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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 6  |  Issue : 2  |  Page : 152-154

Neuroendocrine neoplasm of liver with intratumoral discordance of mitotic and Ki-67 proliferation index


Department of Pathology, Pondicherry Institute of Medical Sciences, Puducherry, India

Date of Submission14-Mar-2020
Date of Decision16-Apr-2020
Date of Acceptance22-Jun-2020
Date of Web Publication21-Dec-2020

Correspondence Address:
Bakiarathana Anand
20, 1st Floor, Thirumurugan Street, Kamaraj Nagar, Puducherry - 605 011
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrsm.jcrsm_15_20

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  Abstract 


A 70-year-old female presented with backache and was found to have multiple lesions in the liver along with additional lesions in the sacral bone, adrenal, and the tail of pancreas. Six computed tomography-guided core biopsies from single lesion in the liver showed a neoplasm composed of small cells with fairly uniform, round nuclei and granular eosinophilic cytoplasm arranged around dilated vascular channels. Mitotic index was 3/10 high-power fields. A suspicion of neuroendocrine neoplasm (NEN) was confirmed by positive immunohistochemistry for synaptophysin. The Ki-67 proliferation index was 30%–40%. These findings confirmed metastatic NEN in the liver with intratumoral discordance in mitotic index of Grade 2 and Ki-67 proliferation index of Grade 3 according to the WHO 2017 grading of gastroenteropancreatic NEN. The discordance between primary and secondary NEN is known; however, the discordance of mitotic and Ki-67 index within the same tumor is unusual and hence we report this case.

Keywords: Discordance, Ki 67, mitotic index, neuroendocrine neoplasm, synaptophysin


How to cite this article:
Anand B, Kurian SS. Neuroendocrine neoplasm of liver with intratumoral discordance of mitotic and Ki-67 proliferation index. J Curr Res Sci Med 2020;6:152-4

How to cite this URL:
Anand B, Kurian SS. Neuroendocrine neoplasm of liver with intratumoral discordance of mitotic and Ki-67 proliferation index. J Curr Res Sci Med [serial online] 2020 [cited 2021 Jan 20];6:152-4. Available from: https://www.jcrsmed.org/text.asp?2020/6/2/152/304196




  Introduction Top


Neuroendocrine neoplasms (NEN) are tumors that arise from the neuroendocrine cells distributed throughout the body.[1] The most common sites include gastrointestinal tract, lungs, and pancreas compared to other rare sites such as gallbladder, thymus, testes, and ovaries.[2] NEN metastasis to liver is the second most common after adenocarcinomas. Metastatic NEN to the liver is more frequent than primary. Liver is the second most common site of metastatic NEN following lymph nodes.[3] Metastatic NEN in liver originating from gastroenteropancreatic (GEP) region is more common due to spread through the portal vein.[4]

GEP-NENs have a variable prognosis, with survival ranging from 6 months to more than 20 years. As the therapeutic options continue to expand, it is increasingly important to define robust prognostic markers to inform clinical decision-making. The Ki-67 proliferation index and mitotic count have proved to be the most useful prognostic histological markers and have been incorporated into the WHO 2017 grading of GEP-NEN.[5],[6]


  Case Report Top


A 70-year-old female presented with complaints of backache for 1 month. Physical examination was normal. Contrast-enhanced computed tomography (CT) and positron emission tomography-CT done elsewhere for further evaluation revealed heterogeneously enhancing multiple lesions in the liver along with additional lesions in the sacral bone, adrenal, and the tail of pancreas [Figure 1]. A CT-guided liver biopsy was done. Six cores of tissue were obtained from single lesion in the liver which showed a neoplasm composed of small cells with fairly uniform, round nuclei and granular eosinophilic cytoplasm arranged around dilated vascular channels [Figure 2]. On light microscopy, mitotic figures (per 10 high-power fields [HPFs]) were evaluated in at least forty fields of highest mitotic activity. The mitotic index thus obtained was 3/10 HPFs. The tumor cells were synaptophysin positive [Figure 3]. Ki-67 proliferation index was carried out in a different core, and the highest region of proliferative activity was noted. The estimated Ki-67 proliferation index was 30%–40% [Figure 4]. These findings confirmed metastatic NEN to the liver with discordance in mitotic index of Grade 2 and Ki-67 proliferation index of Grade 3 within different tumor areas of a single lesion.[6]
Figure 1: Contrast-enhanced computed tomography shows multiple lesions in the liver (a) and a lytic lesion in the sacrum (b) positron emission tomography-computed tomography shows heterogeneously enhancing lesions in the liver, adrenal, and the tail of pancreas (c) and sacrum (d)

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Figure 2: Section shows neoplastic cells arranged around dilated vascular channels (H and E stain × 100)

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Figure 3: Synaptophysin-positive neoplastic cells

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Figure 4: Ki-67 proliferative index 30%–40%

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  Discussion Top


NEN metastases are much more common than primary NEN in liver. In a study of 13,715 NENs, liver was the second most common site of metastasis after lymph nodes.[3]

Liver biopsy is an important tool for grading of NEN, especially when the primary is not identified. Primary hepatic NEN are predominantly single lesion when compared to metastatic NEN which are often multiple. Our patient had multiple lesions involving both lobes of the liver which was similar to the following studies.[4],[7]

A study demonstrated intratumoral heterogeneity in well-differentiated NENs metastatic to the liver with varied Ki-67 indices in different areas within a single lesion. Based on the abovementioned findings, it was predicted that nine core biopsies would be required to obtain the true high Ki-67 proliferation index in a single lesion. In addition, microarray analysis supports the heterogeneous nature of liver lesions in metastatic pancreatic neuroendocrine tumors.[8],[9]

Our patient had metastatic NEN to the liver with discordant mitotic and Ki-67 proliferation index. Lack of concordance between Ki-67 and mitotic index in assigning tumor grade was also seen in the following studies. The authors also suggested that Ki-67 labeling must be performed on all GEP-NENs in addition to mitotic rate to define more accurately the tumor grade and prognosis.[5],[10],[11]


  Conclusion Top


Liver biopsy is an important tool for grading of NEN, especially in unknown primary. Ki-67 staining of core biopsies provides a reliable method of proliferation, for the assessment of prognosis of metastatic NENs to the liver, although the choice of treatment may be affected by intratumoral grade heterogeneity. For discordant mitotic and Ki-67 proliferation index, a higher grade has to be given. Grade discordant tumors have worse prognosis than grade concordant tumors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to thank Dr. Sheila Nair, Sri Narayani Hospital and Research Center, Vellore, for performing immunohistochemistry of synaptophysin and Ki-67 on Ventana platform, thereby aiding in the confirmation of our diagnosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after “carcinoid”: Epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-72.  Back to cited text no. 1
    
2.
Watson RG, Johnston CF, O'Hare MM, Anderson JR, Wilson BG, Collins JS, et al. The frequency of gastrointestinal endocrine tumours in a well-defined population--Northern Ireland 1970-1985. Q J Med 1989;72:647-57.  Back to cited text no. 2
    
3.
Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934-59.  Back to cited text no. 3
    
4.
Burad DK, Kodiatte TA, Rajeeb SM, Goel A, Eapen CE, Ramakrishna B. Neuroendocrine neoplasms of liver-A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification. World J Gastroenterol 2016;22:8956-66.  Back to cited text no. 4
    
5.
Khan MS, Luong TV, Watkins J, Toumpanakis C, Caplin ME, Meyer T. A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. Br J Cancer 2013;108:1838-45.  Back to cited text no. 5
    
6.
Klöppel G. Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med 2017;33:324-30.  Back to cited text no. 6
    
7.
Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumours: The current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: An analysis based on prospectively collected parameters. Endocr Relat Cancer 2010;17:909-18.  Back to cited text no. 7
    
8.
Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: Implications for prognostic stratification. Am J Surg Pathol 2011;35:853-60.  Back to cited text no. 8
    
9.
Couvelard A, Deschamps L, Ravaud P, Baron G, Sauvanet A, Hentic O, et al. Heterogeneity of tumor prognostic markers: A reproducibility study applied to liver metastases of pancreatic endocrine tumors. Mod Pathol 2009;22:273-81.  Back to cited text no. 9
    
10.
McCall CM, Shi C, Cornish TC, Klimstra DS, Tang LH, Basturk O, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 2013;37:1671-7.  Back to cited text no. 10
    
11.
Shi C, Gonzalez RS, Zhao Z, Koyama T, Cornish TC, Hande KR, et al. Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol 2015;143:398-404.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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