Secondary Logo

A Case of Small Cell Carcinoma With Adenocarcinoma Found in a Rectal Fissure

Harinath, Lakshmi, MD, MPH*; Mohanty, Alok, MD*; Pai, Reetesh K., MD; Islam, Mohammed, MD; Silverman, Jan F., MD*

doi: 10.1097/PCR.0000000000000282
Case Reports
Free
SDC

Small cell carcinomas are aggressive high-grade malignancies most commonly diagnosed in the lung, but can also be found in extrapulmonary sites such as the breast, kidney, urinary bladder, uterus, ovary, pancreas, hepatobiliary tree, thymus, skin, and salivary glands. Although the gastrointestinal system has an abundance of neuroendocrine cells, small cell carcinomas in this region have a low incidence. We present the case of a 51-year-old man with a history of pain with bowel movements and recent weight loss. Colonoscopy was performed, which revealed a rectal fissure with a lesion involving the rectum and anal canal. Biopsy of the lesion revealed invasive carcinoma with 2 distinct morphologies, a poorly differentiated small cell component and a minor adenocarcinoma component. We discuss the differential diagnosis of small cell carcinoma that includes mixed adenoneuroendocrine carcinomas and other neuroendocrine neoplasms.

From the *Department of Pathology and Laboratory Medicine, Allegheny General Hospital, Allegheny Health Network; and

Department of Pathology, UPMC Presbyterian Hospital; and

Cancer Institute, Allegheny Health Network, Pittsburgh, PA.

Reprints: Lakshmi Harinath, MD, MPH, Allegheny General Hospital, 320 E North Ave, Pittsburgh, PA 15212. E-mail: Lakshmi.harinath@ahn.org.

The authors have no funding or conflicts to declare.

Extrapulmonary small cell carcinoma (EPSCC) is an aggressive and challenging malignancy that is rarely encountered in clinical practice. In North America, EPSCC has a low incidence rate of 0.1% to 0.4% and is seen in approximately 1 in 20 cases of small cell carcinoma.1,2 The mean survival for all stages in EPSCC is approximately 20 months, and the 5-year overall survival rate is very low at approximately 8.1%.1 The most common extrapulmonary sites where this tumor type is detected include the gastrointestinal (GI) and the genitourinary tracts.1 Small cell carcinoma of the esophagus was first reported by McKeown3 in 1952, and since then, this tumor type has been identified in all parts of the GI tract including the colon, rectum, and pancreas.3–5

Small cell carcinomas represent approximately 0.1% to 1% of all GI malignancies and 0.2% to 1.5% of all colonic carcinomas.1,5,6 According to the Surveillance, Epidemiology and End Results database, colorectal neuroendocrine carcinoma has an incidence of 0.2 per 100,000 inhabitants, with 62% of patients having distant metastasis at the time of presentation.7,8 Although this tumor has a high recurrence rate and frequently presents at an advanced stage with a dismal prognosis, it can sometimes mimic a benign anorectal condition with nonthreatening symptoms, leading to a delay in proper diagnosis and management.6–8 Moreover, up to 40% of these tumors show a nonneuroendocrine component, depending on the primary site of origin.7,9 We report a case of small cell carcinoma with a minor adenocarcinoma component arising in a rectal fissure in a 51-year-old man.

Back to Top | Article Outline

CASE REPORT

A 51-year-old man presented to the emergency department multiple times with pain associated with bowel movements. Physical examination during these visits did not reveal any lesion, and the patient was discharged with stool softeners and advised to follow up with his primary care physician. The patient continued to experience rectal pain that was referred to his gluteal region and worsened in intensity over a period of 4 months. There was no abdominal pain or rectal bleeding, but the patient did have significant weight loss during this period. On a subsequent visit to the emergency department, the patient was diagnosed with a lesion that was palpated at the level of the rectum. He underwent a colonoscopy that revealed a rectal fissure and a small lesion at the level of the rectal ampulla. Computed tomography scan showed no gross abnormality in this area. Based on these findings, the patient underwent a surgical resection of the lesion.

Back to Top | Article Outline

Pathology

The specimen received in the pathology laboratory was labeled as “rectal fissure” and grossly measured 3.5 × 2 × 1 cm. The specimen consisted of tan pink, soft, and focally hemorrhagic mucosa with roughened and cauterized soft tissue. Microscopic examination revealed invasive carcinoma with 2 different morphologies. Most of the specimen revealed solid nests and sheets of neoplastic cells that were round to oval with minimal cytoplasm and indistinct cell borders. The nuclei were hyperchromatic with salt-and-pepper coarse chromatin and indistinct nucleoli. Nuclear molding was evident along with increased mitotic activity and apoptotic debris, but no obvious necrosis (Figs. 1, 2). There was also a minor component of complex, irregular glands consistent with a moderately differentiated adenocarcinoma with necrotic debris and inflammatory infiltrate. This minor component represented less than 5% of the tumor. Based on these findings, a diagnosis of poorly differentiated neuroendocrine carcinoma associated with a minor component of moderately differentiated adenocarcinoma was rendered. The lesion involved the cauterized margins of the specimen and exhibited lymphovascular invasion.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

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.

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

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.

FIGURE 6

FIGURE 6

Back to Top | Article Outline

DISCUSSION

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.

TABLE 1

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.

Back to Top | Article Outline

CONCLUSIONS

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.

Back to Top | Article Outline

REFERENCES

1. Dakhil CS, Wick JA, Kumar AK, et al. Extrapulmonary small cell carcinoma: the University of Kansas experience and review of literature. Med Oncol 2014;31:187.
2. Brennan SM. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer 2010;116:888–895.
3. McKeown F. Oat-cell carcinoma of the esophagus. J Pathol Bacteriol 1952;64:889–891.
4. Choong NW. Small cell carcinoma of the urinary bladder. Mayo Clinic Exp Cancer 2005;103:1172–1178.
5. Brenner B, Shah MA, Gonen M, et al. Small-cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases. Br J Cancer 2004;90:1720–1726.
6. Spiliopoulou P, Panwar U, Davidson N. Rectal small cell carcinoma: a case report and review of the literature. Case Rep Oncol 2011;4:475–480.
7. Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014;120:2814–2823.
8. Kang H, O'Connell JB, Leonardi MJ. Rarr tumors of the colon and rectum: a national review. Int J colorectal disease 2007;22:183–189.
9. Shia J, Tang LH, Weiser MR, et al. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity. Am J Surg Pathol 2008;32:719–731.
10. Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non–small cell carcinomas. Mod Pathol 2012;25:18–30.
11. Bernick PE, Klimstra DS, Shia J, et al. Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum 2004;47:163–169.
12. Pascarella MR, McCloskey D, Jenab-Wolcott J, et al. Large cell neuroendocrine carcinoma of the colon: a rare and aggressive tumor. J Gastrointest Oncol 2011;2:250–253.
13. Minocha V, Shujha S, Ali R, et al. Large cell neuroendocrine carcinoma of the rectum presenting with extensive metastatic disease. Case Rep Oncol Med 2014;2014:386379.
14. Hamilton ST, Aaltonen LA, eds. WHO Classification of Tumours, Vol 2 Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000.
15. Klöppel G, Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2005;19:507–517.
16. Bosman FT, Carneiro F, Hruban RH, et al. World Health Organization (WHO) Classification of Tumours of the Digestive System. 4th ed. Geneva, Switzerland: WHO Press; 2010.
17. La Rosa S, Marando A, Furlan D. Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 2012;36:601–611.
18. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, et al, eds. WHO Classification of Tumors of the Digestive System. Lyon, France: IARC; 2010.
19. La Rosa S, Marando A, Sessa F, et al. Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update. Cancer 2012;4:11–30.
20. Wakahara T, Yamamoto S, Fujita S. A case of advanced rectal adenocarcinoid tumor with long-term survival. Jpn J Clin Oncol 2010;40:690–693.
21. Yagihashi N, Koyama M, Yagihashi S. Rectal adenocarcinoid with lymph node metastasis. Pathol Int 1999;49:563–565.
22. Moyana TN, Qizilbash AH, Murphy F. Composite carcinoid-glandular tumors of the colon and rectum: report of two cases. Am J Surg Pathol 1998;12:607–611.
23. Levendoglu H, Cox CA, Nadimpalli V. Composite (adenocarcinoid tumors) of the gastrointestinal tract. Dig Dis Sci 1990;35:519–525.
24. Rindi G, Klöppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757–762.
25. Rindi G, Klöppel G, Alhman H, et al. European Neuroendocrine Tumor Society (ENETS). TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449(4):395–401.
26. Maru DM, Khurana H, Rashid A, et al. Retrospective study of clinicopathologic features and prognosis of high-grade neuroendocrine carcinoma of the esophagus. Am J Surg Pathol 2008;32:1404–1411.
27. McCusker ME, Cote TR, Clegg LX, et al. Primary malignant neoplasms of the appendix—a population based study from the surveillance, epidemiology, and end-results program, 1973–1998. Cancer 2002;94:3307–3312.
28. Eberhardt J, Brown K, Lo S, et al. Extrapulmonary small cell carcinoma of the anal canal: a case report and review of the literature. Case Rep Med. 2012;2012: Available at: http://dx.doi.org/10.1155/2012/341432. Accessed October 1, 2018.
29. Brenner B, Tang LH, Klimstra DS, et al. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 2004;22:2730–2739.
30. Brenner B, Tang LH, Shia A, et al. Small cell carcinomas of the GI tract: clinicopathological features and treatment approach. Semin Oncol 2007;34:43–50.
Keywords:

adenocarcinoma with small cell carcinoma; extrapulmonary small cell carcinomas; rectal mass; small cell carcinoma

© 2019 Lippincott Williams & Wilkins, Inc.