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Anatomical Pathology, PathWest, QEII Medical Centre, Nedlands, WA, AustraliaSchool of Medicine, University of Western Australia, Crawley, WA, Australia
School of Medicine, University of Western Australia, Crawley, WA, AustraliaFaculty of Health Science and Medicine, Bond University, Robina, Qld, Australia
School of Medicine, University of Western Australia, Crawley, WA, AustraliaDepartment of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
Anatomical Pathology, PathWest, QEII Medical Centre, Nedlands, WA, AustraliaSchool of Medicine, University of Western Australia, Crawley, WA, AustraliaSchool of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
Epithelioid angiosarcoma is a malignant neoplasm showing endothelial differentiation, distinguished from conventional angiosarcoma by prominent epithelioid cytomorphology.
As a result, the differential diagnosis for pathologists is unique and focuses on tumours with predominant epithelioid features. This includes other vascular tumours such as epithelioid haemangioma and epithelioid haemangioendothelioma as well as non-vascular malignant neoplasms such as carcinoma and melanoma. Diagnosis in practice is usually uncomplicated as most examples demonstrate overtly malignant histological findings, allowing separation from benign or borderline vascular tumours. In addition, highly sensitive and specific immunohistochemical markers of endothelial differentiation such as CD31, CD34, ERG and FLI-1, facilitate their distinction from non-vascular mimics.
Herein, we present a challenging tumour which seemed to possess all the immunomorphological hallmarks of epithelioid angiosarcoma but which was ultimately shown to be an unusual manifestation of myeloid sarcoma (also referred to as granulocytic sarcoma)/acute myeloid leukaemia (AML), confirmed with characteristic driver mutations identified on next generation sequencing (NGS). The case highlights a significant diagnostic pitfall which, in our reading, appears to be rarely mentioned in the major surgical pathology textbooks and literature. As also illustrated, their distinction bears significant impact on the patient's clinical management and outcome due to marked differences in treatment strategies.
A 46-year-old female was found to have multiple discrete mass-like and FDG-avid lesions disseminated throughout her skeletal system on MRI and PET, involving numerous vertebral bodies, bilateral ribs, sacrum, iliac bones, acetabula and left femoral head (Fig. 1). These were identified during routine surveillance for a left calf 1.3 mm thick melanoma with BRAF V600E mutation excised 7 years prior, with subsequent inguinal node metastasis and nodal dissection. She also had a 15-year history of JAK2-mutant polycythaemia vera (PCV), on hydroxyurea and right breast lobular carcinoma in situ.
Fig. 1MRI (A,B) and 18F-FDG PET-CT (C,D) showing multifocal, metabolically active destructive mass-like lesions involving the skeletal system, including multiple vertebral bodies, sacrum and acetabulum.
A core biopsy of the left acetabular lesion was performed. However, a definitive diagnosis could not be arrived at, and the clinical team proceeded to an open incisional biopsy of the left proximal humerus. Touch imprints and scrape smears of the fresh tissue did not yield tumour cells, which could only be visualised on a crush preparation, suggesting a stroma-rich neoplasm. Permanent sections revealed a cellular tumour composed of rounded epithelioid cells occurring in repetitive nests, separated by thin fibrous septa (Fig. 2). The tumour cells demonstrated moderately pleomorphic nuclei with finely granular chromatin, small nucleoli and moderate volumes of pale eosinophilic cytoplasm. A minor subset also contained clear cytoplasmic vacuoles reminiscent of so-called ‘blister cells’. Mitotic activity was brisk and there were foci of necrosis. Immature granulocytes could not be appreciated morphologically.
Fig. 2Incisional biopsy of the left humerus showed a cellular tumour composed of rounded epithelioid cells occurring in repetitive nests, separated by fibrous septa (A,B), diffusely expressing CD31, ERG, FLI-1 and Factor VIII (C–F). Non-targeted bone marrow trephine biopsy showed similar nested cells (G), together with a diffuse marrow infiltrate of atypical rounded cells (H).
Initial efforts were largely directed towards consideration of disseminated metastases from her previous BRAF V600E-mutant melanoma. However, immunohistochemistry showed complete absence of S100, SOX10, Melan-A, HMB45 and BRAF V600E mutant protein expression. Cobas RT-PCR (Roche, USA) also confirmed the tumour to be BRAF V600 wild-type, providing strong evidence against metastasis from her previous melanoma. Additional immunostains showed strong and diffuse staining for CD31 (membranous), ERG, FLI-1 and Factor VIII (Fig. 2). Negative markers are summarised in Table 1.
Given the history of PCV, further workup was undertaken for the possibility of leukaemic transformation. A peripheral blood film did not disclose any circulating blasts. Flow cytometry (blast panel) was requested on tissue triaged from the fresh biopsy. Although this was reported as ‘insufficient viable cells for analysis’, the result was interpreted to be due to an absence of haemopoietic cells given that a generous sample was submitted. Additional immunostains on the paraffin sections showed no expression of CD45, CD34, CD33, myeloperoxidase, CD117, CD4, CD68 and CD99. CD43 showed a weak, incomplete membranous pattern, interpreted to be equivocal.
In the absence of evidence to support myeloid leukaemia and given the characteristic morphology and diffuse expression of vascular markers, the patient was diagnosed with epithelioid angiosarcoma, transferred to the care of a sarcoma oncologist and commenced on taxane-based chemotherapy. Follow-up PET scan after five doses of paclitaxel showed a mixed response with some lesions improving and many others progressing.
In order to identify potential treatment targets to optimise her therapy, NGS was performed using the Illumina TruSight Oncology 500 hybrid-capture assay (Illumina, Australia) on a representative paraffin-embedded block with a high tumour cell content. Unexpectedly, the assay revealed a canonical JAK2 p.V617F variant and TET2 p.V1718L variant. The variants were detected at allele frequencies of 64% and 47%, respectively, and hence were unlikely to be from contaminating blood with PCV.
A (non-targeted) bone marrow trephine biopsy of the iliac crest was subsequently performed, showing the same epithelioid tumour cells in nests as seen in the incisional biopsy. However, a dispersed population of atypical, rounded cells was also present, closely associated with the nests and widely infiltrating the marrow space, more typical of a haematological malignancy (Fig. 2). This shared a similar immunoprofile to the nested epithelioid cells.
In view of these new findings, the final diagnosis was revised to acute myeloid leukaemia/myeloid sarcoma (AML/MS), transformed from JAK2-mutant PCV. The patient was transferred to the care of a haematologist and commenced on the ‘7+3’ chemotherapy regimen and later changed to the ‘FLAG-Ida’ regimen, both specific for AML. Her most recent trephine biopsy demonstrated an excellent response, with <4% blasts and absence of the nested epithelioid cells, consistent with morphological complete remission. She is planned for allogeneic stem cell transplantation.
We present this diagnostically challenging case of AML/MS to raise awareness of the significant overlapping features which can potentially exist with epithelioid angiosarcoma, which in our reading, is often overlooked in the major general surgical pathology textbooks and literature. Some mention ERG staining in myeloid neoplasms.
However, few, if any, emphasise the morphological similarities and the potential for all commonly used vascular/endothelial immunomarkers, including CD31, CD34, FLI-1 and Factor VIII, to be positive. As this case illustrates, correct diagnosis is central to the clinical management and outcome, with our patient achieving complete remission only after angiosarcoma-directed taxane-based treatment was changed to multi-agent chemotherapy specific for AML.
In addition to strongly expressing common vascular markers, this case is also notable for several other unusual features which confounded the diagnosis of AML/MS. Whilst bone is not an uncommon site for myeloid sarcoma and whilst there are isolated reports of limited multifocal disease,
it rarely presents as discrete mass lesions disseminated throughout the skeletal system, which led our radiologists to favour metastatic carcinoma or melanoma. The patient was also aleukaemic, with no blasts detectable on the peripheral smear, which can occur uncommonly with myeloid sarcoma.
Furthermore, unexpected for a haematological malignancy was the repetitive nested growth pattern on morphology, more akin to carcinoma or melanoma, and the stroma-rich background, more akin to a sarcoma. Finally adding to the challenge was the absence of staining for commonly used immunomarkers of AML/MS such as CD45, CD34, CD33, myeloperoxidase, CD117 and CD68. It is well known that the histological diagnosis of AML can be difficult due to lack of a single sensitive and specific immunostain and that the expression of available markers is variable, related to the extent of maturation and differentiation along different myeloid lines.
Despite the confounding findings, the diagnosis of AML/MS was finally established through the discovery of JAK2 and TET2 hotspot mutations by NGS. JAK2 encodes a non-receptor tyrosine kinase involved in cytokine and growth factor signalling and hotspot mutations lead to constitutive kinase activity and increased JAK-STAT signalling.
A thorough search of the literature did not disclose reports of these variants in angiosarcoma.
Although pathologists typically view AML/MS and angiosarcoma as fundamentally different nosologically, there are biological reasons which explain the extensive potential overlap in their features. Widely accepted amongst embryologists is the concept of the haemangioblast, a mesodermal-derived bipotent CD34+ common progenitor cell identified in developing embryos, capable of producing both endothelial and multipotent haemopoietic stem cells (the latter capable of developing along erythroid, myeloid and lymphoid lineages).
Perhaps one of the only early clues in this case alluding to the diagnosis of AML/MS was CD43, which showed weak and incomplete membrane staining (and hence was interpreted as equivocal). CD43 is one of the most sensitive markers of myeloid neoplasms and is particularly useful in the differential diagnosis of AML/MS and epithelioid angiosarcoma, as it is not expressed by the latter.
In summary, we present a challenging case of AML/MS highlighting the extensive overlapping features that can exist with epithelioid angiosarcoma, both on morphology and immunohistochemistry. Pathologists should be aware of this diagnostic pitfall due to significant differences in treatment strategies affecting patient outcomes. This case also illustrates the utility of NGS in identifying driver mutations specific for myeloid neoplasms.
Acknowledgements
The authors would like to acknowledge Richard Carey-Smith, Peter Lau and Anne Long for providing the clinical details for this case report.
Conflicts of interest and sources of funding
The authors state that there are no conflicts of interest to disclose.
References
Hart J.
Mandavilli S.
Epithelioid angiosarcoma: a brief diagnostic review and differential diagnosis.
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