Reference Work Entry

Blaustein’s Pathology of the Female Genital Tract

pp 1137-1158

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

  • Judith A. FerryAffiliated withDepartment of Pathology, Massachusetts General Hospital Email author 

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 rare 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.

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 rare 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 rare 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. 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. T-cell lymphoma is very uncommon and the natural killer (NK)-cell lymphoma and Hodgkin’s lymphoma are exceptional [21, 40]. Rare cases of lymphoma arising in the setting of HIV infection or iatrogenic immunosuppression [37, 42, 58] and a few cases of women with a family history of hematologic neoplasia have been described [23]. Endemic Burkitt’s lymphoma is known to have a tendency to involve the ovaries.

Ovarian Lymphoma

Primary Ovarian Lymphoma

Overall, fewer than 1% of lymphomas present with ovarian involvement [14, 21, 22] and fewer than 1.5% of neoplasms arising in the ovary are lymphomas. However, in countries where Burkitt’s lymphoma is endemic, approximately 50% of malignant ovarian neoplasms in childhood are Burkitt’s lymphoma [78].

Clinical Features

Patients range in age from 18 months to 74 years [21], with a peak incidence in the thirties or forties [14, 21, 90]. Occasionally lymphoma develops during pregnancy [21, 49]. Rare patients have been HIV+ [42]. The presenting complaints are generally nonspecific symptoms related to the presence of a mass [14, 61, 90]. A minority have fatigue, weight loss, fever, or abnormal vaginal bleeding [14]. Rarely the lymphoma is an incidental finding [90].

Pathologic Features

Ovarian lymphomas range from microscopic [90] to large masses up to 25 cm in diameter with an average size of 11–14 cm [21, 90]. The external surfaces are usually intact and may be smooth or nodular. On sectioning, the tumors may be soft and fleshy or firm and rubbery, depending on the degree of cellularity and associated sclerosis. They are usually white, tan, or gray-pink and a minority has cystic degeneration, hemorrhage or necrosis [21]. Very rare cases of lymphoma in association with, possibly arising from, a teratoma have been described [53].

The most common lymphoma is diffuse large B-cell type, followed by Burkitt’s lymphoma and follicular lymphoma [14]. Adolescents and children almost always have diffuse, aggressive lymphomas, including Burkitt’s lymphoma, B lymphoblastic lymphoma and diffuse large B-cell lymphoma [40] 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 [21].

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 [78], or be elongate and grow in a storiform pattern, mimicking a sarcoma (Fig. 21.1a–c ). A few diffuse large B-cell lymphomas have a component of follicular lymphoma [61, 90]. Tumor cells are CD20+, and in the few cases studied, expression of bcl6, CD10, and bcl2 is common [90].
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Fig. 21.1

Ovary, diffuse large B-cell lymphoma with spindle neoplastic 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’s Lymphoma

Ovarian Burkitt’s lymphoma is most commonly encountered among children and adolescents [40]. Burkitt’s lymphoma is more often bilateral than other ovarian lymphomas [41]. It is hypothesized that Burkitt’s lymphoma occurring in pregnancy has a tendency to involve hormonally stimulated organs, such as the ovary [49].

Both sporadic and endemic Burkitt’s lymphoma may present with ovarian involvement [13, 43], and ovarian involvement in the setting of immunodeficiency (HIV infection) has been described [42]. The histologic features are the same as those found in other sites. There is a diffuse proliferation of medium-sized, uniform cells with round nuclei containing stippled chromatin and several small nucleoli per cell 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. 21.2a and b ). Occasionally, neoplastic cells are somewhat more pleomorphic, chromatin may be more vesicular, and there is only a single nucleolus within each nucleus. In some cases, designated Burkitt’s lymphoma with plasmacytoid differentiation, there is slightly more cytoplasm and tumor cells contain monotypic cytoplasmic immunoglobulin [13, 43]. Children with Burkitt’s lymphoma usually have typical morphology, while Burkitt’s 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–, Ki67 ∼100% +, and the neoplastic cells harbor a translocation involving c-myc [10, 13, 40, 43]. Endemic Burkitt’s lymphoma typically contains Epstein-Barr virus (EBV), while a minority of cases of sporadic Burkitt’s lymphoma and immunodeficiency-associated Burkitt’s lymphoma in HIV+ patients are positive for EBV [13, 43].
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Fig. 21.2

Ovary, Burkitt’s 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’s lymphoma

Follicular Lymphoma
Ovarian follicular lymphoma mainly affects 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. 21.3a d ) [41, 90].
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Fig. 21.3

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 CD30+ anaplastic large cell lymphoma of T lineage, and B and T lymphoblastic lymphoma presenting with ovarian involvement have been reported [33, 40, 76, 90]. Morphology, in conjunction with expression of terminal deoxynucleotidyl transferase (TdT) distinguishes precursor B and T-cell neoplasms from mature B and T-cell lymphomas.

Staging, Treatment and Outcome

At laparotomy there is involvement of one or both ovaries with approximately equal frequency. Staging discloses extraovarian spread in most cases, often involving pelvic or paraaortic lymph nodes and occasionally peritoneum, other genital organs, or distant sites [14, 21]. 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 [14, 51, 90].

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 [3, 21]. Any type of lymphoma may spread to the ovary, but mediastinal large B-cell lymphoma has a distinct tendency to involve the ovary (Fig. 21.4a and b ) [12, 79, 97]. Acute lymphoblastic leukemia that relapsed in the ovaries during bone marrow remission has been reported [7, 93]. The ovaries were usually not the only site of relapse; there is frequent involvement of the peritoneum, omentum, fallopian tubes, lymph nodes, and central nervous system [7, 93].
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Fig. 21.4

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, and primary small cell carcinoma of hypercalcemic and pulmonary types, adult granulosa cell tumor [61], spindle cell sarcoma, undifferentiated carcinoma, and myeloid sarcoma [21]. 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 non-lymphoid neoplasms because large lymphoid cells can have varying morphology and may overlap in size and shape with other types of neoplastic cells. Burkitt’s 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. Selected features that aid in differential diagnosis are presented in Table 21.1 .
Table 21.1

Differential diagnosis of ovarian diffuse large B-cell lymphoma

Non-lymphoid tumor

Problem

Differential features

Usual immunophenotype of non-lymphoid 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, 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, 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

One case of primary tubal marginal zone B-cell lymphoma associated with salpingitis [63], one possible case of primary tubal follicular lymphoma (Fig. 21.5a and B ), [20] and a bilateral primary tubal peripheral T-cell lymphoma [24] have been described.
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Fig. 21.5

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 [61]. Most are diffuse large B-cell lymphoma or Burkitt’s lymphoma [86]; follicular lymphoma, peripheral T-cell lymphoma and lymphoblastic lymphoma/leukemia have also been reported [7, 61, 67, 86]. Tubal infiltration is also seen at autopsy in cases of disseminated lymphoma [30].

Uterine Lymphoma

Primary Uterine Lymphoma

Less than 1% of extranodal lymphomas arise in this site [22]. Lymphoma arises more often in the cervix than in the corpus, with a 10:1 ratio in one series [87], although other series have not shown such a striking excess of cervical lymphomas [40].

Clinical Features

Uterine lymphoma affects adults over a broad age range [28], with a mean and a median age in the fifth decade [17, 23, 28, 50, 71]. The most common presenting symptom is abnormal vaginal bleeding [1, 8, 9, 11, 21, 23, 28, 50, 86]. Less common complaints are dyspareunia, perineal, pelvic, or abdominal pain. A few patients have systemic symptoms such as fever or weight loss [17, 21, 71]. 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. 21.6 ). The lymphoma may also form a discrete submucosal tumor [8, 28], a polypoid or multinodular lesion [9, 25, 28], or a fungating, exophytic mass; ulceration is unusual [28]. The tumors have been variously described as fleshy, rubbery, or firm, and white-tan to yellow [28]. Extensive local spread to sites such as vagina, parametria, or even pelvic side walls is common [9, 11, 23, 28] and invasion into the urinary bladder is described [38]. Patients commonly exhibit hydronephrosis secondary to ureteral obstruction [11, 21, 28]. Lymphomas of the uterine corpus are usually fleshy or soft, pale gray, yellow, or cream-colored. They may form a polypoid mass or diffusely infiltrate the endometrium, sometimes with deep invasion of the myometrium [21, 28].
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Fig. 21.6

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

The microscopic appearance of the lymphomas is similar to that of the same types of lymphoma seen in nodal and other extranodal sites. 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 [1, 9, 23, 25, 38, 86, 87], accounting for about 70% of cases [17, 86]. Neoplastic cells may be centroblasts, immunoblasts, or multilobated large lymphoid cells, or a combination of these. Cervical lymphomas are frequently associated with prominent sclerosis [25, 41, 86], which may be associated with a cord-like arrangement or spindle-shaped tumor cells [28]. The spindle cell pattern may be sufficiently prominent to mimic a sarcoma resulting in usage of the terms “spindle cell variant” [5] and “sarcomatoid variant” [35]. Rare examples of intravascular large B-cell lymphoma presenting with involvement of the uterus and adnexa have been described [81, 94]. Microscopic examination revealed large atypical lymphoid cells filling the lumens of blood vessels (Fig. 21.7a and b ). One case had the unusual feature of CD5 co-expression by the large atypical CD20+, CD79a+ B cells; neoplastic cells were also positive for EBV [94].
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Fig. 21.7

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 [40]. 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. 21.8a f ) [28].
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Fig. 21.8

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. 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 (c–f, immunoperoxidase technique on paraffin sections)

Extranodal Marginal Zone Lymphoma (MALT Lymphoma)

A few cases of marginal zone B cell lymphoma arising in the endometrium or in the cervix have been described [21, 23, 40, 84, 86, 87].

In 1997 three cases of a distinctive type of low-grade endometrial B-cell lymphoma was described [84]. All affected women were in their sixties and the lymphomas were all incidental findings and confined to the uterus. On microscopic examination all were composed of large nodules with a monotonous population of small lymphoid cells with slightly irregular nuclei and scant cytoplasm adjacent to and sometimes surrounding endometrial glands. Immunohistochemical analysis showed B cells with aberrant co-expression of CD43. The immunoglobulin heavy chain genes were clonally rearranged. Follow-up, when available, was uneventful. The authors were reluctant to subclassify these lymphomas as marginal zone type because of lack of certain features that would support that diagnosis including absence of conspicuous lymphoepithelial lesions, lack of a marginal zone pattern, and lack of reactive follicle centers. In addition, only limited immunophenotyping could be performed. Subsequently, a case with identical histologic features was reported in which neoplastic cells were CD20+, bcl2+, without expression of CD5, bcl6, or cyclin D1. The cellular nodules were associated with altered CD21+ follicular dendritic cell meshworks [33]. This case was interpreted as an endometrial marginal zone lymphoma. These cases are best classified as endometrial marginal zone lymphomas, albeit with distinctive clinical and pathologic features (Fig. 21.9a c ).
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Fig. 21.9

Endometrium, 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) crowded nodules of small lymphoid cells (immunoperoxidase technique on a paraffin section)

Rare Lymphomas

A few cases of Burkitt’s lymphoma [40, 64] and rare cases of B lymphoblastic lymphoma [40], peripheral T cell lymphoma [39], and cervical extranodal NK/T-cell lymphoma [86] have been reported. The uterus is rarely the site of involvement by B-cell post-transplantation lymphoproliferative disorder [58]. Although Hodgkin’s lymphoma in the female genital organs is vanishingly rare, a case of classical Hodgkin’s lymphoma, lymphocyte depletion type, confirmed with immunophenotyping showing CD15 and CD30 expression by the neoplastic cells, has been reported [40].

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 [8, 87]. The type of therapy has varied. In a few cases, young women have been successfully treated using combination chemotherapy and some have preserved fertility [21, 25]. Uterine lymphoma has a relatively good prognosis [9, 21, 59, 86]. Between 70% and 90% of patients are alive and free of disease at last follow-up [8, 17]. Most prognostic information on uterine lymphoma is related to lymphoma arising in the cervix. The 5-year survival for cervical lymphoma is estimated to be approximately 80% [50, 87]. There is not enough information to draw definite conclusions about the prognosis of the rare endometrial lymphomas. However, those with localized disease tend to do well, including, in particular, the endometrial marginal zone lymphomas [23, 84]. Those with advanced disease presenting with endometrial involvement have a worse prognosis [28].

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 [21, 40, 86]. 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, lymphoblastic lymphoma [21, 40, 86], T lymphoblastic leukemia [46] and extranodal NK/T-cell lymphoma [57]. The prognosis is much less favorable than that of primary uterine lymphoma [57, 87].

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 [3].

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 [6, 34, 52, 54, 62]. 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 [6, 52], sometimes with fatal consequences for the newborn [6].

On gross examination, white nodules or white granular areas or infarcts may be present [54, 62]. 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) [6, 52] or the cord blood [85]; involvement of fetal circulation has rarely been associated with spread of the malignancy to the fetus, resulting in death within a few months of delivery [6]. 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 [34]. Aggressive lymphomas of B and T lineage have been documented to involve the placenta [54]. Rare cases of mediastinal large B-cell lymphoma [62], anaplastic large cell lymphoma (ALK-positive) [54], and Epstein–Barr virus-positive aggressive NK-cell leukemia/lymphoma involving the placenta have been described [6]. An example of B-lymphoblastic leukemia, in which neoplastic cells were detected in cord blood, has been reported [85].

Vaginal Lymphoma

Primary Vaginal Lymphoma

Clinical Features

Lymphoma rarely arises in the vagina [21, 71, 89]. 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 forties. Patients present with vaginal bleeding, discharge, pain, dyspareunia or urinary frequency. Some note a mass. The lesion may compress the urethra and cause anuria [95] or bladder distension [89]. 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 [89]. As in the uterine cervix, surface epithelium is usually intact, so that Papanicolaou smears are generally negative [72].

Pathologic Features

The pathologic features are similar to those of cervical lymphoma. Nearly all of the lymphomas are diffuse large B-cell type [21, 40, 89]. Rare cases of follicular lymphoma [11, 28, 40], Burkitt’s lymphoma, lymphoplasmacytic lymphoma [40], T-cell lymphoma [21, 72], and marginal zone lymphoma [95] 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)–, HHV-8–, 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 [5]. Rare primary vaginal lymphomas positive for EBV have been reported [15].

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 [11, 15, 71, 72, 89, 95]. In one series of eight cases of diffuse large B-cell lymphoma, for example, only one patient died of lymphoma [89].

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 [21]. The prognosis is much less favorable than for primary disease [72, 89].

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 [21, 88]. In rare cases the lymphoma has presented as a mass in the region of Bartholin’s gland [82], or as a clitoral mass [40]. Patients appear to be, on average, older than patients with lymphoma arising in other parts of the reproductive tract [40]. A few patients have been HIV+ or iatrogenically immunosuppressed [21, 36, 37, 88]. Diffuse large B-cell lymphoma is the most common type [21, 48, 82, 88]. Other types are rare. Several cases of lymphoplasmacytic lymphoma have been reported [40] and a case of T-cell post-transplantation lymphoproliferative disorder has been described [37]. 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 [40]. Mycosis fungoides may involve the vulva but, typically, skin elsewhere is also involved [86].

Nonneoplastic Lymphoid Proliferations

Two entities, 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.

Lymphoma-Like Lesions

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” [27, 47, 96]. Lymphoma-like lesions almost always occur in women of reproductive age, and may be associated with abnormal vaginal bleeding. 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. Lymphoma-like lesions involving the cervix or endometrium, typically, are found in a background of usual-appearing chronic cervicitis or endometritis, respectively. Large cells (CD20+ B cells) may form aggregates, which may represent follicle centers. Sclerosis is absent (Fig. 21.10 ). When follicle centers are present, they are CD20+, CD10+, bcl6+, and bcl2–, consistent with reactive follicles. Plasma cells are polytypic (mixture of κ+ and λ+). A few cases have occurred in the setting of Epstein-Barr virus infection or pelvic inflammatory disease [27, 47, 96]. In contrast, lymphoma of the lower reproductive tract usually produces a gross abnormality of the involved organ often with extension of the process into adjacent structures. On microscopic examination, lymphomas are 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 [96]. 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.
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Fig. 21.10

Uterine cervix, lymphoma-like lesion. 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)

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 [75], while others are described as soft (Fig. 21.11a ) [65, 69]. 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 [19, 65, 69, 75] and is typically confined to the leiomyoma (Fig. 21.11b ), but occasionally extends for a short distance into the adjacent myometrium [19, 75]. 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 [69, 75]. In a single case, molecular analysis revealed clonal rearrangement of the T-cell receptor gamma chain gene [75]; 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.
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Fig. 21.11

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 [19]. One patient had clinical features suggesting an underlying autoimmune disease [75]. Several patients had been treated with gonadotropin-releasing hormone (GnRH) agonists [75]. Prominent vascular damage within the leiomyomas in addition to lymphoid infiltration has been described in association with luteinizing hormone-releasing hormone therapy [65]. It is possible that the degenerative changes associated with such therapy may elicit an inflammatory response within leiomyomas [65, 69].

In all cases of leiomyoma with lymphoid infiltration follow-up, when reported, has been uneventful [19, 75]. One of the patients in the original series [19] 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 21.2 .
Table 21.2

Differential diagnosis of lower female genital tract lymphoma

Diagnosis

Features against lymphoma

Features supporting lymphoma

Lymphoma-like lesion

Absence of mass

Mass present

Superficial location

Deep extension

Erosion

Subepithelial sparing, no erosion

Mixed infiltrate

Monomorphous infiltrate

Absence of sclerosis

Presence of sclerosis

Evidence of PID or EBV infection

 

Carcinoma, especially small cell carcinoma and lymphoepithelial cell carcinoma

Cohesive growth, nuclear molding in best preserved areas

Discohesive tumor cells

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

Tumor cells: CBs, IBs, or multilobated cells

Presence of SCIS or ACIS

Sparing of normal structures

Cytokeratin+ atypical cells

No SCIS or ACIS

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

Spindle cell sarcoma

Absence of admixed CBs, IBs, multilobated cells

CBs, IBs, or multilobated cells admixed with spindle cells

CD45–, CD20– neoplastic cells

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

Endometrial stromal sarcoma, low-grade

Characteristic tongue-like growth

Closely packed tumor cells

Evenly but loosely distributed cells

Blood vessels usually not prominent

Small arterioles conspicuous

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

Foam cells may be admixed

CD45–, CD20–, CD10+

Embryonal rhabdomyosarcoma

Pediatric patient

Adult patient

Alternating hyper- and hypocellular areas

Even distribution of atypical cells

Myxoid background

Sclerotic background

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

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

Extramedullary hematopoiesis, especially with erythroid predominance

Homogeneous dark chromatin characteristic of erythroid elements

Vesicular or stippled chromatin characteristic of lymphoid cells

Presence of megakaryocytes and maturing myeloid elements

Absence of other hematopoietic cell lines

Evidence of concurrent myeloproliferative disorder

PID, pelvic inflammatory 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 lesion 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 [74]. The WHO Classification uses the term myeloid sarcoma for tumor masses composed of myeloblasts or immature myeloid cells, present in extramedullary sites and in bone. The designation monoblastic sarcoma is used for the uncommon myeloid sarcomas composed of monoblasts [4].

Clinical Features

Myeloid sarcomas involve the reproductive organs in patients from early childhood to advanced age, with a median age of approximately 40 years [26]. It occurs in three settings: (1) known acute myelogenous leukemia; (2) chronic myeloproliferative diseases or related disorders; and (3) with no other evidence of hematopoietic disease [60]. 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 chronic myeloproliferative disease or a myelodysplastic syndrome/myeloproliferative disorder; these cases thus represent relapse or progression of the patients’ prior myeloid neoplasms. Myeloid sarcoma in a patient with a chronic myeloproliferative disorder often coincides with blast crisis [60]. In the FAB classification, the leukemias have included M1, M2, M3, M4 [26], and M5 types [29]. Several have been associated with acute myeloid leukemia with abnormal marrow eosinophilia (AML, M4 eo) [16, 26]. Nearly all patients with myeloid sarcoma and no evidence of bone marrow disease will eventually develop overt leukemia [60]. However, in a few patients with isolated myeloid sarcoma who are treated aggressively with a combination of chemotherapy and radiation, there may be long survival without the development of acute leukemia [31, 55]. In general, patients have not had conditions predisposing to the development of myeloid neoplasia, although one patient had prior chemotherapy for breast cancer [73]. A few patients with acute myeloid leukemia and myeloid sarcoma involving the reproductive organs were exposed to radiation at Hiroshima or Nagasaki [45]. Most cases involve either the ovaries or the uterus. Vaginal and vulvar myeloid sarcomas are rare [26, 66].

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 [26, 66]. The lesions may be subclassified as blastic, immature or differentiated based on the degree of cellular differentiation [4, 26]. 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 [4].

Immunophenotyping on paraffin sections typically shows neoplastic cells that are positive for myeloperoxidase, lysozyme, CD117, 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 [4, 26, 70]. B and T-cell specific antigens are not expressed. Tumor cells are also positive for chloroacetate esterase. Monoblastic sarcomas are lysozyme+, CD68+, but do not express myeloperoxidase [4].

Ovarian Involvement by Myeloid Neoplasia

Leukemia rarely presents initially in the ovary, but infiltration of the ovary at autopsy is quite common. In an autopsy study of 1,206 patients with leukemia who died between 1958 and 1982, there was ovarian involvement by acute myelogenous leukemia in 11% and by chronic myelogenous leukemia in 9% [3] 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 the 21 women with myeloid sarcoma studied by Neiman et al. [60] and only 1 of 9 women studied by Meis et al. [55] had involvement of the adnexa.

A few women and very rarely children have had what apparently was isolated ovarian myeloid sarcoma or ovarian myeloid sarcoma as the first manifestation of acute myeloid leukemia [16, 20, 66, 67]. The ovary can also be a clinically apparent, but usually not an isolated, site of relapse following chemotherapy for acute myelogenous leukemia [66].

The tumors can be unilateral or bilateral and range up to 19 cm in diameter (mean, 10–12 cm). They are typically solid, soft, and white or red-brown, but cystic degeneration, hemorrhage, or necrosis may be seen [20, 67]. A few cases have had a distinct green color on gross inspection [66], thus warranting a designation of chloroma.

Uterine Involvement by Myeloid Neoplasia

Myeloid sarcoma of the uterus is uncommon [66]. In two combined series of patients with myeloid sarcoma from a variety of sites, one of 30 women had myeloid sarcoma involving the corpus, and one had cervical involvement [55, 60]. Patients have been adults, with a mean age in the sixth decade, who typically present with abnormal vaginal bleeding, sometimes accompanied by abdominal pain [28, 29, 70, 73, 80]. Several patients had cervical smears positive for malignancy, although a specific diagnosis was not made [20, 80]. One was considered positive for malignant lymphoma or leukemia [80] and in one, the diagnosis of lymphoma was suggested [20]. The cervix is involved more often than the corpus, but both may be involved simultaneously [28, 73]. In only a minority of cases is tumor confined to the uterus [28]. In most cases tumor involved other reproductive organs, including the vagina [20, 80], vulva [80], ovaries, or fallopian tubes [26, 29], sometimes with parametrial involvement [20], with or without extension to the pelvic side walls [70]. Bulky pelvic masses may be associated with hydroureter [73]. Staging in some cases has revealed concurrent involvement of sites outside the reproductive tract, including lymph nodes [26, 28, 80], gastrointestinal tract [80], breast [26], or mediastinum [26]. Bone marrow examination may reveal acute myeloid leukemia [26]. Among those without acute myeloid leukemia at presentation, progression to acute myeloid leukemia is common [20, 28, 29]. One woman with chronic myelogenous leukemia developed granulocytic sarcomas of the breast and the endometrium, shortly after blast crisis [80]. 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 the mixed – lineage leukemia gene at 11q23 [73]; 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 [20]. The tumors range from gray-tan or gray-blue to green [28]. 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 malignant lymphoma [28]. One cervical biopsy was initially interpreted as small-cell squamous cell carcinoma and in another, the tumor was not recognized [20].

Involvement of the uterus in other forms of myeloproliferative 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 the cases, there is an associated hematologic neoplasm [83]. This author has seen an unpublished case of chronic idiopathic myelofibrosis in which there was extensive extramedullary hematopoiesis (“myeloid metaplasia”) in the endometrium (Fig. 21.12 ).
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Fig. 21.12

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 [20]. In addition, a handful of cases of myeloid sarcoma of the vagina have been documented (Fig. 21.13a and b ). Oliva and coworkers 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 [66]. 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+, lysozyme+, and negative for CD20, CD3, S100, 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 [29]. One 39-year-old patient with Down’s syndrome presented with symptoms related to a myeloid sarcoma of the cervix and vagina [20]. Another case is presented without details in the large series of myeloid sarcomas reported by Neiman et al. [60].
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Fig. 21.13

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 [18]. In another case, a woman with a myelodysplastic/myeloproliferative disorder developed what appeared to be a rash of the clitoris, but that proved to be myeloid sarcoma; acute myeloid leukemia developed two months later [26].

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 [26, 66], and follow-up has often been short. Among patients presenting initially with isolated myeloid sarcoma, progression to acute myeloid leukemia is common [26] even among patients who are treated aggressively [29]. 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 [26, 66].

Differential Diagnosis

The majority of cases of myeloid sarcoma in some large series were initially misdiagnosed, most often as malignant lymphoma [55, 60]. 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 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. In those cases in which a myeloid sarcoma represents the first presentation with disease, it is essential to confirm this unusual diagnosis with immunohistochemistry. 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), T cells (such as CD3), and in selected cases, markers of non-hematolymphoid cells, such as cytokeratin and S-100. 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, so that judicious interpretation of unusual or unexpected immunophenotypic results is required (See Table 21.1 ).

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 the three clinical syndromes: (1) eosinophilic granuloma, which is characterized by unifocal disease; (2) Hand–Schüller–Christian disease which is 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 [56, 92].

Langerhans cell histiocytosis occasionally involves the reproductive organs, most often the vulva and infrequently the vagina or cervix [32, 44]. Endometrial and ovarian involvement has also been reported rarely [2]. Uterine involvement is almost always accompanied by vulvar or vaginal lesions, or both [20, 32]. 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 [32]. Langerhans cell histiocytosis frequently has manifestations in other sites, prior to, or subsequent to, the reproductive organ involvement [2], in particular, in the form of bony lesions [32, 68]. Isolated Langerhans cell histiocytosis involving the reproductive organs is rare [77].

Langerhans cell histiocytosis in the reproductive tract falls into one of the four patterns [2, 68]:
  1. 1.

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

     
  2. 2.

    Isolated genital disease with subsequent dissemination to other sites most often 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 [2, 32]. The presenting complaints are usually vulvar pruritus or dyspareunia [32, 44]. The lesions can be single or multiple [32, 77] They are white or yellow-brown ulcers, papules, ulcerated nodules [32, 91], erythematous plaques, red papules [77], or irregular friable masses [20] and may mimic primary syphilis, squamous cell carcinoma, lymphogranuloma venereum [32], herpes simplex viral infection, or melanoma [20]. The lesions in the cervix are yellow-brown, brown or red papules [20, 32].

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. 21.14a and b ). The cellular infiltrate is often associated with ulceration and a scale crust [32]. 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: they express both S-100 protein and CD1a. 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+. Immunohistochemical studies thus play an important role in confirming the diagnosis [68, 92]. 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 [56].
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Fig. 21.14

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 their rarity and variable behavior, uniform therapy has not been employed. Occasionally, small vulvar lesions may remit spontaneously, although nodular lesions do not [32]. The lesions may be treated initially with simple excision or with topical hydrocortisone. 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 [2, 32, 44]. 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 [56], 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 [77]. Whatever the therapy, incomplete responses, local recurrences, and distant relapses are common [68, 77, 91].

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