and Young 1997). Immunohistochemical studies readily confirm or exclude lymphoma. In contrast to lymphomas in the lower genital tract (see below), the differential diagnosis with inflammatory processes is only rarely problematic.

The main problem in differential diagnosis is distinguishing diffuse large B-cell lymphoma from nonlymphoid neoplasms because large lymphoid cells can have varying morphology and may overlap in size and shape with other types of neoplastic cells. Burkitt lymphoma is a highly cellular tumor with a characteristic histologic appearance. Recognition of follicular lymphoma is facilitated by its at least partially follicular growth pattern. Features helpful in differential diagnosis are presented in Table 1.
Table 1

Differential diagnosis of ovarian diffuse large B-cell lymphoma

Nonlymphoid tumor

Problem

Differential features

Usual immunophenotype of nonlymphoid tumor

Dysgerminoma

DLBCL composed of IBs: IBs have size, shape, and prominent nucleoli, similar to cells of dysgerminoma

Dysgerminoma: sheets and nests of tumor cells, fibrous trabeculae with lymphocytes and histiocytes, nuclei flattened along one side, fine chromatin, abundant clear PAS+ cytoplasm, distinct cell borders (not seen in DLBCL)

PLAP+, OCT4+, CD117+, CD45-, CD20-

Carcinoma

DLBCL with sclerosis can have cord-like or nested pattern resembling carcinoma

Cohesive growth, nuclear molding, lumen formation, and mucin production favor carcinoma; follicles favor small cell carcinoma, hypercalcemic variant

Cytokeratin+, CD45-, CD20-

Spindle cell sarcoma

DLBCL with sclerosis can have spindle cell morphology

Sarcoma lacks admixed CBs and IBs; tumor cells usually more elongate

Mesenchymal markers (varied)+, CD45-, CD20-

Adult granulosa cell tumor

CBs and IBs have large pale vesicular nucleoli that could mimic cells of AGCT; AGCT can have a diffuse pattern, like DLBCL

Trabecular, insular, or micro- or macrofollicular pattern; Call-Exner bodies; more pale, evenly dispersed chromatin; and nuclear grooves favor AGCT

Inhibin+, calretinin+, CD45-, CD20-

Myeloid sarcoma

Large lymphoid cells and primitive myeloid cells overlap morphologically; their patterns of growth are similar

Myeloblasts are slightly smaller than large lymphoid cells; they have more finely dispersed chromatin and usually smaller nucleoli. Some cells may have pink cytoplasm, suggesting myeloid differentiation. Bone marrow exam may show myeloid leukemia. Eosinophilic myelocytes may be present.

Lysozyme+, MPO+/−, CD68+/−, CD34+/−, CD117+

DLBCL diffuse large B-cell lymphoma, IB immunoblast, CB centroblast, AGCT adult granulosa cell tumor, MPO myeloperoxidase

Lymphoma of the Fallopian Tube

Primary Lymphoma of the Fallopian Tube

Primary tubal lymphoma is rare. One case of primary tubal marginal zone lymphoma associated with salpingitis (Noack et al. 2002), one possible case of primary tubal follicular lymphoma (Fig. 5a, b) (Ferry and Young 1991), and a bilateral primary tubal peripheral T-cell lymphoma (Gaffan et al. 2004) have been described.
Fig. 5

Fallopian tube, follicular lymphoma. (a) Whole-mount section shows tube with transmural involvement by crowded lymphoid follicles. (b) High power shows a portion of one of the neoplastic follicles; it is composed of small cleaved cells (centrocytes) with few admixed large non-cleaved cells (centroblasts). Small lymphocytes are present at the periphery of the follicle

Secondary Tubal Involvement by Lymphoma

Tubal involvement is relatively common among patients with lymphoma of the ovaries (Neuhauser et al. 2000). Most are diffuse large B-cell lymphoma or Burkitt lymphoma (Vang et al. 2001b); follicular lymphoma, peripheral T-cell lymphoma, and lymphoblastic lymphoma/leukemia have also been reported (Cecalupo et al. 1982; Osborne and Robboy 1983; Neuhauser et al. 2000; Vang et al. 2001b). Secondary tubal involvement by extranodal marginal zone lymphoma with abundant amyloid deposition has been reported (Mehta et al. 2014). Tubal infiltration is also seen at autopsy in cases of disseminated lymphoma (Iliya et al. 1968).

Uterine Lymphoma

Primary Uterine Lymphoma

Fewer than 1% of extranodal lymphomas arise in this site (Freeman et al. 1972). Lymphoma arises more often in the cervix than in the corpus, with a 10:1 ratio in one series (Vang et al. 2000c), although other series have not shown such a striking excess of cervical lymphomas (Kosari et al. 2005; Mandato et al. 2014).

Clinical Features

Uterine lymphoma affects adults over a broad age range (Harris and Scully 1984), with a mean and a median age in the fifth to sixth decade (Harris and Scully 1984; Perren et al. 1992; Makarewicz and Kuzminska 1995; Dursun et al. 2005; Frey et al. 2006; Mandato et al. 2014). The most common presenting symptom is abnormal vaginal bleeding (Harris and Scully 1984; Makarewicz and Kuzminska 1995; Alvarez et al. 1997; Ferry and Young 1997; Chandy et al. 1998; Vang et al. 2001b; Chan et al. 2005; Frey et al. 2006; Cohn et al. 2007; Mandato et al. 2014). Less common complaints are dyspareunia and perineal, pelvic, or abdominal pain. A few patients have systemic symptoms such as fever or weight loss (Perren et al. 1992; Ferry and Young 1997; Dursun et al. 2005). Because lymphomas are typically not associated with ulceration, uterine lymphoma is only occasionally detected on a Papanicolaou smear.

Pathologic Features
Cervical lymphomas typically produce bulky lesions identifiable on pelvic examination. The classic appearance is diffuse, circumferential enlargement of the cervix (“barrel-shaped” cervix) (Fig. 6). Lymphoma may also form a discrete submucosal tumor (Harris and Scully 1984; Chan et al. 2005), a polypoid or multinodular lesion (Harris and Scully 1984; Chandy et al. 1998; Garavaglia et al. 2005), or a fungating, exophytic mass; ulceration is unusual (Harris and Scully 1984). The tumors have been variously described as fleshy, rubbery, or firm and white-tan to yellow (Harris and Scully 1984). Extensive local spread to sites such as the vagina, parametria, or even pelvic side walls is common (Harris and Scully 1984; Chandy et al. 1998; Frey et al. 2006; Cohn et al. 2007), and invasion into the urinary bladder is described (Kawauchi et al. 2002). Patients commonly exhibit hydronephrosis secondary to ureteral obstruction (Harris and Scully 1984; Ferry and Young 1997; Cohn et al. 2007). Lymphomas of the uterine corpus are usually fleshy or soft and pale gray-, yellow-, or cream-colored. They may form a polypoid mass or diffusely infiltrate the endometrium, sometimes with deep invasion of the myometrium (Harris and Scully 1984; Ferry and Young 1997).
Fig. 6

Uterine cervix, lymphoma. Gross examination shows circumferential expansion of the cervix, the so-called barrel-shaped cervix

The microscopic appearance of the lymphomas is in some cases similar to that of the same types of lymphoma seen in nodal and other extranodal sites and, in some cases, is distinctive. In the cervix, there is often a band of uninvolved normal tissue just beneath the surface epithelium, and the overlying epithelium is usually intact. In a large biopsy or hysterectomy specimen, deep invasion of the cervical wall is usually seen. In small biopsies, squeeze artifact is often prominent.

Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma is the most common type of primary uterine lymphoma by far, in both the corpus and the cervix (Alvarez et al. 1997; Chandy et al. 1998; Vang et al. 2000c, 2001b; Kawauchi et al. 2002; Garavaglia et al. 2005; Frey et al. 2006), accounting for 70–75% of cases (Vang et al. 2001b; Dursun et al. 2005). Neoplastic cells may be centroblasts, immunoblasts, multilobated large lymphoid cells, or a combination of these. Cervical lymphomas are frequently associated with prominent sclerosis (Vang et al. 2001b; Garavaglia et al. 2005; Lagoo and Robboy 2006) which may be associated with a cord-like arrangement or spindle-shaped tumor cells (Harris and Scully 1984). The spindle cell pattern may be sufficiently prominent to mimic a sarcoma resulting in the usage of the terms “spindle cell variant” (Carbone et al. 2006) and “sarcomatoid variant” (Kahlifa et al. 2003; Fratoni et al. 2016). Rare examples of intravascular large B-cell lymphoma presenting with involvement of the uterus and adnexa have been described (Sur et al. 2005; Yamada et al. 2005; Shigematsu et al. 2016). Microscopic examination reveals large atypical lymphoid cells filling the lumens of blood vessels (Fig. 7a, b).
Fig. 7

Uterine cervix, intravascular large B-cell lymphoma. (a) The exocervix has multiple blood vessels containing neoplastic cells. (b) High power shows a dilated blood vessel filled by large, atypical, pleomorphic lymphoid cells. The neoplastic cells were CD20+ and CD3- (not shown), consistent with B lineage

Follicular Lymphoma
Follicular lymphoma is the second most common type of uterine lymphoma; follicular lymphomas of all three grades have been reported (Kosari et al. 2005). These are also often associated with sclerosis. Neoplastic follicles are often found in a perivascular location as they invade into the wall of the cervix (Fig. 8a–f) (Harris and Scully 1984).
Fig. 8

Uterine cervix, follicular lymphoma. (a) Low power shows atypical lymphoid follicles invading deep into the wall of the cervix. The surface epithelium is intact and uninvolved by the lymphoid infiltrate. (b) Higher power shows crowded, ill-defined follicles composed of a monotonous population of small atypical lymphoid cells. (cf) Immunostains show follicles composed of B cells (c, CD20+) surrounded by T cells (d, CD3+). B cells co-express the follicle center-associated marker CD10 (e) as well as BCL2 (f); these immunohistochemical results confirm a diagnosis of follicular lymphoma (cf, immunoperoxidase technique on paraffin sections)

Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma)
A few cases of marginal zone lymphoma arising in the endometrium and rare cases in the cervix have been described (Ferry and Young 1997; van de Rijn et al. 1997; Vang et al. 2000c, 2001b; Kosari et al. 2005; Frey et al. 2006; Tahmasebi et al. 2015; Bennett et al. 2016; Takimoto et al. 2017). Endometrial MALT lymphoma has distinctive features. Affected women range from the fifth to the ninth decade, with a median age in the late 50s or 60s. The lymphomas are often incidental findings, usually do not form a mass, and are almost always confined to the uterus (Iyengar and Deodhare 2004; Tahmasebi et al. 2015; Bennett et al. 2016). On microscopic examination, they are composed of large nodules with a monotonous population of small lymphoid cells with slightly irregular nuclei and scant to moderate amount of pale cytoplasm adjacent to and sometimes surrounding endometrial glands, typically without lymphoepithelial lesions. The lymphoma may be confined to the endometrium or may show myometrial invasion. Immunohistochemical analysis shows a predominance of B cells (CD20+, CD79a+) that are CD10-, BCL2+, BCL6-, CD23-, IgM+, IgD-, and cyclin D1-, usually with CD43 co-expression and rarely with CD5 co-expression. Cellular nodules are associated with CD21+ and CD23+ follicular dendritic cell meshworks. The proliferation index is low. Monotypic plasma cells are present at the periphery of the nodules in a few cases. Immunoglobulin heavy chain genes are clonally rearranged. FISH has been negative for rearrangements of IGH and MALT1. Follow-up is almost always uneventful (Fig. 9a–c) (Iyengar and Deodhare 2004; Tahmasebi et al. 2015; Bennett et al. 2016).
Fig. 9

Endometrial marginal zone lymphoma. (a) Crowded nodules of small lymphoid cells extensively replace the endometrium and extend superficially into the myometrium. (b) Nodules of small, bland lymphoid cells scattered among endometrial glands. (c) Lymphoid cells are predominantly B cells (CD20+). B cells co-expressed CD43 and were associated with CD21+ follicular dendritic meshworks (not shown) (immunoperoxidase technique on a paraffin section)

Rare Lymphomas

A few cases of Burkitt lymphoma (Kosari et al. 2005; Nomura et al. 2006) and rare cases of B-lymphoblastic lymphoma (Kosari et al. 2005), peripheral T-cell lymphoma (Kirk et al. 2001), and cervical extranodal NK/T-cell lymphoma (Vang et al. 2001b; Wang et al. 2015) have been reported. The uterus is rarely the site of involvement by B-cell posttransplantation lymphoproliferative disorder (Nagarsheth et al. 2005).

Staging, Treatment, and Outcome

Although most uterine lymphomas are large at the time of diagnosis (the primary endometrial marginal zone lymphomas are an exception), the majority are localized (Ann Arbor stage I or stage II), with stage I more frequent than stage II (Vang et al. 2000c; Chan et al. 2005; Mandato et al. 2014). The type of therapy has varied. In a few cases, young women have been successfully treated using combination chemotherapy, and some have preserved fertility (Ferry and Young 1997; Garavaglia et al. 2005). Uterine lymphoma has a relatively good prognosis (Ferry and Young 1997; Chandy et al. 1998; Nasu et al. 1998; Vang et al. 2001b). Cervical lymphoma appears to have a better prognosis than lymphoma of the corpus (Nasioudis et al. 2017). The 5-year cause-specific survival for cervical lymphoma is estimated to be 87% compared to 67% for lymphomas of the corpus (Nasioudis et al. 2017). However, lymphomas of the corpus with localized disease tend to do well, including in particular endometrial marginal zone lymphomas (van de Rijn et al. 1997; Frey et al. 2006). Those with advanced disease presenting with endometrial involvement have a worse prognosis (Harris and Scully 1984).

Secondary Uterine Lymphoma

Secondary involvement of the uterus in cases of disseminated lymphoma or lymphoid leukemia is not unusual; it may be asymptomatic or accompanied by vaginal bleeding or discharge (Ferry and Young 1997; Vang et al. 2001b; Kosari et al. 2005). In contrast to primary uterine lymphoma, in which the cervix is much more often involved than the corpus, when the uterus is secondarily involved, the corpus is involved at least as often as the cervix. Lymphomas secondarily involving the uterus are also of more varied types than in primary cases, with less of a predominance of diffuse large B-cell lymphoma. They include diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B- and T-lymphoblastic lymphoma/leukemia (Ferry and Young 1997; Vang et al. 2001b; Lyman and Neuhauser 2002; Kosari et al. 2005; Kazi et al. 2013), and extranodal NK/T-cell lymphoma (Murase et al. 2002). The prognosis is much less favorable than that of primary uterine lymphoma (Vang et al. 2000c; Murase et al. 2002).

Uterine involvement is relatively common in patients dying with lymphoid leukemias. In one autopsy study, 25% of patients with acute lymphoblastic leukemia and 14% with chronic lymphocytic leukemia had involvement of the uterus (Barcos et al. 1987).

Placental Involvement by Lymphoid Neoplasms

Approximately 0.1% of women have a malignancy during pregnancy, subsets of which are lymphomas or leukemias. Rarely, lymphoma or leukemia may be detected in the placenta of these patients (Meguerian-Bedoyan et al. 1997; Catlin et al. 1999; Nishi et al. 2000; Jackisch et al. 2003; Maruko et al. 2004; Chen et al. 2016). Some of the women have been treated successfully, while others have succumbed to their disease. In most instances, placental involvement does not lead to spread of the neoplasm to the fetus, although rarely this does occur (Catlin et al. 1999; Maruko et al. 2004), sometimes with fatal consequences for the newborn (Catlin et al. 1999).

On gross examination, white nodules or white granular areas or infarcts may be present (Meguerian-Bedoyan et al. 1997; Nishi et al. 2000; Chen et al. 2016). On microscopic examination, there is a variably dense infiltrate of neoplastic cells in the intervillous space (maternal circulation). In very rare cases, neoplastic cells are also found within the chorionic villi, involving blood vessels (fetal circulation) (Catlin et al. 1999; Maruko et al. 2004) or the cord blood (van der Velden et al. 2001); involvement of fetal circulation has rarely been associated with the spread of the malignancy to the fetus, resulting in death within a few months of delivery (Catlin et al. 1999). This underscores the importance of careful gross and microscopic examination of the placenta in the setting of maternal malignancy.

The lymphomas and lymphoid leukemias have been of a variety of types, sometimes classified with older nomenclature (Jackisch et al. 2003). Aggressive lymphomas of B and T lineage have been documented to involve the placenta (Meguerian-Bedoyan et al. 1997). Rare cases of mediastinal large B-cell lymphoma (Nishi et al. 2000), diffuse large B-cell lymphoma in an iatrogenically immunosuppressed woman (Chen et al. 2016), ALK+ anaplastic large cell lymphoma (Meguerian-Bedoyan et al. 1997), and Epstein-Barr virus-positive aggressive NK-cell leukemia/lymphoma involving the placenta have been described (Catlin et al. 1999). An example of placental involvement by B-lymphoblastic leukemia, in which neoplastic cells were detected in cord blood, has been reported (van der Velden et al. 2001).

Vaginal Lymphoma

Primary Vaginal Lymphoma

Clinical Features

Lymphoma rarely arises in the vagina (Perren et al. 1992; Ferry and Young 1997; Vang et al. 2000b). As in other parts of the female reproductive organs, primary vaginal lymphoma affects patients over a broad age range; their mean age is in the 40s. Patients present with vaginal bleeding, discharge, pain, dyspareunia, or urinary frequency. Some note a mass. The lesion may compress the urethra and cause anuria (Yoshinaga et al. 2004) or bladder distension (Vang et al. 2000b). Large masses may result in hydronephrosis (Ragupathy and Bappa 2013). The tumors typically result in ill-defined thickening or induration of the vaginal wall, often with invasion of adjacent structures such as the cervix and the rectovaginal septum (Vang et al. 2000b). As in the uterine cervix, the surface epithelium is usually intact, so that Papanicolaou smears are generally negative (Prevot et al. 1992; Ragupathy and Bappa 2013).

Pathologic Features

The pathologic features are similar to those of cervical lymphoma. An estimated 88% are diffuse large B-cell lymphomas (Nasioudis et al. 2017). Rare cases of follicular lymphoma (Harris and Scully 1984; Kosari et al. 2005; Cohn et al. 2007), Burkitt lymphoma, lymphoplasmacytic lymphoma (Kosari et al. 2005), T-cell lymphoma (Prevot et al. 1992; Ferry and Young 1997), and extranodal marginal zone lymphoma (Yoshinaga et al. 2004) have been reported. As in the cervix, vaginal diffuse large B-cell lymphomas are often associated with marked sclerosis and may be “sarcomatoid.” Only a few of these cases have been studied in detail, but they have been CD20+, CD5-, CD10-, BCL6+, MUM1-, CD138-, Epstein-Barr virus (EBV)-, and HHV8-, with somatic mutation of both immunoglobulin and BCL6 genes. These features suggest that the so-called spindle cell variant of diffuse large B-cell lymphoma corresponds to an early germinal center stage of B-cell maturation (Carbone et al. 2006). Rare primary vaginal lymphomas positive for EBV have been reported (Domingo et al. 2004).

Staging, Treatment, and Outcome

Primary vaginal lymphoma typically presents with localized disease (Ann Arbor stage IE or IIE). Treatment has not been uniform, but vaginal lymphoma appears to have a favorable prognosis (Perren et al. 1992; Prevot et al. 1992; Vang et al. 2000b; Domingo et al. 2004; Yoshinaga et al. 2004; Cohn et al. 2007). In one series of eight cases of diffuse large B-cell lymphoma, for example, only one patient died of lymphoma (Vang et al. 2000b).

Secondary Vaginal Lymphoma

Secondary involvement of the vagina by malignant lymphoma, including relapse of lymphoma in the vagina and involvement of the vagina in the setting of widespread disease, is more common than primary vaginal lymphoma (Ferry and Young 1997). The prognosis is much less favorable than for primary disease (Prevot et al. 1992; Vang et al. 2000b).

Vulvar Lymphoma

Primary Vulvar Lymphoma

Primary vulvar lymphoma is exceedingly rare. Patients are adults who present with a nodule, swelling, or induration of the vulva (Ferry and Young 1997; Vang et al. 2000a). In rare cases, the lymphoma has presented as a mass in the region of Bartholin’s gland (Tjalma et al. 2002) or as a clitoral mass (Kosari et al. 2005). Patients appear to be, on average, older than patients with lymphoma arising in other parts of the reproductive tract (Kosari et al. 2005). A few patients have been HIV+ or iatrogenically immunosuppressed (Kaplan et al. 1993; Kaplan et al. 1996; Ferry and Young 1997; Vang et al. 2000a). Diffuse large B-cell lymphoma is the most common type (Ferry and Young 1997; Macleod et al. 1998; Vang et al. 2000a; Tjalma et al. 2002; Clemente et al. 2016), accounting for more than 50% of cases (Nasioudis et al. 2017). Other types are rare. Several cases of lymphoplasmacytic lymphoma (Kosari et al. 2005) and a case of T-cell posttransplantation lymphoproliferative disorder have been described (Kaplan et al. 1993). Vulvar lymphoma is overall relatively aggressive, but occasional patients have long disease-free survival.

Secondary Vulvar Lymphoma

Secondary involvement of the vulva by lymphoma at relapse or in the setting of widespread disease is rare. The lymphomas have been of various types (Fig. 10) (Kosari et al. 2005). Mycosis fungoides may involve the vulva, but typically the skin elsewhere is also involved (Vang et al. 2001b).
Fig. 10

ALK- anaplastic large cell lymphoma involving the vulva. (a) Whole mount shows a dense, diffuse cellular infiltrate extending deep into the biopsy specimen. (b) Neoplastic cells are large and atypical with round, oval, or slightly to deeply indented nuclei, prominent nucleoli, and moderately abundant pink cytoplasm. Mitoses are frequent (oil immersion). (c) An immunostain for CD30 shows diffuse strong staining. The small clusters of positive cells present superficial to the main lesion are clusters of neoplastic cells within lymphatics (immunperoxidase technique on a paraffin section)

Nonneoplastic Lymphoid Proliferations

Chronic inflammation is common in the female genital tract. Two entities, the so-called lymphoma-like lesion and leiomyoma with lymphoid infiltration, stand out as distinctive nonneoplastic lymphoid proliferations that because of their typically extensive, tumor-like nature may mimic lymphoma.

Florid Reactive Lymphoid Hyperplasia (Lymphoma-Like Lesion)

In a small proportion of cases of inflammation of the lower reproductive tract, the lymphoid component is dense and extensive and contains numerous large lymphoid cells, potentially raising the question of malignant lymphoma. The cervix, and less often the endometrium and the vulva, can be involved by these “lymphoma-like lesions” (Young et al. 1985; Hachisuga et al. 1992; Ma et al. 2007). Lymphoma-like lesions almost always occur in women of reproductive age. They may be associated with abnormal vaginal bleeding or may be an incidental finding during work-up of squamous dysplasia or other conditions. Lymphoma-like lesions have occurred in the setting of Epstein-Barr virus, Chlamydia trachomatis, and HIV and HPV infection, with the use of an intrauterine device, and following surgical procedures (Young et al. 1985; Hachisuga et al. 1992; Ma et al. 2007; Geyer et al. 2010; Ramalingam et al. 2012). They are superficially located and are often associated with erosion or ulceration of the overlying epithelium. In the cervix, they typically extend no more than 3 mm into the wall and only rarely extend beyond the deepest endocervical glands. Large masses are very uncommon. The lesions are composed of a polymorphous cellular infiltrate composed of small and large lymphoid cells including immunoblasts, often with admixed plasma cells, and neutrophils. Sclerosis is absent. Lymphoma-like lesions involving the cervix or endometrium typically are found in a background of usual-appearing chronic cervicitis or endometritis, respectively.

Immunohistochemistry reveals a mixture of B and T cells. Large cells are mostly CD20+ B cells; they sometimes co-express CD30. Large B cells may form aggregates, sometimes representing germinal centers (Fig. 11). When germinal centers are present, they are CD20+, CD10+, BCL6+, and BCL2-, consistent with reactive follicles. Plasma cells are polytypic (mixture of κ + and λ+) (Young et al. 1985; Hachisuga et al. 1992; Ma et al. 2007). Surprisingly, finding clonal IGH is common in lymphoma-like lesions (44% in one series) (Geyer et al. 2010). Despite this, patients have been free of lymphoma on follow-up (Young et al. 1985; Hachisuga et al. 1992; Ma et al. 2007; Geyer et al. 2010; Ramalingam et al. 2012).
Fig. 11

Uterine cervix, lymphoma-like lesion. (a) The infiltrate involves the surface epithelium and is composed of loose aggregates of large cells with admixed small lymphocytes, plasma cells, and neutrophils. The large cells were mostly CD20+ B cells; small cells were mostly CD3+ T cells (not shown)

In contrast, lymphoma of the lower reproductive tract usually produces a mass, often with extension into adjacent structures. On microscopic examination, lymphomas are typically composed of a monomorphous population of lymphoid cells (often with sclerosis); tend to invade deeply, sparing a narrow subepithelial zone; and often spread in proximity to blood vessels (Young et al. 1985). In some cases, it may be difficult to distinguish between lymphoma-like lesions and lymphoma. In such cases, rebiopsy may be helpful, as lymphoma-like lesions may resolve spontaneously.

Leiomyoma with Lymphoid Infiltration

Uterine leiomyoma with lymphoid infiltration is a rare lesion that has been described in women between 25 and 53 years of age. On gross examination, the myomas range from 2 to 12 cm. in diameter; they may be grossly typical (Saglam et al. 2005), while others are described as soft (Fig. 12a) (Ohmori et al. 2002; Paik et al. 2004). On microscopic examination, a moderate or marked infiltrate of small lymphocytes with scattered larger lymphoid cells, histiocytes, variable numbers of plasma cells, and, rarely, eosinophils is present. In some cases, reactive follicles may be observed. The infiltrate does not contain neutrophils (Ferry et al. 1989; Ohmori et al. 2002; Paik et al. 2004; Saglam et al. 2005) and is typically confined to the leiomyoma (Fig. 12b) but occasionally extends for a short distance into the adjacent myometrium (Ferry et al. 1989; Saglam et al. 2005). Immunohistochemical analysis has shown B cells (CD20+, CD79a+) in follicles and T cells (CD3+, CD45RO+) outside follicles. In several cases, there is a predominance of CD8+ or TIA-1+ T cells, consistent with a cytotoxic phenotype (Paik et al. 2004; Saglam et al. 2005). In a single case, molecular analysis revealed clonal rearrangement of the T-cell receptor gamma chain gene (Saglam et al. 2005); the significance of this is uncertain as the patient was well with no evidence of lymphoma 3 years later. Occasionally clonal B- or T-cell populations may be found in inflammatory processes, and they are not necessarily indicative of lymphoma.
Fig. 12

Leiomyoma with lymphoid infiltrate. (a) Gross examination of a cross section of the uterus shows one small, white, discrete typical leiomyoma (right) and one yellow-tan leiomyoma with lymphoid infiltration (left). (b) The leiomyoma is extensively involved by a lymphoid infiltrate; the adjacent myometrium is uninvolved. The infiltrate contains multiple lymphoid follicles, mainly near the periphery of the leiomyoma

The etiology of this reactive process is not known, but several patients have had an intrauterine contraceptive device that could have played a role in initiating a chronic inflammatory process (Ferry et al. 1989). One patient had clinical features suggesting an underlying autoimmune disease (Saglam et al. 2005). Several patients had been treated with gonadotropin-releasing hormone (GnRH) agonists (Saglam et al. 2005). Prominent vascular damage within the leiomyomas in addition to lymphoid infiltration has been described in association with luteinizing hormone-releasing hormone therapy (Ohmori et al. 2002). It is possible that the degenerative changes associated with such therapy may elicit an inflammatory response within leiomyomas (Ohmori et al. 2002; Paik et al. 2004).

In all cases of leiomyoma with lymphoid infiltration, follow-up, when reported, has been uneventful (Ferry et al. 1989; Saglam et al. 2005). One of the patients in our original series (Ferry et al. 1989) had a large lipoma excised several months after the diagnosis of leiomyoma with lymphoid infiltration; the lipoma had multiple lymphoid aggregates. This patient was well, with no evidence of lymphoma 8 years later (unpublished data).

The differential diagnosis of leiomyoma with lymphoid infiltration includes uterine lymphoma, but the polymorphous nature of the infiltrate and its confinement to the leiomyoma help to distinguish it from lymphoma. Inflammatory pseudotumor produces a mass lesion within the uterus, but it is composed of fibroblasts and myofibroblasts, rather than smooth muscle cells, and has an infiltrate that includes neutrophils. Pyomyomas are leiomyomas with marked neutrophilic infiltrate with suppurative necrosis and should not be confused with leiomyoma with lymphoid infiltration.

Differential Diagnosis of Lymphoma of the Lower Reproductive Tract

The differential diagnosis of lymphoma of the lower reproductive tract includes chronic inflammatory processes, carcinoma, sarcomas, and others. Lymphomas, particularly lymphomas with sclerosis, are prone to artifactual distortion by crush artifact, compounding the difficulty in reaching the correct diagnosis. Like many cervical lymphomas, idiopathic retroperitoneal fibrosis is a sclerosing process that may result in ureteral obstruction; the presence of many B cells outside follicles and atypical lymphoid cells favor lymphoma, but recognizing atypical lymphoid cells may be difficult if crush artifact is extensive. Features useful in differential diagnosis of selected entities are presented in Table 2.
Table 2

Differential diagnosis of lower female genital tract lymphoma

Diagnosis

Features against lymphoma

Features supporting lymphoma

Lymphoma-like lesion

Absence of mass

Superficial location

Erosion

Mixed infiltrate

Absence of sclerosis

Evidence of STD or EBV infection

Mass present

Deep extension

Subepithelial sparing, no erosion

Monomorphous infiltrate

Presence of sclerosis

Carcinoma, especially small cell carcinoma

Cohesive growth, nuclear molding in best preserved areas

Obliteration of normal structures, e.g., endometrial or endocervical glands

Presence of SCIS or ACIS

Cytokeratin+ atypical cells

Discohesive tumor cells

Tumor cells: CBs, IBs, or multilobated cells

Sparing of normal structures

No SCIS or ACIS

CD45+, CD20+ neoplastic cells (for B-cell lymphoma)

Spindle cell sarcoma

Absence of admixed CBs, IBs, multilobated cells

CD45-, CD20- neoplastic cells

CBs, IBs, or multilobated cells admixed with spindle cells

CD45+, CD20+ neoplastic cells (for B-cell lymphoma)

Endometrial stromal sarcoma, low-grade

Characteristic tongue-like growth

Evenly but loosely distributed cells

Small arterioles conspicuous

Foam cells may be admixed

CD45-, CD20-, CD10+

Closely packed tumor cells

Blood vessels usually not prominent

CD45+, CD20+, CD10−/+ (for B-cell lymphoma)

Embryonal rhabdomyosarcoma

Pediatric patient

Alternating hyper- and hypocellular areas

Myxoid background

Desmin+, myogenin+, Myo-D1+ neoplastic cells

Adult patient

Even distribution of atypical cells

Sclerotic background

CD45+, CD20+ neoplastic cells (for B-cell lymphoma)

Extramedullary hematopoiesis, especially with erythroid predominance

Homogeneous dark chromatin characteristic of erythroid elements

Presence of megakaryocytes and maturing myeloid elements

Evidence of concurrent myeloproliferative disorder

Vesicular or stippled chromatin characteristic of lymphoid cells

Absence of other hematopoietic cell lines

STD sexually transmitted disease, EBV Epstein-Barr virus, SCIS squamous cell carcinoma in situ, ACIS adenocarcinoma in situ, IB immunoblast, CB centroblast

Myeloid Neoplasms of the Female Reproductive Organs

The female reproductive organs are rarely involved by myeloid sarcoma, a mass-forming neoplasm composed of primitive myeloid elements. Myeloid sarcoma was initially described with the name of chloroma, because there was sometimes a sufficiently high myeloperoxidase content to impart a green color to the neoplasm. Subsequently the term granulocytic sarcoma was put forward, to encompass those tumors that lacked a green color (Rappaport 1966). The WHO classification uses the term myeloid sarcoma for tumor masses composed of myeloblasts or immature myeloid cells, present in extramedullary sites and in the bone. The designation monoblastic sarcoma is used for the uncommon myeloid sarcomas composed of monoblasts (Brunning et al. 2001).

Clinical Features

Myeloid sarcomas involve the reproductive organs in patients from early childhood to advanced age, with a median age of approximately 40 years (Garcia et al. 2006). It occurs in three settings: (1) with known acute myeloid leukemia, (2) with myeloproliferative neoplasms or related disorders, and (3) with no other evidence of hematopoietic disease (Neiman et al. 1981). Nearly half of the patients have a prior history of a myeloid neoplasm, which is usually acute myeloid leukemia, but which has occasionally been a myeloproliferative neoplasm or a myelodysplastic syndrome/myeloproliferative neoplasm; these cases thus represent relapse or progression of the patients’ prior myeloid neoplasms. Myeloid sarcoma in a patient with a myeloproliferative neoplasm often coincides with blast crisis (Neiman et al. 1981). In the FAB classification, the leukemias have included M1, M2, M3, M4 (Garcia et al. 2006), and M5 types (Hernandez et al. 2002). Several have been associated with acute myeloid leukemia with abnormal marrow eosinophilia (AML, M4eo) (Drinkard et al. 1995; Garcia et al. 2006). Nearly all patients with myeloid sarcoma and no evidence of bone marrow disease will eventually develop overt leukemia (Neiman et al. 1981). However, in a few patients with isolated myeloid sarcoma who are treated aggressively with combination chemotherapy and radiation, there may be long survival without the development of acute leukemia (Meis et al. 1986; Imrie et al. 1995). In general, patients have not had conditions predisposing to the development of myeloid neoplasia, although one patient had prior chemotherapy for breast cancer (Pullarkat et al. 2007). A few patients with acute myeloid leukemia and myeloid sarcoma involving the reproductive organs were exposed to radiation at Hiroshima or Nagasaki (Liu et al. 1973). Most cases involve either the ovaries or the uterus. Vaginal and vulvar myeloid sarcomas are rare (Oliva et al. 1997; Garcia et al. 2006; Wasson et al. 2015).

Pathologic Features

Microscopic examination reveals a diffuse infiltrate of discohesive atypical cells that may spare certain normal structures, such as endometrial glands, or developing follicles in the ovary. A single-file pattern of growth is common. Mitoses are frequent. The neoplastic cells are medium-sized, with oval to irregular, sometimes distinctly indented nuclei with fine chromatin and small nucleoli. Cytoplasm ranges from very scant to moderate in quantity, sometimes with a pink color, reflecting the presence of myeloid granules. Scattered apoptotic cells are often present. A minority of cases show geographic necrosis. Scattered eosinophil precursor cells may be identified (Oliva et al. 1997; Garcia et al. 2006). The lesions may be subclassified as blastic, immature, or differentiated based on the degree of cellular differentiation (Brunning et al. 2001; Garcia et al. 2006). The blastic type is composed mainly of myeloblasts, the immature type contains promyelocytes in addition to myeloblasts, and the differentiated type contains in addition more mature cells in the neutrophil series (Brunning et al. 2001).

Immunophenotyping on paraffin sections typically shows neoplastic cells that are positive for myeloperoxidase, lysozyme, CD117, and CD43 and often for CD34 and CD68. CD45 (leukocyte common antigen) is usually positive but may be dimly expressed or even negative on paraffin sections, potentially leading to difficulty in recognizing such lesions as hematologic (Brunning et al. 2001; Pathak et al. 2005; Garcia et al. 2006). B- and T-cell-specific antigens are not expressed. Tumor cells are also positive for chloroacetate esterase. Monoblastic sarcomas are lysozyme+ and CD68+ but do not express myeloperoxidase (Brunning et al. 2001).

Ovarian Involvement by Myeloid Neoplasia

Myeloid leukemias rarely present initially in the ovary, but infiltration of the ovary at autopsy is quite common. In an autopsy study of 1206 patients with leukemia who died between 1958 and 1982, there was ovarian involvement by acute myeloid leukemia in 11% and by chronic myeloid leukemia in 9% (Barcos et al. 1987). The authors noted a significant reduction in extramedullary tumor during the later years of the study and attributed this to more aggressive therapy.

The diagnosis of ovarian myeloid sarcoma is appropriate when immature myeloid cells form an ovarian tumor. Among patients with clinically evident myeloid sarcoma, the ovary is rarely involved. None of 21 women with myeloid sarcoma studied by Neiman et al. (1981) and only 1 of 9 women studied by Meis et al. (1986) had involvement of the adnexa. A few women and very rare children have had what apparently was isolated ovarian myeloid sarcoma or ovarian myeloid sarcoma as the first manifestation of acute myeloid leukemia (Osborne and Robboy 1983; Ferry and Young 1991; Drinkard et al. 1995; Oliva et al. 1997; Ding et al. 2015). The ovary can also be a clinically apparent, but usually not an isolated, site of relapse following chemotherapy for acute myelogenous leukemia (Oliva et al. 1997; Cunningham 2013).

The tumors can be unilateral or bilateral and range up to 19 cm in diameter (mean, 10 to 12 cm). They are typically solid, soft, and white or red-brown, but cystic degeneration, hemorrhage, or necrosis may be seen (Osborne and Robboy 1983; Ferry and Young 1991). A few cases have had a distinct green color on gross inspection (Oliva et al. 1997), thus warranting a designation of chloroma.

Uterine Involvement by Myeloid Neoplasia

Myeloid sarcoma of the uterus is uncommon (Oliva et al. 1997). In two combined series of patients with myeloid sarcoma from a variety of sites, 1 of 30 women had myeloid sarcoma involving the corpus, and 1 had cervical involvement (Neiman et al. 1981; Meis et al. 1986). Patients have been adults, with a mean age in the sixth decade, who typically present with abnormal vaginal bleeding, sometimes accompanied by abdominal pain (Spahr et al. 1982; Harris and Scully 1984; Hernandez et al. 2002; Pathak et al. 2005; Pullarkat et al. 2007; Wasson et al. 2015). Several patients had cervical smears positive for malignancy, although a specific diagnosis was not made (Spahr et al. 1982; Ferry and Young 1991). One cervical smear was considered positive for malignant lymphoma or leukemia (Spahr et al. 1982), and in one, the diagnosis of lymphoma was suggested (Ferry and Young 1991). The cervix is involved more often than the corpus, but both may be involved simultaneously (Harris and Scully 1984; Pullarkat et al. 2007). In only a minority of cases is tumor confined to the uterus (Harris and Scully 1984). In most cases tumor involved other reproductive organs, including the vagina (Spahr et al. 1982; Ferry and Young 1991), vulva (Spahr et al. 1982), ovaries, or fallopian tubes (Hernandez et al. 2002; Garcia et al. 2006) sometimes with parametrial involvement (Ferry and Young 1991), with or without extension to the pelvic side walls (Pathak et al. 2005). Bulky pelvic masses may be associated with hydroureter (Pullarkat et al. 2007). Staging in some cases has revealed concurrent involvement of sites outside the reproductive tract, including the lymph nodes (Spahr et al. 1982; Harris and Scully 1984; Garcia et al. 2006), gastrointestinal tract (Spahr et al. 1982), breast (Garcia et al. 2006), or mediastinum (Garcia et al. 2006). Bone marrow examination may reveal acute myeloid leukemia (Garcia et al. 2006). Among those without acute myeloid leukemia at presentation, progression to acute myeloid leukemia is common (Harris and Scully 1984; Ferry and Young 1991; Hernandez et al. 2002). One woman with chronic myeloid leukemia developed myeloid sarcomas of the breast and the endometrium shortly after blast crisis (Spahr et al. 1982). One patient with a history of breast cancer treated with chemotherapy developed an isolated therapy-related uterine monoblastic sarcoma expressing CD45, CD43, CD68, and lysozyme associated with a translocation of KMT2A gene (formerly, mixed-lineage leukemia gene [MLL]) at 11q23 (Pullarkat et al. 2007); acute myeloid leukemia with 11q23 abnormalities can arise as a complication of chemotherapy that includes DNA topoisomerase II inhibitors.

On gross examination, the lesions appear as nodules, ulcers, or large masses, often extending into the vagina or paracervical soft tissue (Ferry and Young 1991). The tumors range from gray-tan or gray-blue to green (Harris and Scully 1984). On microscopic examination, the immature granulocytes tend to infiltrate around, rather than destroy normal structures, a pattern that is also seen in cases of lymphoma. The histological appearance is similar to myeloid sarcoma in other sites.

The correct diagnosis was often not rendered on initial biopsy, particularly in earlier reports, when routine immunophenotyping was less prevalent and fewer antibodies were available for paraffin section immunohistochemistry. The most common misdiagnosis was lymphoma (Harris and Scully 1984). One cervical biopsy was initially interpreted as small cell squamous cell carcinoma, and in another, the tumor was not recognized (Ferry and Young 1991).

Involvement of the uterus by other forms of hematologic disorders is very unusual. Extramedullary hematopoiesis may be seen in the endometrium, involving the endometrial stroma, or less often elsewhere in the reproductive tract. In approximately half of cases, there is an associated hematologic neoplasm (Valeri et al. 2002). We have seen an unpublished case of primary myelofibrosis in which there was extensive extramedullary hematopoiesis (“myeloid metaplasia”) in the myometrium (Fig. 13).
Fig. 13

Endometrium, extramedullary hematopoiesis. Several megakaryocytes with large, dark, atypical nuclei are scattered in the endometrial stroma. A loose cluster of nucleated red blood cells is present near the bottom of the image

Vaginal and Vulvar Involvement by Myeloid Neoplasia

Patients with acute myelogenous leukemia occasionally have leukemic infiltration of the vagina (Ferry and Young 1991). In addition, a handful of cases of myeloid sarcoma of the vagina have been documented (Fig. 14a, b). Oliva and co-workers described three cases in women aged 66, 73, and 76 years, presenting with postmenopausal bleeding, an abnormal Papanicolaou smear, and the presence of a mass. One of them had a prior history of acute myeloid leukemia, one presented with vaginal myeloid sarcoma but was found to have acute myeloid leukemia when a marrow biopsy was performed, and one had apparently isolated myeloid sarcoma. At last follow-up, one was alive with disease, and two had died (Oliva et al. 1997). Another case was described in a 48-year-old woman who presented with vaginal pain and leukorrhea; physical examination revealed an isolated vaginal mass that was green. Evaluation revealed a tumor that was CAE+, CD43+, CD45+, and lysozyme+ and negative for CD20, CD3, S-100, and cytokeratin. Despite treatment the patient rapidly developed overt leukemia, classified as acute myeloid leukemia, M5a. Cytogenetic analysis revealed a complex karyotype. The patient developed myeloid sarcomas in other sites, including the breast and thigh, and she died of leukemia 10 months after presentation (Hernandez et al. 2002). One 39-year-old patient with Down’s syndrome presented with symptoms related to a myeloid sarcoma of the cervix and vagina (Ferry and Young 1991). Another case is presented without details in the large series of myeloid sarcomas reported by Neiman et al. (1981).
Fig. 14

Vagina, myeloid sarcoma. (a) An infiltrate of primitive, discohesive neoplastic cells with finely dispersed chromatin and scant cytoplasm permeates the fibromuscular stroma. (b) The neoplastic cells are positive for myeloperoxidase (immunoperoxidase technique on a paraffin section)

A myeloid sarcoma presenting as a mass in the vulva of an elderly woman has been described; additional work-up showed that she had acute myeloid leukemia (Ersahin et al. 2007). In another case, a woman with a myelodysplastic/myeloproliferative neoplasm developed what appeared to be a rash of the clitoris, but that proved to be myeloid sarcoma; acute myeloid leukemia developed 2 months later (Garcia et al. 2006).

The prognosis of myeloid sarcoma in the reproductive tract is difficult to assess because only small numbers of patients have been studied over many years and treatment has varied. There are only a few sizable series (Oliva et al. 1997; Garcia et al. 2006), and follow-up has often been short. Among patients presenting initially with isolated myeloid sarcoma, progression to acute myeloid leukemia is common (Garcia et al. 2006) even among patients who are treated aggressively (Hernandez et al. 2002). In general, patients with myeloid sarcoma of the female reproductive organs have had a poor prognosis, which will likely improve with advances in therapy for acute myeloid leukemia. Occasional patients, including those with isolated myeloid sarcoma and those with more widespread disease at presentation, do achieve long-term disease-free survival (Oliva et al. 1997; Garcia et al. 2006).

Differential Diagnosis

The majority of cases of myeloid sarcoma in some large series were initially misdiagnosed, most often as lymphoma (Neiman et al. 1981; Meis et al. 1986). This occurs less often currently because of greater use of immunophenotyping and larger number of antibodies available for paraffin section immunohistochemistry. Compared to lymphoma, myeloid sarcoma is generally composed of cells with more finely dispersed chromatin, often with more cytoplasm than a lymphoid cell with the same size of nucleus. The cytoplasm may have a distinct red color. The identification of eosinophilic myelocytes in some cases is very helpful in making a diagnosis of a tumor of primitive myeloid origin. Establishing a diagnosis of myeloid sarcoma is not difficult in a patient who has been previously diagnosed with an acute myeloid leukemia that has been well characterized by flow cytometry but may be challenging without such a history. Using a panel of antibodies to myeloid-associated antigens, such as lysozyme, myeloperoxidase, CD68, CD34, and CD117, in conjunction with markers of B cells (such as CD20) and T cells (such as CD3) and, in selected cases, markers of non-hematolymphoid cells, such as cytokeratin and S-100, will usually establish a diagnosis. It should be noted that certain T-lineage-associated antigens, such as CD43, are not lineage-specific and may be expressed in myeloid sarcomas. Monoblastic sarcomas may express CD4 (usually more faintly than mature T helper cells), as well as CD56, usually considered an NK-cell marker, and they may be negative for CD34 and CD117, markers traditionally considered to detect primitive cells so that judicious interpretation of unusual or unexpected immunophenotypic results is required. See Table 1.

Differentiating pyometra from myeloid sarcoma of the endometrium can at times be difficult. Some myeloid sarcomas show differentiation to mature forms. In the setting of severe acute inflammation, degenerated neutrophils may have nuclei that lose their distinctive lobation and appear round and thus may potentially be mistaken for primitive cells. A diagnosis of myeloid sarcoma should only be made if there is a convincing population of well-preserved primitive myeloid elements.

Histiocytic Neoplasms of the Female Reproductive Organs

Langerhans Cell Histiocytosis

Clinical Features

Langerhans cell histiocytosis, previously known as histiocytosis X, occurs in one of three clinical syndromes: (1) eosinophilic granuloma, characterized by unifocal disease; (2) Hand-Schüller-Christian disease, a chronic progressive multifocal disease typically involving one organ system; and (3) Letterer-Siwe disease, an aggressive, fulminant disorder with multifocal, multisystem involvement by Langerhans cell histiocytosis (Weiss et al. 2001; Montero et al. 2003).

Langerhans cell histiocytosis occasionally involves the reproductive organs, most often the vulva and infrequently the vagina or cervix (Issa et al. 1980; Lieberman et al. 1996). Endometrial and ovarian involvement has also been reported rarely (Axiotis et al. 1991). Uterine involvement is almost always accompanied by vulvar or vaginal lesions or both (Issa et al. 1980; Ferry and Young 1991). Rare cases of congenital Langerhans cell histiocytosis accompanied by placental involvement are reported (Terry et al. 2013). There appears to be a strong association between diabetes insipidus and the presence of mucocutaneous lesions of Langerhans cell histiocytosis, particularly in the female reproductive tract (Issa et al. 1980). Langerhans cell histiocytosis frequently has manifestations in other sites, prior to, or subsequent to, the reproductive organ involvement (Axiotis et al. 1991), in particular in the form of bony lesions (Issa et al. 1980; Padula et al. 2004). Isolated Langerhans cell histiocytosis involving the reproductive organs is rare (Santillan et al. 2003).

Langerhans cell histiocytosis in the reproductive tract falls into one of four patterns (Axiotis et al. 1991; Padula et al. 2004):
  1. 1.

    Isolated genital disease, with local recurrence in some cases but no distant involvement

     
  2. 2.

    Isolated genital disease with subsequent dissemination to other sites, most often the bone, accompanied in some cases by diabetes insipidus

     
  3. 3.

    Initial presentation with oral or skin disease and subsequent genital and multiorgan disease

     
  4. 4.

    Initial presentation with diabetes insipidus and subsequent genital and multiorgan disease

     

Patients with Langerhans cell histiocytosis involving the reproductive tract range from 1 to 85 years; most have been young adults (Issa et al. 1980; Axiotis et al. 1991; Chang et al. 2013). The presenting complaints are usually vulvar pruritus or dyspareunia (Issa et al. 1980; Lieberman et al. 1996). The lesions can be single or multiple (Issa et al. 1980; Santillan et al. 2003). They are white or yellow-brown ulcers, papules, ulcerated nodules (Issa et al. 1980; Venizelos et al. 2006), erythematous plaques, red papules (Santillan et al. 2003), or irregular friable masses (Ferry and Young 1991) and may mimic primary syphilis, squamous cell carcinoma, lymphogranuloma venereum (Issa et al. 1980), herpes simplex viral infection, or melanoma (Ferry and Young 1991). The lesions in the cervix are yellow-brown, brown, or red papules (Issa et al. 1980; Ferry and Young 1991).

Pathologic Features

Microscopically they consist of submucosal nodules or sheets of Langerhans cells with pale, deeply creased, or folded nuclei with delicate nuclear membranes, pale chromatin, and relatively abundant pale pink cytoplasm. There is often an admixture of eosinophils and lymphocytes in some areas, as well as neutrophils in some cases (Fig. 15a, b). The cellular infiltrate is often associated with ulceration and a scale crust (Issa et al. 1980). In the placenta, Langerhans cell histiocytosis may have a low-power appearance resembling chronic villitis (Terry et al. 2013). On microscopic examination, Langerhans cell histiocytosis can be confused with an inflammatory disorder, lymphoma, or carcinoma, but the presence of numerous Langerhans cells admixed with eosinophils should suggest the correct diagnosis. The Langerhans cells have a distinctive immunophenotype: S-100+, CD1a+, and Langerin+. They are also variably positive for CD45, CD68, and lysozyme and negative for CD30, myeloperoxidase, and B- and T-cell-specific markers. Like other histiocytes and monocytes, they may be CD4+ (Weiss et al. 2001; Padula et al. 2004). The majority of cases harbor the BRAF V600E mutation, believed to underlie the pathogenesis of Langerhans cell histiocytosis; such cases express BRAF by immunohistochemistry (Roden et al. 2014). It is uncertain whether Langerhans cell histiocytosis derives from neoplastic transformation of mature Langerhans cells in squamous epithelium or other tissues or whether Langerhans cell histiocytosis is derived from an abnormal marrow-derived cell that assumes characteristics of Langerhans cells (Montero et al. 2003).
Fig. 15

Vulva, Langerhans cell histiocytosis. (a) Low power shows sheets of pale histiocytes, aggregates of small lymphocytes, and occasional eosinophils beneath squamous mucosa. (b) High power shows Langerhans cells with large, oval nuclei with nuclear folds and abundant pale pink cytoplasm, with a few admixed small lymphocytes and eosinophils

Treatment and Outcome

The behavior of Langerhans cell histiocytosis involving the reproductive organs is difficult to predict. Because of its rarity and variable behavior, uniform therapy has not been employed. Occasionally, small vulvar lesions may remit spontaneously, although nodular lesions do not (Issa et al. 1980). The lesions may be treated initially with simple excision or with topical steroids. If these methods are unsuccessful, local radiation therapy may be effective but may be followed by recurrences. In a few cases, systemic steroids or chemotherapy (methotrexate, vincristine, vinblastine, and others) have been used (Issa et al. 1980; Axiotis et al. 1991; Lieberman et al. 1996; Chang et al. 2013). Since Langerhans cells play an important role as antigen-presenting cells in the immune response, immunomodulatory agents such as interferons have been tested as treatment for Langerhans cell histiocytosis. Dramatic responses of cutaneous and anogenital Langerhans cell histiocytosis have been described with interferons and thalidomide (Montero et al. 2003), although response is not always sustained. Thalidomide may be effective because it is an inhibitor of tumor necrosis factor (TNF), which plays a role in generating Langerhans cells from marrow precursors (Santillan et al. 2003). Whatever the therapy, incomplete responses, local recurrences, and distant relapses are common (Santillan et al. 2003; Padula et al. 2004; Venizelos et al. 2006).

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Authors and Affiliations

  1. 1.James Homer Wright Pathology Laboratories of the Massachusetts General HospitalDepartment of Pathology, Harvard Medical SchoolBostonUSA

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