Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

Abstract

Melanocytic, germ cell, trophoblastic, lymphoid, and myeloid tumors are typically encountered in other organs but may rarely involve the uterine cervix. These neoplasms can be diagnostically challenging as they closely mimic primary cervical carcinomas radiologically, clinically, and/or histologically. The experience of the pathologist, a high index of suspicion, pertinent clinical history, careful pathologic examination, and appropriate ancillary studies are essential in arriving at the correct diagnosis. This chapter summarizes definitions, key macroscopic, histologic and cytologic features, characteristic immunoprofiles and main disease entities in the differential diagnosis of melanocytic, germ cell, trophoblastic, lymphoid, and myeloid tumors of the uterine cervix.

12.1 Melanocytic Tumors (Malignant Melanoma)

12.1.1 Definition

A malignant neoplasm composed of cells with melanocytic differentiation. The diagnosis of primary cervical malignant melanoma requires the demonstration of junctional activity in the epithelium in the absence of similar changes elsewhere in the body. The key features of malignant melanoma of the cervix are described in Table 12.1.

Table 12.1 Key features of cervical melanocytic tumors

12.1.2 Synonyms

Invasive melanoma.

12.1.3 Etiology

Primary cervical malignant melanoma has a melanocytic derivation. The proof of the presence of melanocytes in the cervical mucosa was first demonstrated in 3.5% of cervical biopsies in 1959 and further evidenced by diagnosing cervical melanocytic nevi [1,2,3,4]. Various hypotheses have been proposed for primary gynecologic melanomas, including its origin from Schwann cells, melanocyte migration from the neural crest, and melanocytic differentiation from the endocervical epithelium [2, 5,6,7,8]. No specific risk factors have been identified [9], but high levels of estrogen and association with human papillomavirus (HPV) infection and radiation therapy have been reported [10,11,12]. There are limited data on the distribution of mutations in primary cervical melanoma. However, non-vulvar gynecologic melanomas have been shown to harbor mutations in KIT and NRAS in approximately 30% of cases, while BRAF mutations are very rare.

12.1.4 Macroscopy

Malignant melanoma can present as single or multiple pigmented, polypoid to fungating masses or (in approximately 45% of cases) as amelanotic masses mimicking a primary cervical neoplasm [13, 14]. Ulceration may be present [15]. The mean diameter is 3 cm (range 0.3–9). Pigmented lesions are usually dark (blue, blue-black, blue-red, black, black-brown) or sometimes reddish (red, violet-red, brown-red, brown) [13].

12.1.5 Microscopy

Histologic features of primary cervical malignant melanoma are identical to cutaneous and mucosal melanoma. Diffuse, nested, trabecular, and/or fascicular growth patterns may be seen. Neoplastic cells exhibit epithelioid or spindled appearance, and rarely, round or clear cells. The nuclei are large, vesicular to hyperchromatic with prominent nucleoli and brisk mitotic activity, including atypical mitotic figures. Rarely multinucleated giant cells may be present. Melanin production can vary from abundant to focal or absent (Fig. 12.1). When present, melanin pigment granules are readily identified within the cytoplasm of tumor cells. In addition, approximately 50% of cases show junctional activity involving the overlying squamous epithelium. Pagetoid spread of tumor cells in the squamous epithelium may also be present. The tumor may invade the cervical mucosa with stromal desmoplastic reaction. Specific subtypes of primary cervical malignant melanoma, including a clear cell variant and a variant resembling a malignant peripheral nerve sheath tumor (MPNST), have been described [16, 17].

Fig. 12.1

Malignant melanoma. (a–e), Cervical biopsy with a nodular proliferation of high-grade neoplastic cells (H&E). There is epithelial ulceration (a, b). The tumor cells exhibit enlarged, irregular nuclei and prominent nucleoli (c–e). There is junctional activity in the squamous epithelium with atypical melanocytes and an atypical mitotic figure (d). Intracytoplasmic melanin pigment is present (e). (f–h), Immunohistochemical stains show diffuse, strong staining for S100 (f) and melan-A/MART-1 (g), and focal, moderate staining for HMB-45 (h). The patient has no prior history of cutaneous or mucosal malignant melanoma

The four criteria proposed by Morris and Taylor for diagnosis of primary gynecological (vaginal) malignant melanoma include the presence of melanin in the benign epithelium, evidence of junctional activity, absence of melanoma elsewhere in the body, and the distribution of metastases that parallel the spread of squamous cell carcinoma [18]. These criteria may also be applied to cervical melanomas, but in many cases not all criteria are met; it can be difficult to establish definitively whether the melanoma is a primary or secondary lesion in the absence of cervical junctional changes. Clinical-pathologic correlation is essential in such cases.

Immunohistochemically, the tumor cells are positive for S100 protein, HMB-45 (human melanoma black 45), melan-A/MART-1 (melanoma antigen recognized by T cells), SOX10 (SRY-related HMG-box 10) and MITF (microphthalmia transcription factor); they are negative for cytokeratins and muscle markers. A combination of S100 (more sensitive) and HMB-45 (more specific) appears to lead to an accurate and reliable diagnosis in most cases [9, 13]. Ultrastructurally, the neoplastic cells contain intracytoplasmic pre-melanosomes and melanosomes.

Cytologic features range from small, round, deceptively bland cells to pleomorphic, bizarre-shaped cells. Smear preparations usually show single cells with central or eccentric nuclei with coarse chromatin and prominent nucleoli, irregular nuclear membranes, high nuclear-cytoplasmic ratio, and finely granular or wispy cytoplasm with intracytoplasmic melanin pigment. Nuclear molding, multinucleation, and intranuclear inclusions are common. The background shows tumor diathesis [13, 19].

Diagnostic Highlights

• Diffuse, nested, trabecular and/or fascicular growth patterns

• Tumor cells with epithelioid, spindled, round, or clear cytoplasm; large, vesicular to hyperchromatic nuclei; prominent nucleoli; brisk mitoses, including atypical forms

• Rarely multinucleated giant cells

• Variable intracytoplasmic melanin pigment, from abundant to absent

• Junctional activity in 50% of cases

• Pagetoid growth

• Stromal desmoplastic reaction

• Morris and Taylor criteria for primary gynecologic melanoma:

  • 1. Melanin in benign epithelium

  • 2. Junctional activity

  • 3. Absence of melanoma elsewhere

  • 4. Metastases according to the pattern of gynecologic tumor

12.1.6 Differential Diagnosis

In the absence of melanin pigment, diagnosis of primary cervical malignant melanoma may be difficult [9, 20,21,22,23]. Table 12.2 outlines the main differential diagnostic considerations:

• Poorly differentiated squamous cell carcinoma shows at least focal keratin formation and/or intercellular bridges; may be associated with high-grade squamous intraepithelial lesion (HSIL); positive for high molecular weight keratin, p63, p40, and high-risk HPV subtypes; negative for melanocytic markers.

• Poorly differentiated adenocarcinoma shows at least focal gland formation or intracytoplasmic mucin; may be associated with adenocarcinoma in situ and HSIL; positive for low-molecular-weight keratin, CK7 (cytokeratin 7), and PAX8; negative for melanocytic markers. HPV-driven subtypes are also positive for high-risk HPV.

• Leiomyosarcoma (epithelioid or spindle cell variants) is comprised of diffuse sheets or intersecting fascicles of epithelioid or spindle cells; positive for muscle markers such as desmin, h-caldesmon, and SMA (smooth muscle actin); negative for melanocytic markers.

• Embryonal rhabdomyosarcoma shows a cellular subepithelial cambium layer with primitive cells with variable cytoplasmic cross-striations; positive for muscle markers; negative for melanocytic markers.

• MPNST shows densely cellular sweeping fascicles alternating with myxoid areas; rarely palisading, spindled to fusiform tumor cells with hyperchromatic and wavy nuclei, brisk mitoses, pale cytoplasm; necrosis, sometimes with melanin; variably positive for S100; negative for other melanocytic markers; may show loss of methylated H3K27.

• High-grade endometrial stromal sarcoma (YWHAE type) is comprised of high-grade round cells with nested or pseudoglandular patterns separated by thin-walled vessels; brisk mitoses; necrosis; variably positive, but usually negative for CD10, ER and PR (estrogen and progesterone receptors); negative for melanocytic markers.

• Metastatic malignant melanoma is characterized by absence of junctional activity; prior history of cutaneous or mucosal malignant melanoma elsewhere.

Table 12.2 Differential diagnosis of malignant melanoma of the cervix

12.1.7 Prognosis

Primary cervical malignant melanoma is usually diagnosed at an advanced stage and has an extremely unfavorable prognosis, similar to that of melanomas of other gynecologic (vaginal, vulvar) and non-gynecologic (anal, oronasal, esophageal) mucosal sites [9]. Patients with cervical malignant melanoma tend to develop local relapse rather than distant metastases. The most common sites are vagina, vulva, and suture line [13]. The most important prognostic factors are tumor stage and tumor thickness. Additional important features include lymphovascular space invasion (LVSI), the presence of lymphocytes, and neovascularization [9]. Mutation status has not been shown to have prognostic significance; however, patients with KIT (not uncommon) and BRAF (uncommon) mutations may be treated with targeted therapy.

Survival analysis of 78 cases showed that most patients (87.5%) died within 3 years of diagnosis, and 5-year survival was only 10.7%. The mean overall survival was 22.9 months and the median was 12 months (range 0.1–168). Furthermore, although 50% of patients were diagnosed at stage I, the 5-year survival rates were 18.8% for stage I, 11.1% for stage II, and 0% for stages III–IV. Treatment options include surgery alone and neoadjuvant, adjuvant, or palliative treatment with chemotherapy and/or radiation. Given the limited data, the optimal treatment strategy is unclear [9].

12.2 Germ Cell Tumors

12.2.1 Teratoma

12.2.1.1 Definition

Mature cystic teratoma is a tumor composed of mature tissues derived from more than one germ layer. The presence of immature tissue (typically neuroepithelium) defines an immature teratoma. The key features of mature and immature teratomas of the cervix are described in Table 12.3.

Table 12.3 Key features of cervical germ cell tumors

12.2.1.2 Synonyms

Dermoid cyst.

12.2.1.3 Etiology

Four possible origins of uterine and cervical mature cystic teratomas include displaced germinal cells, pluripotential stem cells, metaplasia, and residual fetal tissue [24].

12.2.1.4 Macroscopy

Cystic or solid lesions containing sebaceous material and hair.

12.2.1.5 Microscopy

Mature cystic teratomas are composed of histologic structures of ectodermal, mesodermal, and endodermal derivation, most commonly skin and underlying cutaneous adnexal structures, as well as smooth and skeletal muscle and gastrointestinal or respiratory epithelium.

Immature teratomas exhibit variable amounts of immature tissues, typically neuroepithelial tubules and rosettes lined by overlapping, hyperchromatic cells with numerous mitotic figures and apoptotic bodies (Fig. 12.2). Cellular, mitotically active glia and immature cartilage, adipose tissue, bone, and skeletal muscle may be present. Immature endodermal structures (hepatic, renal, gastrointestinal) are less common. Based on the amount of immature neuroepithelial component, immature teratomas can be graded as grade 1 (immature elements in <1 low-power field [40×] in any slide), grade 2 (immature elements in 1–3 low-power fields in any slide), or grade 3 (immature elements in >3 low-power fields in any slide) [25], but a 2-tiered system is more commonly used (low-grade [grade 1] and high-grade [grades 2–3]) [26].

Fig. 12.2

Immature teratoma. (a–f), Total hysterectomy specimen with a low-grade immature teratoma (H&E). The tumor is composed predominantly of mature tissue elements such as skin and cutaneous appendages (a, b), cartilage, and small foci of immature neuroepithelium (b–f). The immature neuroepithelium is composed of tubules, rosettes and poorly defined clusters of overlapping, atypical, hyperchromatic cells with numerous mitotic figures and apoptotic bodies (c–f). The immature elements are seen in <1 low-power field (40×) in any slide. Therefore, the teratoma is graded as low-grade. The patient has no history of teratoma elsewhere

Immunohistochemically, GFAP (glial fibrillary acidic protein), NSE (neurospecific enolase), S100, SOX2, and glypican-3 are positive in both mature and immature neuroepithelium. SALL4 (Sal-like protein 4) is positive in immature neuroepithelium and mesenchymal elements, as well as mature and primitive enteric tissue. OCT4 (octamer-binding transcription factor 4) and PAX6 are positive in immature neuroepithelium, and CD56 is often positive in mature neuroepithelium. AFP (α-fetoprotein) may be positive in immature gastrointestinal-type glands.

Cytologic features in mature teratoma include fragments of benign epithelial cells (squamous, respiratory, gastrointestinal), sometimes with fragments of mesenchymal tissue (nerve, cartilage, adipose tissue) in a background of cystic contents. Immature teratoma shows malignant primitive-appearing cells.

Diagnostic Highlights

Mature cystic teratoma

• Mature tissues of ectodermal, mesodermal, and endodermal derivation

Immature teratoma

• Immature tissues, most obviously, immature neuroepithelium

• Neuroepithelial tubules and rosettes lined by overlapping, hyperchromatic cells with brisk mitoses

• Cellular glia that can be mitotically active

• Immature mesenchymal and endodermal elements (rare)

• 3-tiered grading:

  • 1 (immature elements in <1 LPF (40×) in any slide)

  • 2 (1–3 LPF in any slide)

  • 3 (>3 LPF in any slide)

• 2-tiered grading:

  • Low-grade / grade 1

  • High-grade / grade 2–3

12.2.1.6 Differential Diagnosis

Mature cystic teratoma does not usually pose a diagnostic challenge. Table 12.4 outlines the main differential diagnostic considerations for immature teratoma:

• Mature cystic teratoma with microscopic foci of neuroepithelium shows mature teratomatous elements and microscopic foci of mature neuroepithelium lacking cytologic atypia or mitotic activity.

• Malignant primitive neuroectodermal tumor. The central type is composed of malignant cells closely resembling central nervous system neoplasms such as ependymoma, medulloblastoma, medulloepithelioma, neuroblastoma, ependymoblastoma, or glioblastoma multiforme. The peripheral type (akin to Ewing sarcoma) is composed of small, round, blue cells. Both are positive for CD99, FLI-1, CD56, S100, NSE, and rarely cytokeratin, and chromogranin. The central type is positive for GFAP, and the peripheral type shows EWSR1 rearrangement, unlike the central type.

• Carcinosarcoma is usually diagnosed in older patients and shows high-grade epithelial and mesenchymal elements including malignant cartilage (as opposed to fetal cartilage), and, almost always, aberrant expression of p53.

Table 12.4 Differential diagnosis of germ cell tumors of the cervix

12.2.1.7 Prognosis

Both mature and immature cystic teratomas of the cervix have had a benign clinical course in all case reports published to date [27,28,29,30].

12.2.2 Yolk Sac Tumor

12.2.2.1 Definition

A primitive malignant germ cell tumor with various histologic patterns recapitulating developmental phases of the normal yolk sac. Rarely, yolk sac tumors may also arise from epithelial neoplasms of gynecologic origin such as endometrioid, high-grade serous or clear cell adenocarcinoma. These somatically derived yolk sac tumors typically occur in older patients and have overlapping morphology and immunophenotype with the epithelial neoplasm; they are not the topic of this discussion. The key features of yolk sac tumor of the cervix are described in Table 12.3.

12.2.2.2 Synonyms

Endodermal sinus tumor .

12.2.2.3 Etiology

The most likely cause is aberrant migration of primordial germ cells. The tumor typically affects the vagina or cervix in young children aged less than 4 years [31, 32], and it can be challenging to establish the primary site [33, 34].

12.2.2.4 Macroscopy

Typically, polypoid mass , frequently ulcerated, with a friable, gray to white cut surface with areas of hemorrhage and/or necrosis. The mean tumor size is 5 cm (range 1–10).

12.2.2.5 Microscopy

The histologic features are identical to those of ovarian and vaginal yolk sac tumors and include a variety of growth patterns such as reticular, microcystic, solid, papillary, and polyvesicular vitelline, with the microcystic pattern being the most common [31, 33]. The stroma may be loose, myxoid to edematous . Approximately 50% of cases show pathognomonic Schiller-Duval bodies comprising papillary structures with a central vascular channel covered by cuboidal to columnar cells, separated by an acellular zone of connective tissue. Schiller-Duval bodies may be difficult to find and may be present only focally. Glandular or hepatoid differentiation may be seen. The tumor cells exhibit variable amounts of light eosinophilic to clear cytoplasm and primitive nuclei, often with prominent amphophilic nucleoli and frequent mitotic figures. Intracytoplasmic hyaline bodies may be present (Fig. 12.3).

Fig. 12.3

Yolk sac tumor. (a–h), Total hysterectomy specimen with a primitive-appearing neoplasm (H&E). Various growth patterns include microcystic or macrocystic (a), solid (b), glandular (c), polyvesicular vitelline with numerous small vesicles surrounded by connective tissue (d) and endoderm resembling secretory endometrium (e). The tumor cells exhibit high-grade nuclei with numerous mitotic figures (f), hyaline globules (g), and Schiller-Duval bodies (h). i–l, Immunohistochemical stains show strong, diffuse staining for SALL4 (i) and pan-cytokeratin (j), with patchy staining for GATA3 (k) and focal staining for CK7 (l)

Immunohistochemically, the tumor cells are positive for SALL4, glypican-3, AFP, GATA3, and LIN28 [35, 36]. Pan-cytokeratin, HNF1β, PAX8, CDX2, and TTF-1 (thyroid transcription factor 1) may be positive. CK7 and EMA (epithelial membrane antigen) are only focally expressed in a minority of tumors. The hepatoid variant is usually positive for CEA (carcinoembryonic antigen), Hep-Par1 (Hepatocyte Paraffin 1) and albumin.

Cytologic features include sheets of malignant cells with irregular nuclear contours, coarse chromatin, and vacuolated cytoplasm. Schiller-Duval bodies (glomerular-like structures) and hyaline globules may be present. The background contains metachromatic basement membrane–like material.

Diagnostic Highlights

• Multiple growth patterns including microcystic (most common), macrocystic, reticular, solid, papillary, polyvesicular vitelline

• Loose, myxoid to edematous stroma

• Schiller-Duval bodies in 50%

• Glandular or hepatoid differentiation (rare)

• Tumor cells with light eosinophilic to clear cytoplasm and primitive nuclei, often with prominent amphophilic nucleoli and brisk mitoses

• Intracytoplasmic hyaline bodies

12.2.2.6 Differential Diagnosis

Table 12.4 outlines the top differential diagnoses:

• Mixed tumor or spindle cell epithelioma is usually diagnosed in women of reproductive age; a well-circumscribed biphasic lesion composed of fascicular spindle cells and focal squamous or glandular epithelial cells with bland cytology, eosinophilic hyaline globules; variable positivity for keratin, ER, PR, and muscle markers.

• Clear cell adenocarcinoma typically affects young and perimenopausal or postmenopausal women with or without diethylstilbestrol exposure and shows tubulocystic, solid, and/or papillary growth patterns; positive for PAX8, EMA, CK7, napsin-A, racemase and HNF1β (hepatocyte nuclear 1β); typically negative for ER and PR.

• Embryonal rhabdomyosarcoma shows a cellular subepithelial cambium layer and primitive cells with variable presence of cytoplasmic cross-striations; positive for desmin, MSA (muscle specific actin), myoglobin, myogenin, and myo-D1. The latter two markers are specific for skeletal muscle differentiation.

• Mesonephric adenocarcinoma affects adult women, and shows “endometrioid-like morphology” frequently admixed with glomeruloid, papillary, tubular or solid growth patterns and, occasionally a background of mesonephric hyperplasia; positive for PAX8, GATA3, and/or TTF-1; negative for ER and PR.

The prognosis for patients with cervicovaginal yolk sac tumors is favorable with platinum-based chemotherapy; cure rates are >95% [37,38,39]. Serum AFP levels are useful for monitoring therapy and for followup. Recurrence typically occurs within 2 years of treatment and carries a poor prognosis [38].

12.2.3 Choriocarcinoma

Pure non-gestational choriocarcinoma is considered a primary germ cell neoplasm. Primary cervical non-gestational choriocarcinoma is extremely rare [40, 41] and displays morphologic and immunohistochemical features similar to those of gestational choriocarcinoma, as discussed in Sect. 12.3 below.

12.3 Trophoblastic Tumors

12.3.1 Choriocarcinoma

12.3.1.1 Definition

Choriocarcinoma can be divided into gestational and non-gestational subtypes. Gestational choriocarcinoma is a malignant trophoblastic tumor consisting of a trimorphic proliferation of intermediate trophoblastic cells, syncytiotrophoblast and cytotrophoblast, in the absence of chorionic villi. Pure non-gestational choriocarcinoma is a germ cell neoplasm. In addition, choriocarcinomatous differentiation may occur in a variety of poorly differentiated somatic neoplasms of gynecologic or non-gynecologic origin [42, 43]. Thus, a malignant tumor with trophoblastic differentiation involving the uterine cervix may be a gestational or non-gestational choriocarcinoma and may represent a primary tumor or a metastasis from other organs. The key features of gestational choriocarcinoma are described in Table 12.5.

Table 12.5 Key features of cervical trophoblastic tumors

12.3.1.2 Synonyms

Chorioepithelioma , chorionepithelioma.

12.3.1.3 Etiology

Gestational choriocarcinoma may arise due to progression of a complete or partial hydatidiform mole, or it may arise after a normal term pregnancy or an ectopic pregnancy [44, 45], with 50% of gestational choriocarcinomas occurring after complete hydatidiform mole, 25% after spontaneous abortion, and 25% after normal term pregnancy. The risk of developing choriocarcinoma is approximately 2% to 3% following a complete mole and 0.1% to 0.5% following a partial mole [46]. Non-gestational choriocarcinoma is likely to have the same origin as the other germ-cell tumors discussed above.

12.3.1.4 Macroscopy

Single or multiple bulky and destructive dark red masses with hemorrhage and necrosis.

12.3.1.5 Microscopy

Choriocarcinoma may be circumscribed but usually shows invasive and destructive growth in surrounding tissues. There is a trimorphic pattern consisting of all three types of trophoblast: large intermediate trophoblast with abundant amphophilic to eosinophilic cytoplasm, smaller cytotrophoblast, and multinucleated syncytiotrophoblast. There is conspicuous mitotic activity, up to 22 per 10 high-power fields. Extensive recent and remote hemorrhage and necrosis are seen (Fig. 12.4). LVSI is common. No residual chorionic villi are present.

Fig. 12.4

Gestational choriocarcinoma. (a–h), Total hysterectomy specimen with a markedly atypical mass-forming lesion containing multiple foci of necrosis and hemorrhage and ulceration of the overlying squamous epithelium (H&E). The tumor is composed predominantly of medium-sized cytotrophoblast and intermediate trophoblast and scattered large, multinucleated syncytiotrophoblast cells (b–h). Chorionic villi are not present. (i) An immunohistochemical stain for β-hCG shows strong, diffuse staining in both the syncytiotrophoblast (the most darkly stained cells) and cytotrophoblast cells

Immunohistochemically, β-hCG (β human chorionic gonadotropin) and HSD3B1 show diffuse staining in syncytiotrophoblast, with weak and focal expression of β-hCG in the cytotrophoblast or intermediate trophoblast cells. The intermediate trophoblast cells are positive for Mel-CAM/CD146 (melanoma cell adhesion molecule), HLA-G (human leukocyte antigen G) and MUC4 (mucin 4). Keratin is diffusely positive , and hPL (human placental lactogen), SALL4, p63 and inhibin-α show variable staining. The Ki-67 labeling index is usually >90%.

Cytologic features include clusters of syncytiotrophoblast and cytotrophoblast in a background of tumor diathesis.

Diagnostic Highlights

• Trimorphic pattern with three types of trophoblast (villous intermediate trophoblast, syncytiotrophoblast, cytotrophoblast)

• Marked cytologic atypia

• Mitoses up to 22 per 10 high-power fields

• Extensive hemorrhage and necrosis

• No chorionic villi

• LVSI

12.3.1.6 Differential Diagnosis

Table 12.6 outlines the top differential diagnoses for trophoblastic tumors involving the cervix:

• Epithelioid trophoblastic tumor is well-circumscribed; composed predominantly of nests or cords of chorionic-type intermediate trophoblast with only rare syncytiotrophoblast; eosinophilic fibrinoid matrix; no diffuse β-hCG.

• Placental site trophoblastic tumor is usually an infiltrating mass; composed of confluent sheets or infiltrating monomorphic implantation-site intermediate trophoblast; variable necrosis; no diffuse β-hCG.

• Non-gestational choriocarcinoma shows identical profiles to the patient’s benign tissue by DNA polymorphism analysis or short tandem repeat genotyping [47, 48].

• Invasive mole shows residual hydropic chorionic villi; loss of p57 staining in cytotrophoblast and villous stromal cells in complete mole.

• Normal immature trophoblast of early gestation in curettings lacks significant cytologic atypia, necrosis , or destructive growth; found in small quantities; chorionic villi may be seen on deeper sectioning.

• Exaggerated placental site is usually an incidental microscopic finding composed of implantation-site trophoblastic cells separated by hyalinized stroma and lacking mitotic activity; admixed with chorionic villi and fragments of decidua; absence of confluent masses (Fig. 12.5). Frequently associated with molar pregnancies.

• Poorly differentiated carcinoma with trophoblastic differentiation may show areas of more conventional carcinoma.

• Poorly differentiated carcinoma with anaplastic features or giant cells lacks admixture of cytotrophoblast and syncytiotrophoblast; positive for EMA; negative or weakly positive for β-hCG.

Table 12.6 Differential diagnosis of trophoblastic tumors involving the cervix

Fig. 12.5

Exaggerated placental site. (a–d), Endocervical curettings for retained products of conception (H&E). There are fragments of endomyometrium with an increased number of mononucleated and multinucleated implantation-site intermediate trophoblast cells with abundant eosinophilic cytoplasm, with hyperchromatic and irregular nuclei. The cells are widely spaced and lack mitotic activity. There is no necrosis (a–d). Scant chorionic villi are also present (d). (e and f), Immunohistochemical stains show the trophoblast cells to be negative for p63 (e), with a Ki-67 labeling index of virtually 0% on dual pan-cytokeratin (red chromogen) and Ki-67 (brown chromogen) stain (f)

12.3.1.7 Prognosis

Patients with untreated choriocarcinoma develop metastases in more than 50% of cases, most commonly to the vagina, lung , liver, brain, or kidney [49]. Cure rates are greater than 90% with chemotherapy [50]. Limited follow-up data for primary cervical gestational choriocarcinoma suggests similar favorable clinical outcomes [51,52,53,54].

12.3.2 Placental Site Trophoblastic Tumor

12.3.2.1 Definition

A trophoblastic tumor consisting of neoplastic implantation site intermediate trophoblast cells. The key features of placental site trophoblastic tumor are described in Table 12.5.

12.3.2.2 Synonyms

Atypical choriocarcinoma; syncytioma; chorioepitheliosis; trophoblastic pseudotumor [55].

12.3.2.3 Etiology

Arises from trophoblast with differentiation towards implantation site intermediate trophoblast. Most cases follow normal pregnancy; antecedent complete moles have been reported in 16% of cases and missed abortion in 13% [56].

12.3.2.4 Macroscopy

Expansile to infiltrative, poorly circumscribed, solid masses of 1–10 cm in size, with solid and fleshy, white-tan to light yellow cut surface with focal hemorrhage and necrosis [57]. The tumors may be endophytic or protruding and often extend to serosa, broad ligament, or adnexa.

12.3.2.5 Microscopy

The tumor is composed of central sheets and peripheral cords and nests of round to polygonal intermediate trophoblast with eosinophilic to clear cytoplasm and moderate to marked cytologic atypia. Rare multinucleated cells resembling syncytiotrophoblast are seen. The tumor has infiltrative borders , with the tumor cells separating myometrial smooth muscle fibers at the periphery. Large nests of tumor cells may replace vascular walls. Associated eosinophilic extracellular matrix may be seen. Necrosis may be present. Mitotic activity is up to 6 per 10 high-power fields (Fig. 12.6).

Fig. 12.6

Placental site trophoblastic tumor. (a–e), Total hysterectomy specimen with proliferation of atypical epithelioid cells involving myometrium (H&E). The tumor is composed of solid sheets of monomorphic implantation site intermediate trophoblast cells separating myometrial smooth muscle bundles (a–d). Chorionic villi are not present. The tumor cells replace the vascular walls (e). (f) A dual pan-cytokeratin (red chromogen) and Ki-67 (brown chromogen) immunohistochemical stain shows a Ki-67 labeling index of 30% in the trophoblastic cells

Immunohistochemically, the tumor shows diffuse staining for hPL, Mel-CAM, MUC-4, HSD3B1, keratins, EMA, GATA3, MUC4, CD10, and HLA-G, with focal staining for PLAP (placental alkaline phosphatase), and no immunoreactivity for p63 and SALL4. Scattered multinucleated cells are positive for β-hCG and inhibin-α. The Ki-67 labeling index is approximately 10–30% [58].

Cytologic features of intermediate trophoblast cells include scattered, small clusters or single large, polygonal cells with ovoid, hyperchromatic nuclei, prominent nucleoli, distinct cell membranes, and abundant eosinophilic or granular cytoplasm in an inflammatory background [59, 60].

Diagnostic Highlights

• Central sheets and peripheral cords and nests of intermediate trophoblast cells

• Round to polygonal tumor cells with eosinophilic to clear cytoplasm and moderate to marked cytologic atypia

• Mitoses up to 6 per 10 high-power fields

• Rare multinucleated cells resembling syncytiotrophoblast

• Infiltrative borders with tumor cells separating myometrial smooth muscle fibers at tumor periphery

• Large nests of tumor cells replacing vascular walls

• Associated eosinophilic extracellular matrix

• Necrosis may be present

12.3.2.6 Differential Diagnosis

Table 12.6 outlines the top differential diagnoses:

• Placental site nodule is usually an incidental microscopic lesion, <5 mm in size, composed of single or multiple well-circumscribed, oval nodules or plaques with chorionic-type intermediate trophoblast cells arranged singly or in cords within hyalinized matrix and lacking cytologic atypia or mitotic activity; the center of nodules may be less cellular; Ki-67 < 8% (Fig. 12.7).

• Atypical placental site nodule is a larger nodule, measuring 5–10 mm in size; more cellular with cytologic atypia and conspicuous mitotic activity; Ki-67 8–10%; the diagnosis is difficult because of a lack of definitive criteria [56].

• Exaggerated placental site. (See Fig. 12.5 and Differential Diagnosis in Choriocarcinoma, above.)

• Epithelioid trophoblastic tumor. (See Differential Diagnosis in Choriocarcinoma, above.)

Fig. 12.7

Placental site nodule. (a–c), Endocervical curettings for abnormal vaginal bleeding (H&E). There is a single nodule <3 mm in size, with cords of chorionic-type intermediate trophoblast cells embedded within hyalinized matrix, with eosinophilic to clear cell cytoplasm and lacking significant cytologic atypia or mitotic activity. (d and e), Immunohistochemical stains show the trophoblast cells to be positive for p63 (d) with a Ki-67 labeling index of approximately 1% on dual pan-cytokeratin (red chromogen) and Ki-67 (brown chromogen) stain (e)

12.3.2.7 Prognosis

Most women with placental site trophoblastic tumor are cured by hysterectomy, but 25–30% of patients may develop recurrent disease, and approximately 50% of those succumb to the disease [61]. Clinical predictors of poor prognosis include high serum β-hCG levels, age 35 years or older, pregnancy at least 48 months antecedent, and previous term pregnancy. Pathologic indicators of adverse outcome are deep myometrial invasion, stage III or IV, extensive coagulative necrosis, high mitotic rate (>5 per 10 high-power fields), and clear cytoplasm. In addition, advanced stage and clear cytoplasm are independent predictors of overall survival ; stage and age are independent predictors of recurrence or disease-free survival [57]. Women with stage I disease have a 10-year overall survival probability of 90% (range 77–100%), and do not benefit from adjuvant chemotherapy, whereas women with stage II–IV disease require combined treatment with surgery and chemotherapy. Their 10-year overall survival probability is 52% (range 3–100%) for stage II, and 49% (range 26–72%) for stage III–IV. Only 22% of patients with recurrent or refractory disease are alive beyond 60 months. The only significant independent predictor of overall and recurrence-free survival is time since antecedent pregnancy; a cut-point of 48 months since antecedent pregnancy has been suggested to predict probability of survival with 93% specificity, 100% sensitivity, 100% positive predictive value, and 98% negative predictive value [62].

12.3.3 Epithelioid Trophoblastic Tumor

12.3.3.1 Definition

A trophoblastic tumor consisting of neoplastic chorionic-type intermediate trophoblast cells. The key features of epithelioid trophoblastic tumor are listed in Table 12.5.

12.3.3.2 Synonyms

Atypical choriocarcinoma; “multiple nodules of intermediate trophoblast” [63,64,65].

12.3.3.3 Etiology

Arises from trophoblast with differentiation towards chorionic-type intermediate trophoblast [66, 67]. Most cases (67%) follow normal term pregnancy; hydatidiform moles and spontaneous abortion have each been reported in 16% of cases. Occurrence in premenopausal and postmenopausal women is common [68]. Malignant transformation from an atypical placental site nodule has been suggested [69, 70].

12.3.3.4 Macroscopy

Expansile solid mass measuring 0.5–5 cm, with endophytic or exophytic growth. The tumor may be solid or cystic on cut section, with hemorrhage and necrosis. Approximately 50% of cases arise from the uterine cervix or lower uterine segment [71].

12.3.3.5 Microscopy

The tumor has pushing borders and consists of well-circumscribed sheets, nests, and cords of intermediate trophoblast cells and a central small vessel. Extensive or “geographic” necrosis is often present. Eosinophilic extracellular hyaline-like matrix material may mimic keratin, leading to misdiagnosis as carcinoma in some cases. The tumor may colonize the overlying cervical epithelium, mimicking HSIL. The tumor cells exhibit mild to moderate nuclear atypia, prominent nucleoli, and up to 9 mitotic figures per 10 high-power fields (Fig. 12.8). The tumor periphery may show scattered, decidualized, benign stromal cells [71].

Fig. 12.8

Epithelioid trophoblastic tumor. (a–i), Cervical biopsy with fragments of endocervical tissue containing nests and cords of epithelioid cells surrounding benign endocervical glands (H&E). The cells exhibit mild to moderate nuclear atypia (a–i) and scattered mitotic figures (e, g, h). Nodular growth pattern with characteristic “geographic” necrosis (i) (courtesy of Dr. R. Soslow). Chorionic villi are not present. (j and k), Immunohistochemical stains show the tumor cells to be positive for p63 (j), CK18, and PLAP, with a Ki-67 labeling index of approximately 20% on dual pan-cytokeratin (red chromogen) and Ki-67 (brown chromogen) stain (k)

Immunohistochemically, the tumor is diffusely positive for p63, PLAP, keratins (pan-cytokeratin, CK18), EMA, inhibin-α, HLA-G, GATA3, H3D3B1, HLA-G, cyclin E, and CD10; focally positive for hPL, Mel-CAM and β-hCG; and negative for SALL4; Ki-67 10–25% [58].

Cytologic features are those of intermediate trophoblastic cells. (See Placental site trophoblastic tumor, above.) A differential diagnosis between different gestational trophoblastic diseases cannot be made on the basis of cytologic examination [59, 60].

Diagnostic Highlights

• Sheets, nests, and cords of intermediate trophoblast cells

• Rare syncytiotrophoblast

• Hyaline-like material

• May colonize cervical mucosal epithelium

• Mild to moderate cytologic atypia with prominent nucleoli

• Mitoses up to 9 per 10 high-power fields

• Decidualized stromal cells at tumor periphery (variable)

• “Geographic” necrosis

12.3.3.6 Differential Diagnosis

Table 12.6 outlines the top differential diagnoses:

• Placental site nodule and atypical placental site nodule. (See Differential Diagnosis in Placental Site Trophoblastic Tumor, above.)

• Squamous cell carcinoma may be associated with HSIL (p16 and HPV-positive), features of squamous differentiation such as keratinization or intercellular bridges; lacking decidualized benign stromal cells at tumor periphery; negative for inhibin-α, HLA-G, Mel-CAM, hPL, and usually CK18.

• Choriocarcinoma exhibits mononuclear trophoblast surrounded by syncytiotrophoblast; shows extensive necrosis and hemorrhage; Ki-67 > 90%.

• Epithelioid leiomyosarcoma is positive for smooth muscle markers; negative for markers of trophoblastic differentiation.

• Poorly differentiated carcinoma with trophoblastic differentiation. (See Differential Diagnosis in Choriocarcinoma, above.)

12.3.3.7 Prognosis

Similar to placental site trophoblastic tumor, 25% of patients with epithelioid trophoblastic tumor develop metastases with a mortality rate of 10% [72]. The survival is nearly 100% for nonmetastatic disease and 50–60% in metastatic disease. The only unfavorable histologic feature has been shown to be a high mitotic count (>6 per 10 high power fields) [73].

12.4 Lymphoid Tumors

12.4.1 Definition

Malignant neoplasms composed of lymphoid cells.

12.4.2 Synonyms

Lymphoma.

12.4.3 Etiology

Cervical lymphoid tumors have a hematopoietic origin and can be part of a systemic process or present primarily with cervical involvement. The most common type is B-cell lymphoma. A systematic review from 2014 identified 143 cases of primary diffuse large B-cell lymphoma (DLBCL) of the uterus, of which 108 (75.5%) had cervical involvement [74], including case reports and case series [74,75,76,77,78,79]. Three additional cases were also published much earlier [80,81,82]. The second-most-common type of primary cervical lymphoma is follicular lymphoma (FL). The cervix also may be involved by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the most common adult leukemia, which is characterized by lymphocytosis due to the accumulation of small B lymphocytes in the blood, bone marrow, and lymphoid tissues. These lymphomas are often diagnosed incidentally in asymptomatic patients; rarely, diagnosis is based on gynecologic manifestations such as vaginal bleeding or abnormal colposcopic findings [78, 79, 83,84,85,86,87,88,89]. Rare cervical Burkitt lymphomas, extranodal NK/T-cell lymphomas, marginal zone lymphomas, mucosa-associated lymphoid tissue–type lymphomas, and Hodgkin lymphomas have also been described [78, 90,91,92,93,94]. The key features of lymphoid tumors involving the cervix are described in Table 12.7.

Table 12.7 Key features of the most common cervical lymphoid tumors

12.4.4 Macroscopy

Lymphomas tend to form sharply demarcated, bulky masses and may cause circumferential enlargement of the cervix (“barrel-shaped” cervix). Gross features include submucosal lesions with intact overlying epithelium [95, 96], polypoid single or multinodular lesions, and exophytic masses [95, 97, 98]. The mean tumor diameter is 4 cm. The cut surface of the tumors is often fleshy, rubbery, or firm with homogenous white-tan to yellow appearance [95]. Extension into deep soft tissues and surrounding organs is not uncommon.

12.4.5 Microscopy

Lymphomas tend to show a narrow band of uninvolved stroma beneath surface epithelium, and deep extension into the cervical wall with pushing borders, sparing of endocervical glands, prominent sclerosis, and rarely ulceration or necrosis. Histologic features of relatively common lymphomas are summarized below:

Cervical DLBCL is often associated with deep infiltration and marked sclerosis [90, 98, 99], with sheets or cords of dyscohesive lymphoid cells, storiform growth, or spindle-shaped tumor cells [95]. Tumors with spindle cell morphology have been termed “spindle cell variant” [100] or “sarcomatoid variant” [101] and may mimic sarcoma. Rarely, ulceration or necrosis may be seen. The neoplastic cells exhibit large vesicular, oval, irregular, and multilobated nuclei with coarse to vesicular chromatin and brisk mitotic activity (Fig. 12.9). Associated crush artifact is common.

Fig. 12.9

Diffuse large B-cell lymphoma. (a–c), Total hysterectomy with diffuse sheets of neoplastic cells involving the middle and outer thirds of the cervical wall (H&E). The tumor cells exhibit large vesicular, oval to spindle-shaped, irregular, and multilobated nuclei with coarse to vesicular chromatin and brisk mitotic activity (c). The background stroma is sclerotic (a, b). (d–g), Immunohistochemical stains show the tumor to be positive for CD20 (d), Bcl-2 (e), Bcl-6 (f), and CD10 (g). The patient has no prior history of hematolymphoid disease

FL typically shows nodular growth of monomorphous large follicles lacking a mantle zone and extending into the cervical wall and paracervical soft tissue (Fig. 12.10). Cervical FL frequently shows sclerosis. The neoplastic cells are predominantly small lymphoid cells (centrocytes) admixed with larger lymphoid cells (centroblasts). Occasional tingible body macrophages may be seen. FL is graded based on the number of centroblasts per high-power field of view:

• Grade 1: 0–5

• Grade 2: 6–15

• Grade 3: >15, further categorized as grade 3A (centrocytes admixed with centroblasts) and 3B (sheets of centroblasts with rare or no centrocytes)

Fig. 12.10

Follicular lymphoma. (a–c), Total hysterectomy with an extensive lymphoid infiltrate (H&E) with prominent germinal centers and composed of a mixture of variably sized cells with angulated nuclei and condensed chromatin (centrocytes) and larger cells with oval or multilobated nuclei, vesicular chromatin, and several nucleoli (centroblasts). (d–g), Immunohistochemical stains show the tumor to be positive for CD20 (d) with expression of Bcl-2 (e), Bcl-6 (f), and CD21 (g) in the neoplastic germinal centers, and negative for CD5, CD43 and cyclin D1. The patient has no prior history of hematolymphoid disease

Grades 1 and 2 are considered low-grade. All three grades have been described in the cervix [78, 90, 91].

CLL/SLL is characterized by a vaguely nodular growth pattern with alternating dark zones of mature lymphocytes and lighter zones, termed a proliferation center, containing prolymphocytes (medium-sized cells with dispersed chromatin and small nucleoli) and paraimmunoblasts (medium to large cells with round to oval nuclei, dispersed chromatin, and central eosinophilic nucleoli) admixed with small lymphocytes (clumped chromatin, round nuclei, occasional small nucleoli) (Fig. 12.11). Cytologic atypia and mitotic activity are usually inconspicuous.

Fig. 12.11

Chronic lymphocytic leukemia/small lymphocytic lymphoma. (a–c), Cervical cone biopsy with nodular and perivascular lymphoid infiltrates (H&E). The lymphoid cells show small to medium-sized cells with dispersed chromatin and generally inconspicuous nucleoli (c). (d–f), Immunohistochemical stains show the lymphoid cells to be positive for CD20 (d), CD5 (e), CD23 (f), and CD43, and negative for cyclin D1. The patient has a prior history of chronic lymphocytic leukemia

Immunohistochemistry can help with diagnosis:

• DLBCL is positive for pan B-cell markers, in addition to Bcl-6, CD10, Bcl-2, CD5, MUM1, and CD43.

• FL is positive for pan B-cell markers; neoplastic follicles express Bcl-6, Bcl-2, and CD10. CD5, CD43, and cyclin D1 are usually negative; follicular dendritic cell meshworks are highlighted by CD21 or CD23.

• CLL/SLL is positive for pan B-cell markers with co-expression of CD5 and CD23; CD43, PAX5 and CD11c may be positive.

Some cytogenetic findings are also characteristic of these lymphomas [102]:

• DLBCL: 3q27 abnormalities involving BCL6 are found in 30% of cases, t(14;18) involving BCL2 in 20–30%, and MYC rearrangement in 10%.

• FL: IgH and IgL gene rearrangements, t(14;18)(q32;q21) with IGH-BCL2 rearrangement is found in 70–95% of cases.

• CLL/SLL: IGH and IGL gene rearrangements, trisomy 12, del 13q, del(17p), or del(11q) may be present.

Cytologically, lymphomas typically show a dispersed population of monotonous but atypical lymphocytes, sometimes with obscuring blood and inflammation in the background.

• DLBCL is comprised of cells with a high nuclear-cytoplasmic ratio, some with prominent nucleoli, in a bloody background.

• FL exhibits a mixture of centrocytes (variably sized cells with cleaved or angulated nuclei and condensed chromatin) and centroblasts (large cells with noncleaved oval or multilobated nuclei, vesicular chromatin, and several nucleoli), often with germinal center aggregates.

• CLL/SLL is primarily composed of small lymphocytes with clumped chromatin and scattered prolymphocytes (medium-sized cells with dispersed chromatin and conspicuous nucleoli) and paraimmunoblasts (medium to large cells with round to oval nuclei, dispersed chromatin, and conspicuous central nucleoli).

Diagnostic Highlights

All lymphomas

• Mass lesion

• Narrow band of uninvolved stroma beneath surface epithelium

• Deep extension into cervical wall with pushing borders

• Sparing of endocervical glands

• Prominent sclerosis

• Rarely ulceration or necrosis

DLBCL

• Sheets or cords of dyscohesive lymphoid cells and, less commonly, storiform growth or spindle-shaped tumor cells

• Tumor cells with large, vesicular, oval, irregular and multilobated nuclei with coarse to vesicular chromatin and brisk mitotic activity

• Associated crush artifact

FL

• Nodular growth of monomorphous, large follicles lacking a mantle zone and extending into the cervical wall and paracervical soft tissue

• Admixture of centrocytes and centroblasts

• Occasional tingible body macrophages

CLL/SLL

• Vaguely nodular growth pattern with alternating dark zones of mature lymphocytes and lighter zones containing prolymphocytes and paraimmunoblasts admixed with small lymphocytes, termed proliferation centers

• Inconspicuous cytologic atypia and mitotic activity

12.4.6 Differential Diagnosis

Secondary involvement of the uterine cervix by a variety of lymphomas in the setting of systemic disease is significantly more common than primary cervical lymphomas [90, 95, 97, 103]. In such cases, clinical correlation is essential in ruling out systemic involvement. Cervical lymphomas should also be differentiated from poorly differentiated primary neoplasms. In general, the absence of an associated intraepithelial lesion, diffuse and infiltrative growth pattern, positive lymphoid markers, and/or a prior history of lymphoma should raise suspicion and trigger additional work-up for lymphomas in cervical specimens.

Table 12.8 lists the top differential diagnoses:

• Secondary involvement by systemic disease may be suspected based on clinical history of systemic lymphoma or concurrent tumor in lymph nodes and/or extragenital organs.

• Reactive lymphoid infiltrate should be differentiated from CLL/SLL based on superficial band-like infiltrate composed of B-cells and T-cells and neutrophils; no mass lesion, infiltrative growth or sclerosis; common surface erosion; in addition, a history of CLL/SLL, recent lymphocytosis, older age, and/or CD20-positive lymphocytic infiltrates should raise suspicion for cervical involvement by CLL/SLL.

• Reactive lymphoid follicles show central polarized germinal centers with dark and light zones surrounded by peripheral, sharply demarcated mantle zones; lack of coalescing follicles; germinal centers positive for Bcl-6 and CD10 but negative for Bcl-2.

• Mantle cell lymphoma is composed of intermediate-size nuclei with irregular contours; usually negative for CD23; positive for pan B-cell markers, CD5, cyclin D1 and t(11;14)(q13;q32).

• Marginal zone B-cell lymphoma is characterized by common bone marrow involvement, sometimes with lymphocytosis; atypical centrocyte-like cells (histiocytoid lymphocytes with round to reniform or cleaved nuclei, contrasted against dark-staining lymphocytes) infiltrating around reactive B-cell follicles and interfollicular areas; positive for pan B-cell markers, and CD5 in 20%; negative for CD5 and cyclin D1.

• Small cell neuroendocrine carcinoma is composed of nests, islands, or sheets of cohesive tumor cells with salt-and-pepper chromatin; positive for high-risk HPV, p16, epithelial and neuroendocrine markers; variable expression of TTF-1, aberrant p53; common loss of Rb.

• Lymphoepithelial-like squamous cell carcinoma exhibits cohesive nests of cells; positive for epithelial markers, p63, and p40; negative for lymphoid markers.

• Malignant melanoma is positive for melanocytic markers; negative for lymphoid markers.

• High-grade endometrial stromal sarcoma may be positive for CD10, ER and PR in some types and negative in others; negative for lymphoid markers.

Table 12.8 Differential diagnosis of lymphoid and myeloid tumors involving the cervix

12.4.7 Prognosis

Primary cervical lymphomas are usually localized and have a favorable clinical outcome. High-stage disease is associated with a less favorable outcome [104]. Germinal center B-cell–like DLBCL subtype is associated with better overall survival [105].

12.5 Myeloid Tumors

12.5.1 Definition

Malignant neoplasm of myeloid origin. Myeloid sarcoma is a mass-forming lesion composed of primitive myeloid cells. The key features of myeloid sarcoma involving the cervix are described in Table 12.9.

Table 12.9 Key features of cervical myeloid sarcoma

12.5.2 Synonyms

Myeloid sarcoma is also known as chloroma (due to high myeloperoxidase content imparting a green color), granulocytic sarcoma (for tumors lacking a green color), or extramedullary myeloid tumor.

12.5.3 Etiology

Myeloid sarcoma may be associated with acute myeloid leukemia, chronic myeloproliferative disorders, or no clinical evidence of hematologic disease.

12.5.4 Macroscopy

The cervix may be diffusely enlarged or nodular.

12.5.5 Microscopy

Myeloid sarcoma is composed of a diffuse proliferation of primitive, monotonous myeloid cells with medium to large, oval, irregular, reniform or folded nuclei, and fine chromatin, prominent nucleoli, and scant to moderate cytoplasm. Admixed maturing cells with recognizable myeloid differentiation may be seen, as well as lymphocytes, tingible body macrophages, and megakaryocytes [106,107,108]. Sclerosis and vascular wall involvement are common (Fig. 12.12). Rarely, pseudo-alveolar, trabecular, or cord-like patterns may be present.

Fig. 12.12

Myeloid sarcoma. (a–e), Total hysterectomy with diffuse sheets of neoplastic cells involving the outer half of the cervical wall (H&E). The tumor cells exhibit large, oval, irregular, reniform or folded nuclei, fine chromatin, prominent nucleoli, and scant to moderate cytoplasm (b–e). Scattered megakaryocytes are seen (d, e). (f–i), Immunohistochemical stains show the tumor to be positive for CD34 (f), CD45 (g), myeloperoxidase (h), and CD117 (i). The patient has no prior history of hematologic disease

Immunohistochemically, myeloid sarcoma is positive for CD68, CD43, CD33, CD117, myeloperoxidase, and lysozyme; variably positive for CD34, CD13, CD14, CD15, CD45, antitrypsin, and antichymotrypsin; negative for pan B (CD20, CD19, CD79a) and T cell (CD3) markers, melanocytic marker, keratins, and muscle markers.

Flow cytometry shows immature myeloid precursors. Genetic testing shows chromosomal aberrations in 55% of cases. One case of myeloid sarcoma confined to the cervix had a t(11;19)(q23;p13.3) involving the MLL and ELL genes [107].

Cytologically, the tumor cells exhibit scant cytoplasm and round to oval nuclei with finely dispersed chromatin. Cytoplasmic vacuoles may mimic signet ring cells.

Diagnostic Highlights

• Diffuse sheets of primitive monotonous myeloid cells

• Tumor cells with medium to large, oval, irregular, reniform or folded nuclei, fine chromatin, prominent nucleoli, and scant to moderate cytoplasm

• Admixed maturing cells with recognizable myeloid differentiation, lymphocytes, tingible body macrophages and megakaryocytes

• Sclerosis and vascular wall involvement

• Rarely, pseudo-alveolar, trabecular, or cord-like patterns

12.5.6 Differential Diagnosis

Same as lymphoid tumors (see Table 12.8).

12.5.7 Prognosis

Limited outcome data suggest that prognosis depends on the extent of disease and underlying genetic abnormalities [106, 107, 109].