To better characterize this malignancy, a panel of immunohistochemical stains was performed that included synaptophysin, chromogranin, p63, p40, p16, TTF1, and CDX2. TTF1 revealed weak, patchy nuclear staining in a subset of neuroendocrine carcinoma tumor cells (Fig. 3). All the neuroendocrine markers were strongly positive in the small cell carcinoma component and negative in the adenocarcinoma component (Fig. 4). CDX2 was positive in adenocarcinoma and negative in neuroendocrine carcinoma, supporting a primary anorectal tumor (Fig. 5). P40 was completely negative, whereas p63 showed weak, focal areas of staining. P16 revealed diffuse, strong positivity in both morphologies, but human papillomavirus (HPV) types 16 and 18 in situ hybridization results were negative. However, this did not exclude the possibility of HPV-associated carcinoma because not all HPV subtypes are detected by this assay.
The tumor also revealed a very high Ki-67 index, with more than 95% of the cells showing positive staining (Fig. 6). The morphology and unique immunohistochemical profile led to a diagnosis of extrapulmonary small cell carcinoma with a minor, moderately differentiated adenocarcinoma component. This patient was treated with concurrent chemoradiation therapy similar to the current treatment protocol for small cell carcinoma of the lung. The patient is doing well and is currently status post radiotherapy and continuing his chemotherapy with cisplatin and etoposide.
Considering the histology and location of the tumor, some of the main entities that need to be ruled out include large cell neuroendocrine carcinoma (LCNEC), mixed adenoneuroendocrine tumor (MANEC), and pulmonary small cell carcinoma metastatic to the anorectal region. The tumor cells in this case revealed weak, patchy positivity for TTF1, which is not suprising since a sizeable proportion of EPSCCs can be TTF1 positive.10 Clinical and radiological correlation was essential in order to diagnose this disease process. The patient underwent a positron emission tomography/computed tomography scan that did not reveal any pulmonary mass or distant metastasis, thereby ruling out metastatic pulmonary neuroendocrine carcinoma.
Colorectal LCNECs are rare and require characteristic morphologic features and immunohistochemical profile for a diagnosis. In a study conducted by Bernick et al,11 of 6495 patients with colorectal cancer, 0.6% had neuroendocrine carcinoma, and only 0.2% of those was LCNEC.11–13 Histologically, LCNEC can be densely cellular and/or arranged in nests or trabeculae with nuclear palisading and is composed of cuboidal/polygonal cells with slightly granular cytoplasm. The nuclei reveal fine to coarsely granular chromatin pattern with thin nuclear membranes and prominent nucleoli. These tumors are mitotically very active (≥20 mitoses per 10 high-power field [HPF]) with Ki-67 greater than 20% and are frequently accompanied by necrosis.11,13 There can be focal glandular differentiation, rosette formation, or intracytoplasmic mucin in some cases.14,15 These tumors can also show focal squamous differentiation within the endocrine areas but are usually not associated with low-grade well-differentiated neuroendocrine neoplasm.11 Demonstration of neuroendocrine differentiation with at least two of the immunohistochemical stains such as synaptophysin, chromogranin, and CD 56 is essential for diagnosis, and the percentage of tumor cells required to stain positive with these markers ranges between 20% and 50%.11–13 Although the neoplastic cells in our case were arranged in sheets, were strongly positive for neuroendocrine markers and did have a glandular component, the other features described above, namely, the characteristic morphology of polygonal cells with vesicular nuclei with prominent nucleoli and granular cytoplasm, were notably absent in the current specimen, therefore this entity was ruled out.
Mixed adenoneuroendocrine tumor of the GI tract is defined as carcinoma with features of both high-grade neuroendocrine and adenocarcinoma wherein the adenocarcinoma component exceeds 30% of the tumor.7,15 If the differentiated adenocarcinoma component is less than 30%, then the term high-grade, poorly differentiated neuroendocrine carcinoma with glandular differentiation is used and if it is more than 70%, then the term adenocarcinoma with neuroendocrine differentiation is appropriate.7,16 Morphologic features of the neuroendocrine component may suggest large cell neuroendocrine differentiation with uniform, polygonal/cuboidal tumor cells in a broad trabecular or nested pattern with nuclear palisading, vesicular nuclei and prominent nucleoli, necrosis, and a very high proliferative index. The neuroendocrine component may also be of the small cell type with cells exhibiting high nuclear-to-cytoplasmic ratios, scant cytoplasm, nuclear molding with stippled chromatin, and inconspicuous nucleoli. In some lesions, the glandular and neuroendocrine components may be present separately, whereas in others they may diffusely admixed with each other.17 Positive immunohistochemical staining with the neuroendocrine markers is essential for the large cell component, but not for the small cell neuroendocrine component.17–19 The neuroendocrine component of high-grade MANEC may exhibit p53, CDX2, and TTF1 staining. C-KIT reactivity may also be seen that has been linked to a worse prognosis.17,19 In our case, most of the lesion was excised with minimal residual tumor present in the patient, with the pathology specimen revealing classic small cell neuroendocrine type morphology and less than 5% of glandular differentiation, thereby making MANEC a less likely possibility.
Another rare but important entity that one needs to be aware of is the goblet cell carcinoma previously known as the adenocarcinoid tumor. Although these tumors are usually seen in the appendix, a handful of cases have been reported in the colorectum.20–22 These tumors possess mixed features of both carcinoid and adenocarcinoma and usually grow in the submucosa. Histologically, solid tumor cell clusters or tubule-like structures composed of mucin-rich signet ring cells are seen. The tumor cells may be small with round nuclei and eosinophilic cytoplasm arranged in organoid/nested pattern with neurosecretory granules, suggesting neuroendocrine differentiation. The cells also reveal mild to moderate atypia, and Ki-67 is usually low (<20%).23 Focal positivity for neuroendocrine markers and MUC2 positivity highlighting mucin production is seen in these tumors.20 Some important features helpful in differentiating the aforementioned entities are listed in Table 1.
Both the World Health Organization and the European Neuroendocrine Society utilize the mitotic rate and Ki-67 for grading neuroendocrine tumors of the GI system. The 2010 World Health Organization classifies neuroendocrine tumors into low (G1 and G2) and high grade (G3). Tumors with less than 2 mitoses/10 HPF or tumors with less than or equal to 2% Ki-67 proliferation index are classified as G1. Tumors with 2 to 20 mitoses/10 HPF or those with 3% to 20% Ki-67 proliferation are considered as G2. G3 denotes high-grade neuroendocrine carcinoma, including small cell and large cell carcinoma, with mitoses of more than 20/10 HPF and Ki-67 proliferation index of more than 20%.24,25 Our specimen was classified as a G3 tumor because it revealed poorly differentiated small cell carcinoma with a very high proliferation index of 95%.
The differences between small cell neuroendocrine carcinoma, LCNEC, and MANEC are subtle and generally not critical with regard to disease management as the treatment for all three entities is usually the same. Although all of these tumors behave aggressively with a dismal prognosis, there are some reports in the literature that suggest that MANEC may have better prognosis than the other two tumor types.26 The management and prognosis of adenocarcinoid tumors are most dependent on the glandular component, although some reports indicate that survival tends to be better than that of adenocarcinoma.20,27
Currently, there are no prospective studies that evaluate treatment options for small cell carcinomas arising outside the lung, and most of these diseases have been reported in the literature in the form of case reports and small case series, with authors concentrating on one particular site of origin. Hence, there is paucity of data that are needed for forming appropriate management guidelines.6,7 Extrapulmonary small cell carcinoma is currently treated like small cell carcinoma of the lung, although there is evidence to suggest that there are some etiological, clinicopathological, and behavioral differences between the two entities.7 There are reports suggesting reemergence of the disease in other body sites that is attributed to the non–small cell clonal proliferation after an initial positive response to the treatment.28,29 In addition, the prognostic significance of the nonneuroendocrine differentiation is unclear and may have a significant impact on the patient outcome.29,30 Hence, definitive diagnosis using histopathologic criteria is important in order to enable formulation of new treatment protocols specific to the disease entity.
Neuroendocrine tumors of the GI tract (especially small cell carcinomas) are rare and are challenging for clinicians to manage because of a dearth of standardized treatment guidelines with established outcomes. It is important for pathologists to arrive at an accurate diagnosis and rule out the other entities that are considered in the differential diagnosis to facilitate proper management of this disease process. Although EPSCC, LCNEC, and MANEC are usually treated in a similar fashion, documentation of the presence of nonneuroendocrine differentiation is essential for future identification of the significance of the amount and type of nonneuroendocrine morphology with regard to tumor behavior, survival rates, and treatment implications. There is a definite need for evidence-based reviews with clinicopathological correlation and prospective studies focusing on tumor type with differentiation, progression, treatment, and survival that will lead to a better understanding of this disease.
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Keywords:© 2019 Lippincott Williams & Wilkins, Inc.
adenocarcinoma with small cell carcinoma; extrapulmonary small cell carcinomas; rectal mass; small cell carcinoma