Neuroendocrine Carcinoma, Mixed Epithelial/Mesenchymal and Mesenchymal Tumors, and Miscellaneous Lesions of the Cervix

Cytologic Features

The diagnosis of neuroendocrine carcinoma is challenging by cytology alone and is subject to low sensitivity and specificity. Small cell clusters with a high nuclear-cytoplasmic ratio and nuclear molding typify this tumor, but these features may be misinterpreted as a high-grade squamous intraepithelial lesion (SIL), adenocarcinoma, or lymphoma. Furthermore, in liquid-based samples, nuclear molding may not be conspicuous. Immunohistochemical studies, which are discussed in detail later, are often required for confirmation. Even so, the distinction between primary neuroendocrine tumors of the cervix and endometrial neoplasia cannot be made on Papanicolaou (Pap) smears alone and need to be interpreted in correlation with clinical findings.

Histologic Features

Classification of cervical neuroendocrine neoplasms into small cell carcinoma, large cell carcinoma, atypical carcinoid, and typical carcinoid tumors is based solely on morphology ( Table 15.1 ). The reader is advised that the diagnostic reproducibility of these categories is unknown, and there may be coexisting patterns or transitions from one to another over time. Furthermore, the clinical significance of subdividing tumors within this classification is unclear.

Features common to one or more of the proposed categories of neuroendocrine carcinoma, as outlined earlier, include variable organoid or trabecular architecture and uniform cells with small to medium-sized nuclei. Extent of organoid architectural pattern, nuclear pleomorphism, mitotic activity, and necrosis help to categorize these tumors (see Table 15.1 ; Fig. 15.1 ).

Rarely encountered well-differentiated neuroendocrine neoplasm (carcinoid) exhibits trabecular, organoid, nested, or cordlike growth patterns; minimal or no necrosis; and small uniform cells with round nuclei and finely granular chromatin ( Fig. 15.2 ). Another low-grade neuroendocrine tumor (atypical carcinoid) exhibits the previously stated features with increased mitotic activity (usually 5 to 10 mitoses per 10 high-power fields), a greater degree of nuclear atypia, or conspicuous necrosis ( Fig. 15.3 ).

The most prevalent types are the high-grade neuroendocrine carcinomas, including large and small cell neuroendocrine carcinoma, which exhibit necrosis, abundant mitoses (usually more than 10 mitoses per 10 high-power fields), and progressive loss of organoid architecture ( Figs. 15.4 to 15.7 ). In some neuroendocrine carcinomas, an insular/trabecular pattern of growth or discohesive architecture may not be obvious to readily prompt a consideration of neuroendocrine carcinoma on H&E (see Fig. 15.7 ). If the observer is unsure of the distinction, staining with neuroendocrine markers (chromogranin A, synaptophysin, neuron-specific enolase) is advised.

Small cell neuroendocrine carcinoma is morphologically similar to the classic pulmonary “oat cell” carcinoma and demonstrates many of the following features: (1) uniform cell population; (2) hyperchromatic nuclei; (3) a high nuclear–cytoplasmic ratio with nuclear packing (see Fig. 15.4 ); (4) tumor cells arranged in irregular aggregates, often with little cohesion; and (5) occasional rosettes or poorly defined acini. In addition, the nuclei contain coarse to opaque chromatin and, because there is little cytoplasm, they often appear to “mold” with adjacent nuclei. These tumors may also extensively infiltrate the underlying cervical stroma. Additional histologic features more commonly identified in poorly differentiated neuroendocrine carcinoma versus squamous cell carcinoma include (1) vascular invasion (see Fig. 15.5 ), which is observed in as many as 90% of cases by Van Nagell et al. and in 78% of early-stage lesions by Boruta et al.; and (2) conspicuous lack of coexisting inflammation in contrast to most cases of conventional squamous cell carcinoma. Furthermore, by virtue of their rapid growth, broad zones (geographic areas) of necrosis are often seen in these tumors (see Fig. 15.6 ). Large-cell neuroendocrine carcinoma exhibits a similar picture, with a pseudo-trabecular arrangement of cells that have more abundant cytoplasm, large nuclei (similar in nuclear size to small cell non-keratinizing squamous cell carcinoma), and prominent nucleoli (see Fig. 15.7 ).

As noted in the previous section, neuroendocrine neoplasms can be associated with in situ or invasive adenocarcinoma or squamous cell carcinoma. Unless it is of limited extent or of isolated cells, presence of neuroendocrine component should drive the primary histologic classification, because it most likely governs the clinical outcome.

Molecular Features

Current data on molecular profiles of cervical neuroendocrine carcinoma are based on single institution-case series. Slightly above 40% of small cell neuroendocrine carcinomas have exhibit loss of heterozygosity in various regions of the short arm of chromosome 3 (3p), and the majority demonstrate vascular endothelial growth factor (VEGF) overexpression. Frumovitz et al. interrogated mutational hotspots in 50 cancer-related genes via next-generation sequencing in 24 cases of small cell neuroendocrine carcinoma. Although no single mutation was found common to most cases, over 40% of cervical small cell carcinoma harbored at least one actionable genetic alteration. Most common mutations were seen in PIK3CA (18%), KRAS (14%), and TP53 (11%), suggesting that targeted therapies may be possible options for management.

Immunohistochemistry

The diagnosis of a neuroendocrine carcinoma of the cervix is not a perfect science. It is based primarily on morphology with two caveats:

• Not every neuroendocrine carcinoma will be recognized immediately. Some may closely resemble poorly differentiated adenocarcinomas.

• Immunostains will not always corroborate the histologic diagnosis, even when fairly certain. Suffice to say that if the pathologist is on the fence, the immunostain (positive or negative) carries the most weight.

The majority of neuroendocrine carcinomas will be (1) positive for low-molecular weight cytokeratin, such as AE1/AE3 and variably positive for cytokeratins 7 and 20 ; (2) diffusely positive for p16 ; and (3) positive for at least one of the neuroendocrine markers, including synaptophysin (60% to 90%), chromogranin (50% to 76%) ( Fig. 15.8 ), CD56 (70% to 90%), and neuron-specific enolase (up to 75%).

Important points regarding the distinction of neuroendocrine tumors from squamous carcinomas include:

• Expression of synaptophysin and chromogranin in large cell neuroendocrine carcinoma is more variable.

• Expression for chromogranin and synaptophysin has been detected in up to 20% and 9%, respectively, in non-neuroendocrine carcinoma of the cervix.

• One study found that no single parameter would reliably distinguish between the two, including chromogranin staining and testing for HPV-18.

Neuroendocrine carcinomas have the propensity to manifest certain clinical syndromes as a result of peptide hormone production. Immunoreactivity for these peptides have been variably demonstrated in these tumors, such as serotonin, somatostatin, gastrin, glucagon, and pancreatic polypeptide.

Differential Diagnosis

As alluded to in the earlier discussion, the differential diagnosis of neuroendocrine carcinoma depends on its diagnostic subcategory.

• Carcinoid tumor must be distinguished from primary or metastatic tumor with microacinar architecture ( Fig. 15.9 ). Fortunately, these tumors are very uncommon.

  

• Small and large cell neuroendocrine carcinoma are most easily confused with their morphologic mimics, including (1) small cell nonkeratinizing squamous cell carcinoma ( Fig. 15.10 ), (2) undifferentiated carcinoma, (3) solid adenocarcinoma ( Fig. 15.11 ), (4) primitive neuroectodermal tumor (PNET), (5) lymphoma or granulocytic sarcoma, and (6) melanoma (see the discussion presented later and Table 15.2 ). Separation of these entities will be facilitated if not always completely solved, by immunohistochemistry (see Table 15.2 ). For example, nuclear expression of thyroid transcription factor-1 (TTF-1), a general marker for pulmonary and thyroid primary neoplasms, was reported in one study to be detected (weak to strong reactivity) in up to 70% of cervical small and large cell neuroendocrine carcinomas. Thus TTF-1 expression will not exclude a cervical primary. Likewise, CD99, a nonspecific marker for Ewing/PNET as well as certain lymphomas and a wide range of carcinomas and sarcomas, is detected in up to half of cervical neuroendocrine carcinomas.

  
  
  Table 15.2

  Histochemical Distinction of Small Cell or Undifferentiated Tumors of the Cervix and Their Mimics

  Diagnosis	Immunophenotype (+)
  Neuroendocrine carcinoma	Chromogranin (+), synaptophysin (+), p16 (+), p63 (±)
  Small cell nonkeratinizing squamous carcinoma	p63 (+), p16 (+)
  Basaloid carcinoma	p63 (+)
  Peripheral neuroectodermal tumor (PNET)	O13 (p30/32MIC2) (+)
  Lymphoma	LCA(CD45), CD20(L26), CD3 (+)
  Granulocytic sarcoma (acute myeloid leukemia [AML])	Lysozyme, chloracetate esterase (+)
  Melanoma	SOX10, HMB-45, S-100 (+)
  Embryonal rhabdomyosarcoma	Myoglobin, desmin, myo-D1, MYF-4 (+)

The absolute distinction of neuroendocrine carcinomas from poorly differentiated cervical carcinomas may be nearly impossible at times, owing to several factors:

• Many neuroendocrine carcinomas arise in association with squamous cell carcinoma or adenocarcinoma ( Fig. 15.12 ).

  

• Some growth patterns defy the distinction between glandular and neuroendocrine origin ( Fig. 15.13 ).

  

• Neuroendocrine carcinoma and other epithelial tumors cannot be distinguished by HPV type or expression of neuroendocrine markers. Squamous differentiation can be helpful up to a point.

• SILs are usually associated with small-cell squamous carcinoma but may be associated with neuroendocrine carcinoma.

• Expression of p63 has been investigated as a biomarker discriminating squamous from other forms of differentiation in cervical cancers. Wang et al. showed that over 90% of squamous cell carcinoma and 0% of adenocarcinoma in their study were strongly positive (>75%) for p63. Focal to diffuse expression of p63 has been seen in less than 30% to slightly above 40% of cervical neuroendocrine carcinoma across studies. Thus, p63 may be useful for differentiating neuroendocrine carcinoma from squamous cell carcinoma, although it may not distinguish neuroendocrine carcinoma from glandular neoplasia ( Fig. 15.14 ). In most cases, the distinction of squamous from neuroendocrine will be based on histologic features.

  

Clinical Background

Endocervical polyps are benign glandular proliferations in the cervix. They are common and occur over a wide age range, with a mean in the fifth decade ( Table 15.4 ). Some polyps occur at the endocervical–lower uterine segment junction and harbor both endometrioid (or tubal) and endocervical epithelium. These are variously termed lower uterine segment polyps or mixed endocervical/endometrial polyps .

Endocervical polyps are clinically relevant because approximately 40% are symptomatic and often present with bleeding. Given the high frequency of association with menopause, symptomatic polyps require an additional endometrial sampling to exclude an endometrial origin or coincident endometrial pathology to explain the bleeding. Fewer than 0.1% are malignant, and most of these are metastatic uterine carcinoma. Some authors have speculated that unopposed estrogen associated with menopause is responsible for endocervical polyps, but there is no conclusive evidence to support this theory.

Gross Examination (Clinical Presentation)

The polyps typically have a lobulated or hyperemic surface, and arise within or above the cervical os. They are usually solitary lesions that range in general from a few millimeters to 4 cm in size (with an average of 1 cm).

Histologic Features

The majority of endocervical polyps identified clinically are confirmed histologically (see Table 15.4 ). Microscopically endocervical polyps consist of dilated endocervical glands in association with collagenous stroma, as well as prominent vascularity at the base of the polyp. Inflamed or myxoid stroma is common. Infarction due to torsion may be present. A very small percentage (0.1% to 2%) of cases are associated with a squamous (SIL) or columnar adenocarcinoma in situ (AIS) precursor. Squamous metaplasia may be present on surface epithelium.

Endocervical polyps exhibit a wide range of morphologic features reflecting the mixture of glands and stroma with variable predominance of either, including (1) polypoid microglandular hyperplasia in which the epithelium is the predominant component ( Fig. 15.15A ); (2) typical epithelial/stromal polyps (see Fig. 15.15B ); (3) predominately stromal polyps, sometimes with atypical stromal cells, similar to those seen more commonly in the vagina (see Fig. 15.15C and D ); and (4) polyps with atypical features, defined as hypercellular stroma and irregular gland architecture but not fulfilling the criteria for adenosarcoma ( Fig. 15.16 ).

Rare reports of hamartomatous polyps containing benign cartilage and endocervical polyps with extensive formations of sebaceous glands, sweat glands, and hair follicles have been described. Polypoid endometriosis involving the cervix may present as lobulated polyps or masses clinically mimicking endocervical polyps or malignancy, of which distinction can be confirmed by histologic evaluation.

Differential Diagnosis

The clinical differential diagnosis on gross examination of a cervical polypoid growth includes benign lesions, such as (1) prolapsed endometrial polyp, (2) endocervical submucosal leiomyoma, (3) adenomyoma, (4) polypoid endometriosis, as well as (5) malignant lesions, including adenosarcoma. Adenosarcoma should be suspected if polyps recur following removal. However, 10% to 20% of benign polyps will also recur. Very large polyps invariably raise the suspicion of malignancy (e.g., sarcoma, adenosarcoma). Nonetheless, in a literature survey of extremely large polyps (10 to 17 cm in diameter), none were malignant. Moreover, reports of adenosarcoma initially misdiagnosed as a benign polyp have not recorded large size as a presenting feature (discussed later). In general, with the exception of a subtle adenosarcoma, most other polypoid lesions can be easily distinguished from benign endocervical polyps.

Management

Treatment of endocervical polyps consists of removal. In patients who are symptomatic (most commonly abnormal bleeding), concurrent endometrial sampling should be performed to exclude concomitant endometrial polyps or other pathology. There is no universal agreement that polyps found incidentally require any action other than outpatient (if possible) removal.