An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas

Yu, Sanhong; Hornick, Jason L.; González, Raúl

doi:10.1007/s00428-021-03085-7

Cited by 9 publications

(11 citation statements)

References 55 publications

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“…Even though NET metastasis to the breast is considered rare, especially when originating from an ileal primary, an in-depth analysis found the rate to be 4.7% among female patients with small intestinal NETs, remarkably similar to our results 62–65. It would certainly be important to distinguish these events from primary mammary tumors, especially when the patient presenting with the lesion has no prior history of NET 66–68…”

Section: Discussionsupporting

confidence: 87%

“…[62][63][64][65] It would certainly be important to distinguish these events from primary mammary tumors, especially when the patient presenting with the lesion has no prior history of NET. [66][67][68] A limitation of this retrospective study concerns selection bias, which was addressed by employing strictly defined and comprehensive inclusion and exclusion criteria, by using nonconstricting search parameters, and by reviewing all consecutive cases identified in the search. Underscoring this fact, the demographic characteristics of this patient cohort (51.9% female, mean age: 60.3 y) and basic clinicopathologic features of tumors in this study (79.6% ileal, 46.3% multifocal) are very similar to those previously published for small bowel NETs.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Pathologic Prognostic Factors in Neuroendocrine Tumors of the Small Intestine

Polydorides¹,

Liu²

2021

American Journal of Surgical Pathology

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The precise contributions of histopathologic features in the determination of stage and prognosis in small intestinal neuroendocrine tumors (NETs) are still under debate, particularly as they pertain to primary tumor size, mesenteric tumor deposits (TDs), and number of regional lymph nodes with metastatic disease. This single-institution series reviewed 162 patients with small bowel NETs (84 females, mean age: 60.3 ± 12.0 y). All cases examined (100%) were immunoreactive for both chromogranin A and synaptophysin. Primary tumor size > 1 cm (P = 0.048; odds ratio [OR] = 3.06, 95% confidence interval [CI]: 1.01-9.24) and lymphovascular invasion (P = 0.007; OR = 4.85, 95% CI: 1.53-15.40) were associated with the presence of lymph node metastasis. Conversely, TDs (P = 0.041; OR = 2.73, 95% CI: 1.04-7.17) and higher pT stage (P = 0.006; OR = 4.33, 95% CI: 1.53-12.28) were associated with the presence of distant metastasis (pM). A cutoff of ≥ 7 positive lymph nodes was associated with pM (P = 0.041), and a thusly defined modified pN stage (pNmod) significantly predicted pM (P = 0.024), compared with the prototypical pN (cutoff of ≥ 12 positive lymph nodes), which did not. Over a median follow-up of 35.7 months, higher pNmod (P = 0.014; OR = 2.15, 95% CI: 1.16-3.96) and pM (P < 0.001; OR = 11.00, 95% CI: 4.14-29.20) were associated with disease progression. Proportional hazards regression showed that higher pNmod (P = 0.020; hazard ratio = 1.51, 95% CI: 1.07-2.15) and pM (P < 0.001; hazard ratio = 5.48, 95% CI: 2.90-10.37) were associated with worse progression-free survival. Finally, Kaplan-Meier survival analysis demonstrated that higher pNmod (P = 0.003), pM (P < 0.001), and overall stage group (P < 0.001) were associated with worse progression-free survival, while higher pM also predicted worse disease-specific survival (P = 0.025). These data support requiring either chromogranin or synaptophysin, but not both, for small bowel NET diagnosis, the current inclusion of a 1 cm cutoff in primary tumor size and the presence of TDs in staging guidelines, and would further suggest lowering the cutoff number of positive lymph nodes qualifying for pN2 to 7 (from 12).

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Evaluation of Pathologic Prognostic Factors in Neuroendocrine Tumors of the Small Intestine

Polydorides¹,

Liu²

2021

American Journal of Surgical Pathology

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“…In a previous study [4], we demonstrated that colorectal MANECs with a histologically recognizable neuroendocrine carcinoma component confirmed by synaptophysin positivity are associated with a significantly poorer prognosis when compared to conventional adenocarcinomas NOS and other adenocarcinoma subtypes [4]. However, this study did not examine the clinical relevance of the expression of synaptophysin, the gold standard marker for the immunohistochemical confirmation of a neuroendocrine differentiation [21], in conventional colorectal adenocarcinomas without a histological pattern suggestive of neuroendocrine differentiation. In the current study, we screened 1002 conventional adenocarcinomas for synaptophysin expression and found that approximately a quarter of these tumors harbored synaptophysin-positive cells, albeit mostly as scattered tumor cells embedded in the epithelium of the neoplastic glands.…”

Section: Discussionmentioning

confidence: 70%

Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker?

Konukiewitz

Kasajima

Schmitt

et al. 2021

Cancers

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Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear. Methods: We investigated synaptophysin expression in 1002 conventional colorectal adenocarcinomas and correlated the results with clinicopathological characteristics and patient survival and compared the survival characteristics of synaptophysin expression groups to MANECs. Results: Synaptophysin expression in conventional colorectal adenocarcinomas was associated with a shortened disease-free survival (p = 0.037), but not with overall survival or disease-specific survival (DSS) in univariate analyses and without any survival impact in multivariate analyses. Patients with “true” MANECs, on the other hand, showed a significantly shorter survival than all conventional adenocarcinomas with or without synaptophysin expression in uni- and multivariate analyses (e.g., multivariate DSS: p < 0.001, HR: 5.20). Conclusions: Our study demonstrates that synaptophysin expression in conventional colorectal adenocarcinomas, in contrast to MANECs, is not associated with a significantly poorer clinical outcome when compared to adenocarcinomas without synaptophysin expression. Furthermore, our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, also strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation.

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“…For example, TTF1 may help identify pulmonary carcinoids and MTC, PDX1 may assist in recognizing NENs of the upper gastrointestinal tract including the pancreas, whereas CDX2 and SATB2 may highlight NENs of the lower gastrointestinal tract. In addition, testing for various hormones may be useful, including calcitonin for MTC, serotonin for lower gastrointestinal NENs, islet hormones for pancreatic NENs, and GLP1 for rectal NENs, to name just a few [35,36]. NECs outside of the head and neck area occasionally may metastasize to the jaws and major salivary glands [36].…”

Section: Metastastic Neuroendocrine Neoplasia Of Unknown Primarymentioning

confidence: 99%

Top 10 Histological Mimics of Neuroendocrine Carcinoma You Should Not Miss in the Head and Neck

Juhlin

Bal

2023

Head and Neck Pathol

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Background The spectrum of neuroendocrine neoplasia (NEN) of the head and neck region is wide-ranging and diverse, including a variety of diagnoses stretching from benign and low-malignant tumor forms to highly proliferative, poor prognosis neuroendocrine carcinoma (NEC). Moreover, there are several non-neuroendocrine differential diagnoses to keep in mind as well, displaying various degree of morphological and/or immunohistochemical overlap with bona fide neuroendocrine lesions. Methods Review. Results While the growth patterns may vary, well-differentiated NEN usually display a stippled “salt and pepper” chromatin, a granular cytoplasm, and unequivocal expression of neuroendocrine markers such as chromogranin A and synaptophysin. However, these features are often less pronounced in NEC, which may cause diagnostic confusion—not the least since several non-NEC head and neck tumors may exhibit morphological similarities and focal neuroendocrine differentiation. Conclusion As patients with NEC may require specific adjuvant treatment and follow-up, knowledge regarding differential diagnoses and potential pitfalls is therefore clinically relevant. In this review, the top ten morphological and/or immunohistochemical mimics of NEC are detailed in terms of histology, immunohistochemistry, and molecular genetics.

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An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas

Cited by 9 publications

References 55 publications

Evaluation of Pathologic Prognostic Factors in Neuroendocrine Tumors of the Small Intestine

Evaluation of Pathologic Prognostic Factors in Neuroendocrine Tumors of the Small Intestine

Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker?

Top 10 Histological Mimics of Neuroendocrine Carcinoma You Should Not Miss in the Head and Neck

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