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Rectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features arising in a patient with ulcerative colitis: a case report

Abstract

Background

Colorectal carcinoma with enteroblastic differentiation is a rare subtype of colorectal carcinomas expressing at least one characteristic immunohistochemical marker among α-fetoprotein, glypican-3, and spalt-like transcription factor 4. On the other hand, colorectal carcinoma with neuroendocrine differentiation is also a unique subtype of colorectal carcinomas showing expression of at least one distinctive marker among chromogranin A, synaptophysin, and CD56.

Case presentation

We experienced an extremely rare case of rectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features in a 53-year-old male patient with long-standing ulcerative colitis (UC). Most of the tumor cells were positive for enteroblastic differentiation markers and approximately a half of them for neuroendocrine differentiation markers. Some tumor cells showed only enteroblastic differentiation, and some did only neuroendocrine feature, but some showed both enteroblastic and neuroendocrine differentiation.

Conclusion

Colorectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features has not been reported yet. Neoplastic transformation from pluripotent stem cells in dysplastic epithelium of long-standing UC patients may be associated with such dual differentiation features.

Background

Carcinomas with enteroblastic differentiation (ED) are a rare variant of carcinomas with histological features of clear cytoplasm like embryonal gastrointestinal (GI) epithelia and tubulopapillary or solid growth pattern. They characteristically express enteroblastic markers such as α-fetoprotein (AFP), glypican-3 (GPC3), and spalt-like transcription factor 4 (SALL4). To our knowledge, approximately 80 cases of primary colorectal carcinoma (CRC) with ED including colorectal clear cell carcinoma have been reported to date [1,2,3,4,5,6,7,8].

CRCs with neuroendocrine differentiation (NED) or colorectal neuroendocrine carcinomas are also a rare type of CRCs accounting less than 1% of all CRCs [9]. According to the 2022 WHO Classification of Neuroendocrine Neoplasms, neuroendocrine neoplasms (NENs) with both epithelial and neuroendocrine tumor components in all organ systems are called mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) [9]. NENs associated with UC might develop, and 38 cases of CRC with NED in UC patients have been reported to date [10,11,12,13,14,15,16].

To our knowledge, however, CRC with both enteroblastic differentiation and neuroendocrine differentiation has not been reported yet in the English literature. We describe here the first case of such rectal carcinoma in a 53-year-old male patient with long-standing UC.

Case presentation

A 53-year-old Japanese man suffered from UC for 34 years. He was initially diagnosed with UC in 1987 when he was 19 years old. Medications including oral prednisolone and azathioprine were transiently effective, but the disease frequently relapsed. During the follow-up, a surveillance colonoscopy with biopsy was repeated, and the recent colonoscopy revealed a flat lesion in the lower rectum, and rectal biopsy was done. Specimen of the rectal biopsy was diagnosed as adenocarcinoma. He admitted to our hospital for treatment for the long-standing UC with rectal cancer. A total colectomy with the ileoanal anastomosis was performed. He has no recurrency for 4 months after the surgery.

Grossly, the resected flat tumor of the lower rectum was 2.5 × 2.5 cm in size (Fig. 1). Histological examination showed that the tumor had a component of moderately differentiated tubular adenocarcinoma with focal clear cytoplasm (Fig. 2a). The tumor cells predominantly arranged in glandular pattern, and most had hyperchromatic nuclei and prominent nucleoli (Fig. 2a). Immunohistochemistry revealed that the clear cells were positive for both GPC3 (Fig. 2b) and nuclear SALL4 (Fig. 2c), indicating enteroblastic differentiation. They were negative for AFP (Fig. 2d). In addition to the glandular growth pattern, tumor had a component of solid and nested growth pattern (Fig. 3a). Those tumor cells were positive for synaptophysin (Fig. 3b) and focally positive for chromogranin A (Fig. 3c), indicating neuroendocrine differentiation. They were negative for CD56 (Fig. 3d). Thus, some tumor cells showed only enteroblastic differentiation, and some tumor cells did only neuroendocrine feature, but other tumor cells were positive for both enteroblastic differentiation markers and neuroendocrine differentiation markers, indicating amphicrine cells (Fig. 4a, H&E; b, SALL4 immunohistochemistry; c, synaptophysin immunohistochemistry). Some tumor cells are both negative for enteroblastic differentiation markers and neuroendocrine differentiation markers (Fig. 4a, H&E; b, SALL4 immunohistochemistry; c, synaptophysin immunohistochemistry). Diffuse and strong staining for p53 was observed in most of the tumor cells (data not shown), suggesting the presence of TP53 mutation. Ki-67 labeling index of the tumor cells was more than 90% (data not shown). The tumor cells infiltrated into the submucosal layer with lymphatic invasion and venous invasion. One out of the five dissected lymph nodes showed metastasis. No distant metastasis was found by imaging tests. Thus, the tumor staging was regarded as pT1bN1a(1/5)M0 according to TNM classification [17]. The mucosa (5 × 3 cm) adjacent to the flat tumor showed low-grade dysplasia.

Fig. 1
figure 1

Macroscopic findings of the resected flat 2.5 × 2.5 cm tumor in the lower rectum. Arrows indicate the lesion

Fig. 2
figure 2

Representative histology of the rectal carcinoma with ED. a The tumor was composed of predominantly moderately differentiated adenocarcinoma with focal clear cell features (H&E × 400). Immunohistochemistry revealed that the tumor cells with clear cytoplasm and prominent nucleoli were positive for nuclear SALL4 (b) and cytoplasmic GPC3 (c) but negative for AFP (d) (× 400)

Fig. 3
figure 3

Representative histology of the rectal carcinoma with NED. The tumor was composed of predominantly poorly differentiated carcinoma with focal necrosis (a, H&E × 400). Immunohistochemistry revealed that the tumor cells forming solid nests were positive for cytoplasmic synaptophysin (b), focally positive for cytoplasmic chromogranin A (c), but negative for CD56 (d) (× 400)

Fig. 4
figure 4

Representative histology of rectal carcinoma showing dual differentiation toward enteroblastic and neuroendocrine features in the same cells. a Tumor cells partially arranged in glandular patterns and partially showed solid growth (H&E × 40). SALL4 (b) was immunohistochemically positive in a part of the tumor cells, and synaptophysin (c) was also positive in a part of them. Expression of SALL4 (b) and synaptophysin (c) was overlapping in some tumor cells

Discussion

Patients with long-standing UC have a high risk of CRC. The risk of developing CRC increases up to 2% after 10 years, 8% after 20 years, and 18% after 30 years [18]. The most frequent type of CRC associated with UC is adenocarcinoma, but other types of carcinoma such as squamous cell carcinoma, small cell carcinoma, and “hepatoid” carcinoma have been described [19]. In the present report, we described the first case of CRC with dual differentiation toward enteroblastic and neuroendocrine features in a patient with long-standing UC.

In our case, components of both enteroblastic differentiation and neuroendocrine differentiation were rather widely observed in the rectal carcinoma. Guadagno et al. described a case of incidental neuroendocrine microcarcinoma coexistent with a high-grade adenoma in the rectum, in which distant metastases of the neuroendocrine carcinoma component occurred in a few months [20]. Since neuroendocrine carcinoma component should be considered extremely malignant even if the lesion is very small, we should accurately differentiate the neuroendocrine carcinoma component from usual solid-type adenocarcinoma through the appropriate immunohistochemical examination. The careful follow-up is also needed in our case.

UC-associated carcinoma is considered to develop from dysplasia through a pathway called inflammation-dysplasia-carcinoma sequence [21]. Long-standing inflammation may cause “pancellular damage” involving all types of colonic epithelial cells, probably resulting in development of tumor with NED derived from pluripotent stem cells in dysplastic epithelium. Shigaki K. et al. observed that about 30–50% of UC-associated dysplasia had a feature of NED, suggesting that the multipotential cell might be capable of giving rise to neoplasia with NED [22]. Thus, pluripotent stem cells in dysplastic epithelium of long-standing UC patients may differentiate not only to neuroendocrine features but also to enteroblastic features. In 2020, Yamashiro Y. et al. identified 39 (4.01%) out of 971 CRC cases which was immunohistochemically positive for at least one enteroblastic marker, but only approximately one fourth of them contained tumor cells with clear cytoplasm [23]. Apparent clear cytoplasm of the tumor cells as in the present case could be reminiscent of ED, but the enteroblastic features in CRC may be rather overlooked when the tumor cells do not have obviously clear cytoplasm and is observed only by H&E staining. Immunohistochemical staining of AFP, GPC3, and SALL4 in many cases of CRC in UC patients may clarify whether quite a few CRC in UC patients might show ED.

Conclusion

We reported the first case of CRC with dual differentiation toward enteroblastic and neuroendocrine features. Background of long-standing UC may be associated with such features.

Availability of data and materials

All data supporting the funding of this study are available within the article.

Abbreviations

UC:

Ulcerative colitis

ED:

Enteroblastic differentiation

GI:

Gastrointestinal

AFP:

α-Fetoprotein

GPC3:

Glypican-3

SALL4:

Spalt-like transcription factor 4

CRC:

Colorectal carcinoma

NED:

Neuroendocrine differentiation

NENs:

Neuroendocrine neoplasms

MiNENs:

Mixed neuroendocrine-non-neuroendocrine neoplasms

References

  1. Hellstrom HR, Fisher ER. Physaliferous variant of carcinoma of colon. Cancer. 1964;17:259–63.

    Article  CAS  PubMed  Google Scholar 

  2. Remo A, Grillo F, Mastracci L, Fassan M, Sina S, Zanella C, et al. Clear cell colorectal carcinoma: time to clarify diagnosis. Pathol Res Pract. 2017;213:447–52.

    Article  PubMed  Google Scholar 

  3. Gurzu S, Jung I, Bara T, Bara T Jr, Serester O. Immunohistochemical and molecular features of primary clear cell-adenocarcinoma of the rectum, as predictive factors for individualized therapy. Romanian J Morphol Embryol. 2014;55:629–33.

    Google Scholar 

  4. Oyama Y, Nishida H, Kusuda T, Kadowaki T, Arakane M, Okamoto K, et al. Colon adenoma and adenocarcinoma with clear cell components–two case reports. Diagn Pathol. 2019;14:37.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Murakami T, Yao T, Yatagai N, Yamashiro Y, Saito T, Sakamoto N, et al. Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological study of five cases. Histopathol. 2020;76:325–32.

    Article  Google Scholar 

  6. Tochio T, Mukai K, Baba Y, Asakawa H, Nose K, Tsuruga S, et al. Early stage clear cell adenocarcinoma of the colon examined in detail with imageenhanced endoscopy: a case report. Clin J Gastroenterol. 2018;11:465–9.

    Article  PubMed  Google Scholar 

  7. Abada E, Anaya IC, Abada O, Lebbos A, Beydoun R. Colorectal adenocarcinoma with enteroblastic differentiation: diagnostic challenges of a rare case encountered in clinical practice. J Pathol Transl Med. 2022;56:97–102.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Young RH, Hart WR. Metastatic intestinal carcinomas simulating primary ovarian clear cell carcinoma and secretory endometrioid carcinoma: a clinicopathologic and immunohistochemical study of five cases. Am J Surg Pathol. 1998;22:805–15.

    Article  CAS  PubMed  Google Scholar 

  9. Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr Pathol. 2022;33:115–54.

    Article  CAS  PubMed  Google Scholar 

  10. Owen DA, Hwang WS, Thorlakson RH, Walli E. Malignant carcinoid tumor complicating chronic ulcerative colitis. Am J Clin Pathol. 1981;76:333–8.

    Article  CAS  PubMed  Google Scholar 

  11. Miyazaki H, Mizushima T, Miyoshi N, Takahashi H, Haraguchi N, Hata T, et al. Two cases of rectal neuroendocrine carcinoma associated with long-standing ulcerative colitis. Nihon Shokakibyo Gakkai Zasshi. 2020;117:521–31.

    PubMed  Google Scholar 

  12. Marchioni Beery RM, Devers TJ, Clement JM. A case of primary colonic small-cell carcinoma arising in a patient with long-standing ulcerative colitis. Gastrointest Cancer Res. 2014;7:119.

    PubMed  PubMed Central  Google Scholar 

  13. Costa JM, Rodrigues AP, Fernandes D, Costeira F, Vieira F, Gonçalves R, et al. Adenocarcinoma is not always the diagnosis - colon neoplasia in patient with long-standing ulcerative colitis under long-term prednisone maintenance therapy. Clin Res Hepatol Gastroenterol. 2019;43:362–4.

    Article  CAS  PubMed  Google Scholar 

  14. Wick MR, Weatherby RP, Weiland LH. Small cell neuroendocrine carcinoma of the colon and rectum: clinical, histologic, and ultrastructural study and immunohistochemical comparison with cloacogenic carcinoma. Hum Pathol. 1987;18:9–21.

    Article  CAS  PubMed  Google Scholar 

  15. Kinugasa H, Hiraoka S, Oka S, Okada H. Ulcerative colitis associated with a mixed neuroendocrinenon-neuroendocrine neoplasm. Intern Med. 2020;59:2085–6.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Al Buthi SA, Bin Gheshayan SF, Al Samaani I, Al Ahmadi B, Al Selaim NA. A mixed neuroendocrine/non-neuroendocrine neoplasm arising in the background of ulcerative colitis: a case report and review of the literature. Am J Case Rep. 2022;23:e934396.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Brierley JD, Gospodarowicz MK, Wittekind C, editors. Classification of malignant tumours. 8th ed. Geneva and Hoboken: International Union Against Cancer and Wiley-Blackwell; 2016.

  18. Eaden JA, Abram KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wong NA, Harrison DJ. Colorectal neoplasia in ulcerative colitis-recent advances. Histopathol. 2001;39:221–34.

    Article  CAS  Google Scholar 

  20. Guadagno E, Cervasio M, De Rosa F, Modica R, Faggiano A, De Caro DB, et al. An incidental rectal neuroendocrine microcarcinoma (‘micro NEC’) coexistent with a high grade adenoma. Pathol Int. 2020;70:300–2.

    Article  PubMed  Google Scholar 

  21. Zisman TL, Rubin DT. Colorectal cancer and dysplasia in inflammatory bowel disease. World J Gastroenterol. 2008;14:2662–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shigaki K, Mitomi H, Fujimori T, Ichikawa K, Tomita S, Imura J, et al. Immunohistochemical analysis of chromogranin A and p53 expressions in ulcerative colitis–associated neoplasia: neuroendocrine differentiation as an early event in the colitis-neoplasia sequence. Hum Pathol. 2013;44:2393–9.

    Article  CAS  PubMed  Google Scholar 

  23. Yamashiro Y, Saito T, Hayashi T, Murakami T, Yanai Y, Tsuyama S, et al. Molecular and clicicopathological features of colorectal adenocarcinoma with enterblastic differentiation. Histopathol. 2020;77:492–502.

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank all people involved in this work.

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All of the authors participated in the collection of the clinical and pathological data and agreed with its content. RK, KK, TM, YH, MU, and HI performed the surgery. TK and SH evaluated pathology of this case. TK wrote the initial draft of the manuscript, and SH supervised the writing of the manuscript. The authors read and approved the final manuscript.

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Correspondence to Seiichi Hirota.

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Kihara, T., Kuwahara, R., Kusunoki, K. et al. Rectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features arising in a patient with ulcerative colitis: a case report. World J Surg Onc 20, 371 (2022). https://doi.org/10.1186/s12957-022-02838-1

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