Miscellaneous Lesions and Tumors of the Uterine Cervix and Corpus

FIGURE 9.1 Cervical cone with lymphoma. Note the heavy infiltrate surrounding the endocervical glands and extending deep into the stroma (A); endocervical epithelium is not involved by the process (B).

FIGURE 9.2 Lymphoma involving the endometrium, dense neoplastic infiltrate with a vague nodular pattern (A); the endometrial glands are spared (B).

Greater than 80% of non–Hodgkin lymphomas involving the uterus, whether as primary or secondary disease, are B-cell lymphomas, mainly diffuse large B-cell lymphoma (e-Figs. 9.6 and 9.7) followed by follicular lymphoma. However, marginal zone lymphoma, Burkitt lymphoma, mucosa-associated lymphoid tissue–type lymphoma, and intravascular lymphoma have all been reported (1,37). In addition, rare cases of Hodgkin disease and a rare case of lymphomatoid granulomatosis have been reported (5,8). T-cell lymphoma is much less common, and involvement of the uterus is almost always part of a disseminated process (9). Only rare cases of primary T-cell lymphoma, NK lymphoma, and Hodgkin lymphoma involving the uterus have been reported (1 4,5,915).

The differential diagnosis includes other tumors discussed in this chapter, including neuroendocrine carcinoma and neuroectodermal tumor as well as the following entities:

Florid reactive lymphoid hyperplasia (lymphoma-like lesion of the cervix) (e-Figs. 9.89.11) (1618)

Heterogeneous inflammatory infiltrate composed of small lymphocytes, plasma cells, and immunoblasts

Inflammatory infiltrate extends into the cervical epithelium frequently, resulting in ulceration

When nodular aggregates are present, they are less well circumscribed and have a germinal center–like appearance

Leiomyoma with extensive lymphoid infiltration (e-Figs. 9.12 and 9.13) (19,20)

Heterogeneous lymphoid infiltrate often with plasma cells and occasional histiocytes

Plump smooth muscle cells

Severe chronic endometritis

Follicular cervicitis

Sarcoma (considered for cases with associated stromal sclerosis or spindled cells) (3,21)

Granulocytic sarcoma (extramedullary myeloid cell tumor, chloroma, monocytic sarcoma) (e-Figs. 9.149.16)

Usually a previous history of acute myeloid leukemia (AML), myeloproliferative disorder, or myelodysplastic syndrome; less commonly as a mass involving the uterine body or cervix at initial presentation and some can evolve into AML

Diffuse infiltrate of moderately sized cells with irregular/angulated nuclei and fine chromatin; eosinophilic precursors, neutrophils, and monocytoid differentiation can be seen

Naphthol AS-D chloroacetate esterase stain, myeloperoxidase, lysozyme, and CD117 (c-Kit) positive and negative for CD3 and CD20 (22)

As inflammatory lesions in the uterus are much more common than lymphomas, it is more likely that a lymphoma would be overlooked and that the infiltrate be ascribed to a reactive process. Therefore, when marked inflammation is present, care should be taken to observe whether the infiltrate is heterogeneous. It should be noted that a small subset of reactive lymphoid hyperplasia of the cervix has demonstrated clonal expansion possibly secondary to local antigen challenge (18). Overreliance on molecular techniques when the histologic and clinical picture are not supportive of lymphoma should be avoided.

Immunoperoxidase studies are required to make a definitive diagnosis of lymphoma. An immunoperoxidase panel that includes CD45, CD3, and CD20 should establish the lymphoid nature of the cells and show a mixture of T and B cells if the process is reactive. If the infiltrate is shown to have a predominance of B cells, then a diagnosis of lymphoma should be entertained (e-Figs. 9.17 and 9.18).

Once the diagnosis of lymphoma is made, it is important to establish the stage of the tumor. This requires a thorough physical examination, blood tests, bone marrow biopsy, and imaging studies. Criteria to distinguish primary from secondary lymphoma involving the uterus include clinical confinement to the uterus, no evidence of leukemia, and a long interval between the diagnosed uterine lymphoma and any extrauterine lymphoma (5,23). The distinction is important because some have reported that localized lymphomas confined to the cervix may be cured by resection alone or in combination with radiotherapy (1). In addition, it is important to subclassify the type of lymphoma since prognosis, and in some cases, treatment may differ based on the lymphoma subtype. Subclassification is usually made with the use of immunohistochemistry studies and in some cases by either genetics or molecular genetics (1,24). Table 9.1 outlines lymphoma subtypes and the immunoperoxidase studies frequently used to evaluate them.

Neuroendocrine Tumors of the Cervix

Neuroendocrine tumors of the cervix account for up to 2% of cervical neoplasias (25,26). According to the College of American Pathologists and the National Cancer Institute workshop, these tumors are classified as follows (27):

Typical (classical) carcinoid tumor

Atypical carcinoid tumor

Small cell neuroendocrine carcinoma

Large cell neuroendocrine carcinoma

An association with high-risk human papillomavirus subtypes has been described for atypical carcinoid, small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma (2832).

Typical and Atypical Carcinoid Tumor

The histologic features of these tumors resemble their counterparts in the gastrointestinal tract and lung. Typical carcinoids are composed of small, uniform cells with finely granular chromatin arranged in trabeculae, cords, or nests. Mitoses are inconspicuous (Fig. 9.3, e-Fig. 9.19). When increased cellularity, nuclear pleomorphism, and increased mitoses (approximately 5 to 10 per 10 high-power fields [HPFs]) are observed, the tumor is considered to be an atypical carcinoid. In addition, atypical carcinoid may have foci of necrosis (Fig. 9.4, e-Figs. 9.209.22). Immunohistochemically, these tumors express chromogranin, synaptophysin, and CD56. The experience with carcinoid tumors of the cervix and their behavior is limited. However, atypical carcinoid tumors of the uterine cervix have been reported to have metastases (32). Therefore, it is important to distinguish typical from atypical carcinoid. In the gastrointestinal tract, mitotic index and Ki-67 labeling index are utilized to predict behavior, with tumors containing ≤2 mitoses per 10 high power fields (HPFs) and having a Ki-67 index of ≤2% considered low-grade/G1 (typical carcinoid) tumors. Those tumors with 2 to 10 mitoses per 10 HPFs and a Ki-67 index of 3% to 20% are of intermediate grade (33). There is some suggestion that these thresholds may be site specific (34), so it remains to be determined whether these criteria and grading scheme could be applied to carcinoid tumors of the cervix. Because the most important differential diagnosis of these neoplasms is metastatic carcinoid/atypical carcinoid tumor, usually from the gastrointestinal tract, inclusion of this information could be clinically helpful. The distinction of a metastatic from a primary cervical carcinoid tumor must be made on clinical grounds. Also, it has to be kept in mind that a thorough microscopic examination is required before rendering the diagnoses of carcinoid or atypical carcinoid of the uterine cervix since these neoplasms can be seen adjacent to high-grade neuroendocrine carcinomas.

FIGURE 9.3 Typical carcinoid tumor, uniform cells arranged in acinar structures.

FIGURE 9.4 Atypical carcinoid tumor. Note the mitotic figure.

Small Cell and Large Cell Neuroendocrine Carcinoma

Small cell and large cell neuroendocrine carcinomas also tend to resemble their counterparts in the respiratory tract and are characterized by early nodal and distant metastases with a worse prognosis than squamous cell carcinoma (25,35). Grossly, these tumors tend to be bulky, and patients often present with vaginal bleeding. Occasionally, patients may have an associated paraneoplastic syndrome; Cushing syndrome, carcinoid syndrome, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have all been reported (26).

FIGURE 9.5 Small cell neuroendocrine carcinoma, the neoplastic cells have scanty cytoplasm and nuclei with hyperchromatic, finely granular chromatin and numerous mitoses.

Microscopically, small cell neuroendocrine carcinoma is composed of small cells (less than two to three times the diameter of a resting lymphocyte) with hyperchromatic, finely granular nuclei with inconspicuous to absent nucleoli. Mitoses are usually numerous and necrosis is frequently observed (Fig. 9.5, e-Figs. 9.239.25). The differential diagnosis may include lymphoma, squamous cell carcinoma, and neuroectodermal tumors. Attention to the light microscopic features is of utmost importance, as neuroendocrine markers (chromogranin, synaptophysin, and CD56) may be negative in some cases (26,36,37). Of the immunomarkers, CD56 is the least specific. Thyroid transcription factor 1 (TTF-1) can be positive in up to 34% of the cases (38). For tumors in which the morphology is not classic, a positive cytokeratin stain may help exclude lymphoma and often a neuroectodermal tumor. A panel that includes CD45, for lymphoma, and p40, for squamous differentiation (39), may be helpful in ruling out a small cell neuroendocrine carcinoma.

The architectural features of large cell neuroendocrine carcinoma include insular, trabecular, glandular, and solid patterns. The cells are larger than those in small cell carcinomas, cytoplasm may be abundant, and vesicular nuclei with prominent nucleoli are often encountered (40,41). Mitotic figures and apoptotic bodies are frequent, and comedo-like or geographic necrosis is often present (Fig. 9.6, e-Figs. 9.26–9.36) (26,40,41).

FIGURE 9.6 Large cell neuroendocrine carcinoma, the neoplastic cells have a moderate amount of cytoplasm and some of the nuclei show nucleoli.

Neuroendocrine carcinoma (small or large cell type) is frequently observed in combination with other more common subtypes of cervical carcinoma (i.e., squamous cell carcinoma and adenocarcinoma both in situ and invasive) (28,40,42). It is important to exclude the presence of neuroendocrine differentiation in tumors of combined histology because the neuroendocrine component, even when minor, appears to predict more aggressive behavior (43).

Primitive Neuroectodermal Tumors

The term primitive neuroectodermal tumor is used to encompass tumors that belong to the Ewing/peripheral PNET family of tumors as well as tumors that more closely resemble central-type PNETs such as medulloblastoma and neuroblastoma. Both central- and peripheral-type PNETs have been described in the cervix and endometrium (4457). These tumors are typically composed of small, fairly uniform cells with scant cytoplasm, round to oval nuclei, and inconspicuous nucleoli. These cells are often arranged diffusely but may exhibit a vague, nested pattern or trabeculae. The majority of tumors have, at least focally, a fibrillary background. Occasionally, rosettes are identified and, rarely, mature elements such as ganglion cells or astrocytes (Fig. 9.7, e-Figs. 9.37 and 9.38) (50). Neuroectodermal tumors are usually negative for keratin and epithelial membrane antigen (EMA). Synaptophysin, CD99, and neurofilament protein are the markers most reliably positive in these tumors (e-Figs. 9.39–9.41) (50). Neuroectodermal differentiation has been observed as a component of mixed endometrial tumors associated with endometrioid adenocarcinoma, carcinosarcoma, and adenosarcoma (51,52,57,58). Combined tumors have also been reported in the cervix, but may be less common. It is hypothesized that tumors lacking a chromosome 22 rearrangement may be more similar to central-type neuroectodermal tumors such as neuroblastoma and medulloblastoma, whereas those with such a rearrangement should be considered within the peripheral PNET/Ewing sarcoma family of tumors. In tumors that express synaptophysin and neurofilament but are negative for cytokeratin, consideration should be given to performing either polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) to exclude the presence of a chromosome 22 rearrangement because a chemotherapeutic regimen more akin to that used for peripheral PNET/Ewing sarcoma outside of the gynecologic tract may be used. Recognition of a neuroectodermal tumor is important, as it may be a marker of more aggressive disease.

FIGURE 9.7 Primitive neuroectodermal tumor, small cells with scanty cytoplasm arranged in trabeculae (A); note the presence of rosettes (B).


The presence of non-neoplastic, melanin-laden cells in cervical and/or endometrial stroma has been reported, but is a rare, usually incidental phenomenon (59,60). The differential diagnosis of pigmented lesions in the cervix and endometrium includes the following:

Incidental melanosis (61)

Melanin pigment in the basal epithelium

No melanin extravasation or melanin-laden cells in the stroma

Benign blue nevus (Fig. 9.8, e-Figs. 9.42–9.44) (6268)

Elongated, wavy, heavily pigmented dendritic cells just below the endocervical epithelium

Also known as stromal melanocytic foci (62,63,66)

Malignant melanoma (Fig. 9.9, e-Figs. 9.45 and 9.46)

Junctional activity with atypical melanocytes at the primary site

In the cervix, stromal infiltration is seen

Absence of clinically evident primary or regressed primary elsewhere

FIGURE 9.8 Blue nevus, heavily pigmented dendritic cells surrounding the endocervical epithelium.

FIGURE 9.9 Malignant melanoma of the uterine cervix, junctional component (A); invasive component with epithelioid cells (B).

Malignant melanoma primary in the endometrium or cervix is rare (6978) and in the setting of a small biopsy the potential for misdiagnosis is high, given the tendency of melanoma to mimic more commonly encountered entities in the cervix. A panel of markers including pan keratin, CD45, and S100 should differentiate carcinoma and lymphoma from melanoma. Tumors positive only for S100 or negative for all three markers may be further investigated. If melanoma is a serious consideration, then HMB-45, MART-1, and MiTF are useful immunoperoxidase studies in the diagnosis of melanoma (79). When melanoma is identified in a cervical or endometrial biopsy, one must always rule out metastatic melanoma, which is more common than a uterine primary (75).


Although originally thought to represent a pseudotumor, inflammatory myofibroblastic tumor is now regarded as a true neoplasm due to rare reports of local recurrence and/or metastasis and the demonstration of a translocation involving the ALK receptor gene at chromosome 2p23 in many of these tumors (80,81). This uncommon neoplasm in the uterus (8085) is characterized by spindle to stellate and occasional ganglion-like cells with minimal to no pleomorphism, a variably myxoid stroma, and a lymphoplasmacytic infiltrate. The mitotic index is low with an average mitotic count of 2 mitoses per 10 HPFs (Fig. 9.10, and e-Figs. 9.47–9.52). Although these tumors usually have an epicenter in the myometrium, occasionally they can protrude into the endometrial cavity and potentially be part of an endometrial sampling (e-Figs. 9.53 and 9.54) (80,8284). In cases with a noticeable myxoid background, the differential diagnosis is with myxoid smooth muscle tumors. While the latter expresses smooth muscle markers (smooth muscle actin, desmin, and caldesmon), the former may variably express these markers as well (83,84). Although the experience is limited, all uterine inflammatory myofibroblastic tumors tested for ALK by immunohistochemistry have exhibited cytoplasmic staining in 25% to . 50% of cells (e-Fig. 9.55) (80,8385). Expression of this marker has not been reported in smooth muscle tumors or in other tumors in the differential diagnosis including endometrial stromal tumors with myxoid features.

FIGURE 9.10 Inflammatory myofibroblastic tumor, spindle cells in a slightly myxoid background (A) and inflammatory cells (B).


Germ cell tumors arising in the endometrium or cervix are extremely rare with only isolated case reports of yolk sac tumor (YST) and teratoma occurring at these anatomical sites (86102).

Endometrial or cervical YST, either pure or as part of a malignant mixed Müllerian tumor, shares histologic features with its ovarian counterpart. Most commonly, a reticular or microcystic pattern is noted at least focally. Cystic spaces are lined by primitive-appearing cells with pale to clear cytoplasm and hyperchromatic, irregular nuclei (e-Figs. 9.56–9.59). Schiller-Duval bodies may be conspicuous in only a minority of these tumors. Most YSTs have eosinophilic, periodic acid–Schiff (PAS)-positive, and diastase-resistant intra- and extracellular hyaline bodies. Occasionally, variants of YST such as glandular and hepatoid may be encountered, which can mimic either an endometrioid carcinoma or a hepatoid carcinoma. An immunoprofile of AFP (+), cytokeratin 7 (-), and EMA (-) is supportive of a diagnosis of YST over endometrioid carcinoma or clear cell carcinoma, the other primary tumor in the differential diagnosis.

Primary teratomas of the endometrium or cervix may be mature or immature. The presence of immature neuroepithelium is required for the diagnosis of the latter (Fig. 9.11, e-Figs. 9.60–9.62). The differential diagnosis of this type of tumor includes malignant mixed Müllerian tumor, endometrioid adenocarcinoma with heterologous elements, and a PNET. In contrast to a malignant mixed Müllerian tumor, the mesenchymal and epithelial elements in a uterine teratoma usually have a benign histologic appearance, although a rare case containing malignant transformation of these elements has been reported (98). Occasionally, the immature rosette-like structures encountered in immature teratoma can simulate endometrioid adenocarcinoma. Immature teratoma is distinguished by a fibrillary background (e-Fig. 9.63) and associated glial cells. The immature neuroepithelial structures observed in teratoma can also be seen in PNET. However, in PNETs a monotonous population of small round blue cells is the predominant feature. In addition PNETs lack the combination of mature elements and immature neuroepithelium that is seen in immature teratoma.

FIGURE 9.11 Immature teratoma in endometrium.


Lesions encompassed under the category of gestational trophoblastic disease have an abnormal proliferation of trophoblastic cells and can be divided into two groups: those associated with abnormal development of pregnancy, or molar disease (hydatidiform mole, persistent gestational trophoblastic disease, and invasive mole), and tumors arising from trophoblastic tissue (choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor). These lesions may arise in either the cervix or the endometrium and their diagnosis on a limited sample can be difficult, due in part to overlapping histologic features among some of these entities as well as possible confusion with certain lesions of different histotypes, either benign or malignant.

Hydatidiform Mole

Classically, hydatidiform mole is characterized by villi with variable degrees of hydropic change and abnormal trophoblastic proliferation (103). Molar pregnancy has been separated into two categories, partial mole and complete mole, based on the cytogenetic composition of the conceptus (104106). The terminology reflects the extent to which the histologic changes are observed. In the later stages of a molar pregnancy, both complete and partial moles may have “grape-like” villi that are visible grossly. In partial mole, such villi are often intermixed with normal placental tissue, and fetal parts may be identified. In contrast, complete mole is composed exclusively of hydropic villi (105107). The classic histologic features diagnostic of a molar pregnancy are villous edema and concentric hyperplastic, trophoblastic proliferation. When the villous edema is fully developed, central clearing, or cistern formation, may be observed (103,107). In complete moles, the villi tend to be uniformly enlarged and rounded with marked trophoblastic proliferation that may have atypia (Fig. 9.12, e-Figs. 9.64–9.68). Partial moles usually do not have uniform development of hydropic villi, which results in a dimorphic population consisting of hydropic villi admixed with smaller, fibrotic immature villi (Fig. 9.13, e-Figs. 9.69 and 9.70) (107). In contrast to complete moles that may have more rounded villi, the villi in partial moles tend to be irregular with scalloped borders and stromal trophoblastic pseudoinclusions (Fig. 9.14, e-Figs. 9.71–9.73). The circumferential proliferation of the trophoblast is usually less pronounced in a partial mole compared with a complete mole (104,107,108). In the past, the presence of vessels within the villous mesenchyme was considered a feature typically seen in partial moles (104

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Jul 4, 2016 | Posted by in UROLOGY | Comments Off on Miscellaneous Lesions and Tumors of the Uterine Cervix and Corpus
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