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 ).

Spectrum of neuroendocrine carcinomas of the cervix, beginning with A, low grade, and terminating in F, poorly differentiated, morphology.

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 ).

Low-grade neuroendocrine carcinoma. Organoid arrangement of cells with uniform nuclei, minimal hyperchromasia, and low mitotic index.

Atypical carcinoid. A, Greater degree of cellular crowding and increased mitotic index. B, Nuclear hyperchromasia with variable chromatin coarseness.

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 (high-grade). A, The characteristic blue appearance reflects the high nuclear/cytoplasmic ratio and nuclear packing. B, At higher power, streams of loosely aggregated tumor cells invade the stroma with minimal inflammatory response. C, Tumor cells in a Papanicolaou (Pap) smear exhibit the characteristic nuclear molding.

Vascular invasion in neuroendocrine carcinoma. Note the minimal associated inflammation.

Geographic necrosis in a poorly differentiated neuroendocrine carcinoma.

A and B, Large cell neuroendocrine carcinoma (high-grade).

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:

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

  
  
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  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%).

A, Neuroendocrine carcinoma. B, Chromogranin staining is strongly positive. C, Another neuroendocrine carcinoma emerging from a poorly differentiated adenocarcinoma. D, Chromogranin staining. E, CD56 staining. F, p63 staining is negative.

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

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

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

  
  
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  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.

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

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  A, Small tubules in a metastatic adenocarcinoma mimic neuroendocrine carcinoma. B, A primary adenocarcinoma forming small tubules with uniform nuclei.

  
  
  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  Neuroendocrine carcinoma versus small cell squamous carcinoma. A, Small cell squamous carcinoma with discrete nesting pattern and preserved polarity. B, Neuroendocrine carcinoma with more haphazard nesting pattern, showing numerous randomly arranged fracture lines caused by poor cohesion and disorganized growth.

  
  

  
  

  
  

  

  
  

  
  

  A and B, Solid poorly differentiated carcinoma of the cervix. C, Needle biopsy of the lung recurrence. D, The lung tumor stains strongly for chromogranin.

  
  
  
  

  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:

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

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  A, Squamous differentiation in the center of a poorly differentiated neuroendocrine carcinoma. B, Adenocarcinoma in situ (upper) merging with neuroendocrine carcinoma (lower) .

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

  
  

  
  

  
  

  

  
  

  
  

  Poorly differentiated carcinoma with features of both adenocarcinoma and neuroendocrine carcinoma.

  
  
  
  
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  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.

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

  
  
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  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.

  
  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  

  
  

  
  

  Poorly differentiated non-neuroendocrine carcinomas. A, Nests of p63-negative poorly differentiated carcinoma associated with an adenosquamous carcinoma in situ. B, Undifferentiated papillary carcinoma associated with an adenocarcinoma. C, Undifferentiated papillary carcinoma of the cervix (HPV-18 positive). D, Note the variable p63 staining.

  
  

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 ).

A, Endocervical polyp with prominent microglandular changes. B, Typical endocervical polyp. C, Endocervical polyp composed principally of stroma (stromal polyp). D, Mild stromal atypia.

A, Atypical endocervical polyp with mildly irregular glands. B, Slight gland irregularity may suggest adenosarcoma. The distinction from the latter requires attention to periglandular stromal accentuation, mitotic index, and nuclear atypia in the adjacent stroma. C, Higher magnification of mild periglandular stromal cuffing in an atypical stromal polyp. Note the tubal metaplasia in the glands, a feature that will not in itself distinguish this entity from adenosarcoma. D, Mild polypoid architecture on the surface of an atypical polyp.

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.

Histologic Features

Endocervical adenomyoma is classically a well-demarcated biphasic tumor with glands set in a stroma composed of predominantly smooth muscle arranged in fascicles. The glands, which are lined by benign endocervical type mucinous epithelium, are cystic or irregularly shaped, and exhibit a somewhat lobular growth pattern. Larger glands can present as short papillary infoldings. Surface squamous, endometrioid, and tubal metaplasia can be present. The stroma is typically devoid of desmoplastic response ( Fig. 15.17A and B ).

A to D, Adenomyomas containing irregular admixture of glands and myomatous stroma.

Unusual features have been reported in association with benign endocervical adenomyoma, including a stromal reaction in the form of (1) histiocytic and giant cell reaction in response to focal gland rupture and mucin extravasation, (2) adenofibroma-like growth pattern with prominent papillary projections, as well as a (3) symplastic-like stroma with bizarre nuclei and multinucleated cells. Focal surface squamous intraepithelial neoplasia and stromal adipose tissue were also reported in rare cases.

Presence of marked architectural glandular complexity, focal cytologic atypia, squamous morules, and focal necrosis may render a diagnosis of atypical polypoid adenomyoma when there are insufficient features to warrant a diagnosis of adenosarcoma qualitatively or quantitatively. We recommend follow-up with monitoring of the patient for regrowth of the polyp when we encounter unusual lesions of any sort.

Immunohistochemistry

Immunohistochemistry is of little value in making a diagnosis of classic adenomyoma, although immunostains can be diagnostic adjuncts in challenging cases. The myomatous stromal component can be highlighted by smooth muscle actin, desmin, and H-caldesmon. Casey et al. reported diffuse positivity of ER, CK7, and PAX8, positivity for carcinoembryonic antigen (CEA; apical), as well as negativity for MUC6 consistent with a benign endocervical immunophenotype in the glandular components of endocervical adenomyoma, differentiating them from histologic mimics, such as minimal-deviation adenocarcinoma and lobular endocervical glandular hyperplasia (LEGH), which typically exhibit a gastric immunophenotype. Immunoreactivity for ER was recapitulated in a subsequent case report by Takeda et al., although focal reactivity for MUC6 was observed in that study. Furthermore, adenomyoma shows either retention or heterogenous PAX2 expression, which helps to distinguish it from minimal-deviation adenocarcinoma in which PAX2 expression is often lost.

Differential Diagnosis

When cervical adenomyoma presents as a mural-based mass, the principal differential diagnosis is with minimal-deviation adenocarcinoma (adenoma malignum), because both tumors may exhibit similarly shaped irregular glands lined by bland mucinous epithelium. Distinction is made based on the well-circumscribed nature and frequent lobular glandular arrangement of adenomyoma, which is rarely seen in adenoma malignum, because the latter typically presents as an ill-defined lesion with haphazard infiltrative glandular growth. Other histologic features that helped differentiate between the two entities include presence of stromal desmoplasia, stromal cytologic atypia, and mitotic activity, which are identified at least focally in all cases of adenoma malignum but not present in adenomyoma. In curettage specimens, the well-circumscribed nature of cervical adenomyoma may not be well appreciated, and the combination of glands and smooth muscle stroma may suggest invasion if one is not alert to the possibility of adenomyoma.

The primary malignant tumors to exclude is müllerian adenosarcoma, which, in contrast to adenomyoma, contains cellular stroma with periglandular condensation and minimal smooth muscle differentiation, and often demonstrates nuclear atypia, mitoses, and intraglandular papillary projections not seen in adenomyoma.

Benign pseudoneoplastic glandular lesions also need to be distinguished from endocervical adenomyoma. Similar to adenomyoma, laminar endocervical glandular hyperplasia (LEGH) can present in premenopausal women as a well-demarcated lesion and lobular proliferation of glands. In LEGH, however, there is a lack of myomatous stroma, and the glands are lined by columnar mucinous epithelium with an eosinophilic granular appearance and a gastric immunophenotype (positive for HIK1083, which highlights gastric mucous cells, and M-CGMC-1, which stains pyloric-type mucin). Benign endocervical polyp may also contain smooth muscle bundles, but those are often minor components of the lesion and should not be confused with adenomyoma. Endocervicosis may raise consideration of endocervical adenomyoma, but the former lacks a myomatous stroma and is less well circumscribed. Mesonephric hyperplasia in the cervix can be lobular in architecture. A cervical lesion coined mesonephric adenomyoma has been reported in literature with mesonephric-type glands composing of CD10–positive ER-negative simple cuboidal epithelium, setting in a stroma containing abundant smooth muscle.

Outcome and Management

Endocervical adenomyomas are usually cured by local excision or simple polypectomy. Residual tumor after polypectomy can be found at hysterectomy and recurrence 3 years after polypectomy has been reported in rare cases.