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CASE REPORT Table of Contents  
Ahead of print publication
A case report of isolated bone marrow metastasis from neuroendocrine tumor of occult primary: A pathologist's perspective on this unusual presentation - A case report


 Department of Pathology, Apollomedics Super Speciality Hospital, Lucknow, Uttar Pradesh, India

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Date of Submission07-May-2022
Date of Decision19-Jul-2022
Date of Acceptance08-Aug-2022
Date of Web Publication22-Sep-2022
 

  Abstract 


Introduction: Neuroendocrine tumors (NETs) are poorly understood neoplasms that, although slow growing compared with epithelial malignancies, can behave aggressively. Bone marrow (BM) is an uncommon site of metastasis by neuroendocrine tumors (NETs), occurring in approximately 5% of the cases. Despite advanced diagnostic techniques, primary site cannot be deciphered in few patients. Case: A 46-year-old male with a recent history of myocardial infarction, rapidly worsening back pain from past two months. He was referred to us with a suspicion of multiple myeloma with multiple lytic lesions of bone. The patient underwent a BM examination, which revealed extensive infiltration of the marrow with tumor cells positive for immunohistochemical (IHC) markers of NET with high proliferation index. Thus, a diagnosis of “metastatic NET” was rendered. Conclusion: In an occult primary, a panel of IHC biomarkers are of key importance to confirm the nature and grade of the tumor. Site-specific markers may be lost in high-grade tumors. Thus, in an era of theradiagnostics, immunohistochemistry remains a tool of paramount vitality, to accurately classify these tumors, and may aide in finding the primary site of neoplasm.

Keywords: Bone marrow, immunohistochemistry, metastasis, neuroendocrine neoplasm, neuroendocrine tumor


How to cite this URL:
Singh P, Somani K, Sujatha K. A case report of isolated bone marrow metastasis from neuroendocrine tumor of occult primary: A pathologist's perspective on this unusual presentation - A case report. Apollo Med [Epub ahead of print] [cited 2022 Sep 27]. Available from: https://apollomedicine.org/preprintarticle.asp?id=356693





  Introduction Top


Neuroendocrine tumors (NETs) include a wide range of neoplasms at various anatomic locations, with diverse behavior and prognosis. A large subset of patients present with distant metastases at the time of diagnosis, mostly in the liver.[1] Bone marrow (BM) metastases are a late event and often occur after or in concurrence with liver deposits.[2] Isolated marrow metastases from NET are a rare finding and have been primarily reported as individual case reports.[3] Rapid and accurate diagnoses are critical for patient management, which can be challenging on small targeted biopsies.

We present a case, who presented with metastatic NET from the occult primary site and initial detection on BM biopsy evaluation.


  Patient Information and Clinical Findings Top


We present the case of a 46-year-old male with a recent history of myocardial infarction (3 months back) with hypertension, rapidly worsening back pain, and headache for 2 months.

He was referred to our center, with a suspicion of multiple myeloma because of incidental detection of multiple lytic lesions of the spine and cranial vault. He underwent a few initial investigations as under:

Diagnostic assessment

  • Hematologic findings: Hemoglobin: 10.0 g/dl, total leukocyte count: 9.39/l × 109/l (differential: neutrophil 78, lymphocyte 13, eosinophil 4, and monocyte 4), and platelet count: 3.79/L × 10 9/L. No rouleaux formation or plasmacytoid lymphocytes were noted on the peripheral blood smear. However, occasional nucleated red blood cells were noted
  • Biochemical profile: Serum creatinine: 1.2 mg/dl; serum calcium: 10.2 mg/dl. Simultaneously, BM examination and myeloma work-up were done
  • Serum electrophoresis and immunofixation: Negative for M band. Serum-free light chain assay: Normal kappa-to-lambda ratio (1.35)
  • Bone marrow aspiration: Particulate marrow with reduced megakaryocytes. Normal hematopoietic elements with no increase in plasma cells. Occasional entrapped clusters of round cells of unknown nature were noted
  • Bone marrow trephine biopsy: Diffuse infiltration by metastatic tumor in nested pattern and separated by thin fibrovascular septa. The tumor cells were minimally pleomorphic with round nuclei, stippled chromatin, inconspicuous nucleoli, and moderate amount of cytoplasm with fine cytoplasmic granules. Brisk mitotic activity (~5/10 HPF) was noted. Normal hematopoietic elements were sparsely seen [Figure 1].
Figure 1: Bony trabecula with marrow space infiltrated with tumor (H and E, ×200)

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On immunohistochemistry (IHC), tumor cells showed cytoplasmic positivity for synaptophysin, chromogranin, and granular cytoplasmic positivity for cytokeratin. Tumor cells were negative for thyroid transcription factor-1 (TTF-1), calretinin, CDX2, CD138, and CD20. Ki-67 labeling index was ~30% [Figure 2]a, [Figure 2]b, [Figure 2]c.
Figure 2: (a) Synaptophysin: Strong cytoplasmic positive (×400). (b) (Inset) chromogranin: Cytoplasmic granular positive (×400). (c) (Inset) Ki-67 index: ~30% (×400)

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Despite the application of various IHC markers on the marrow biopsy, the primary site could not be identified. Thus, a diagnosis of metastatic NET (of unknown primary) was given.

Follow-up and outcome

In view of the Histopathological examination (HPE) with IHC report, a subsequent 18F-fluorodeoxyglucose (FDG) whole-body positron emission tomography–computed tomography (PET-CT) revealed hypermetabolic large (6.8 cm × 12.0 cm × 9.5 cm) anterior mediastinal mass (probable primary) with hypermetabolic left axillary and mediastinal lymphadenopathy with extensive skeletal lesions likely metastatic. Post FDG-PET, the likely site of origin was mediastinum/thymus. Contrast-enhanced CT abdomen revealed no mass. Debulking surgery was not advised due to high risk, under cardiovascular thoracic surgery and endocrine surgery consultation. The patient was given samarium-153 therapy for bone pains, and subsequently, Ga DOTANOC scan was planned for uptake, to plan further management.

The patient survived for 8 months post therapy and finally succumbed to the disease.


  Discussion Top


Neuroendocrine neoplasm arises from neuroendocrine cells of the gastroenteropancreatic and the bronchopulmonary tract. Although neuroendocrine neoplasms were initially considered rare cancers, in the last few decades, there has been a rampant increase in the incidence with the use of modern diagnostic modalities.[4]

Mediastinal/thymic NET accounts for 5% of all the neoplasm, with an incidence of 1 in 5 million individuals. Of the NET, mediastinal location as the primary site is 0.4%.[5]

BM metastasis with solid tumors is a relatively common finding. However, marrow metastasis of neuroendocrine neoplasms is a rare and late event.[6] BM follows liver and other intra-abdominal sites in percentage incidence of metastasis and is frequently associated with coexistent liver deposits. However, our case presented with isolated BM metastasis, with no other site involvement, which is a rare phenomenon.

The presence of marrow metastases has been observed to affect the prognosis of NET patients, but its role in determining the therapeutic approach is still unclear.

In a NET of unknown primary, a panel of immunohistochemistry markers, i.e., TTF-1, CDX-2, ISL-1, and PDX-1, along with other biomarkers can be used to determine the primary site of origin and provide prognostic information to guide therapy. A brief algorithmic IHC-based approach to the diagnosis is demonstrated in [Figure 3].
Figure 3: Assimilated from cancer cytopathology, volume: 124, issue: 12, pages: 871–884, first published: August 16, 2016, DOI (10.1002/cncy. 21765)

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BM metastases indicate an advanced stage, in which a systemic therapy should be recommended, including alpha-interferon, chemotherapy, mammalian target of rapamycin inhibitor, tyrosine kinase inhibitor, and peptide receptor radionuclide therapy.[7],[8]


  Conclusion Top


Isolated BM metastasis of neuroendocrine neoplasms is a rare finding, which of course depicts a higher stage of disease and needs to be detected soon. Despite extensive BM metastasis, blood examination revealed no significant leukoerythroblastic picture.

Such cases of occult primary with metastatic lesions, need to be worked up with proper immunohistochemical profile, to aid in finding the primary site, along with other diagnostic modalities.

Declaration of patient consent

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

Acknowledgement

We thank the patient attendant for allowing us to share the patient's clinical details. We would also like to extend our gratitude to our technical staff for the support. Finally, we wish to thank the editorial board of Apollo medicine journal for accepting the case report for publication.

Conflicts of interest

There are no conflicts of interest.

Informed consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Author's contribution

Dr. Kavita Somani and Dr. Pretty Singh: conception of the idea, drafting the article, Critical revision of the article and Final approval of the version to be published. Dr. K Sujatha: Critical revision of the article and Final approval of the version to be published.

Financial support and sponsorship

Nil.



 
  References Top

1.
Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: A population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015;121:589-97.  Back to cited text no. 1
    
2.
Kos-Kudla B, O'Toole D, Falconi M, Gross D, Kloppel G, Sundin A, et al. ENETS consensus guidelines for the management of bone and lung metastases from neuroendocrine tumors. Neuroendocrinology 2010;91:341-50.  Back to cited text no. 2
    
3.
Helbig G, Straczyńska-Niemiec A, Szewczyk I, Nowicka E, Bierzyńska-Macyszyn G, Kyrcz-Krzemień S. Unexpected cause of anemia: Metastasis of neuroendocrine tumor to the bone marrow. Pol Arch Med Wewn 2014;124:635-6.  Back to cited text no. 3
    
4.
Altieri B, Di Dato C, Martini C, Sciammarella C, Di Sarno A, Colao A, et al. Bone metastases in neuroendocrine neoplasms: From pathogenesis to clinical management. Cancers (Basel) 2019;11:E1332.  Back to cited text no. 4
    
5.
Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: A SEER database analysis of 160 patients. Ann Surg 2010;251:1117-21.  Back to cited text no. 5
    
6.
Faggiano A, Ferolla P, Grimaldi F, Campana D, Manzoni M, Davì MV, et al. Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: The NET management study. J Endocrinol Invest 2012;35:817-23.  Back to cited text no. 6
    
7.
van der Pluijm G. Epithelial plasticity, cancer stem cells and bone metastasis formation. Bone 2011;48:37-43.  Back to cited text no. 7
    
8.
Pavel M, Valle JW, Eriksson B, Rinke A, Caplin M, Chen J, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasms: Systemic therapy-biotherapy and novel targeted agents. Neuroendocrinology 2017;105:266-80.  Back to cited text no. 8
    

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Correspondence Address:
Pretty Singh,
Department of Pathology, Apollomedics Super Speciality Hospital, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_72_22



    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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