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HHV-8

Friday 12 December 2003

Digital case

- HPC:335 : Plasmocytic Castleman disease (associated to Kaposi sarcoma)

Definition: Human herpesvirus-8 (HHV-8) is associated with several distinct lymphoproliferative disorders: primary effusion lymphoma, multicentric Castleman disease (MCD), MCD-associated plasmablastic lymphoma and HHV-8+, Epstein-Barr virus (EBV)+ germinotropic lymphoproliferative disorder.

Pathology

There is a strong association between HHV-8 and Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma.

HHV-8 has also been reported to be present in pemphigus vulgaris, extranodal marginal zone lymphoma of salivary gland, hemophagocytic syndrome, multiple myeloma, Kikuchi lymphadenitis, and sarcoidosis.

However, the latter list of diseases is controversial as viral detection varies among studies.

Two publications by Gómez-Román et al. documenting HHV-8 in lesional myofibroblasts of inflammatory myofibroblastic tumor, drew attention to the possible role of the virus in the pathogenesis of this tumor.

In the largest series to date, twenty cases of pulmonary inflammatory myofibroblastic tumor were studied for the presence of HHV-8. Whereas the demographic, clinical, and histological features in all cases were typical for inflammatory myofibroblastic tumor, no viral DNA or latent nuclear antigen was identified utilizing immunohistochemical or molecular studies.

- Kaposi sarcoma
- HHV-8-associated lymphoproliferative disorders

  • HHV8-associated multicentric Castleman disease (MCD)
  • HHV8-associated multicentric Castleman disease-associated plasmablastic lymphoma
  • HHV8+ Epstein-Barr virus+ germinotropic lymphoproliferative disorder
  • HHV8-associated lymphomas
    • HHV8-associated primary effusion lymphoma
    • HHV8-associated solid lymphoma
    • HHV-8+, EBV+ multicentric plasmablastic microlymphoma (17721201)

- HHV8-associated pulmonary inflammatory pseudotumor (#12170101 #)

HHV8-associated pulmonary inflammatory pseudotumor

A small number of inflammatory myofibroblastic tumors have been reported to harbor human herpesvirus-8 (HHV-8), implicating the virus in its pathogenesis.

HHV-8 infects a wide range of normal cells including endothelial cells, lymphoid cells, dendritic cells, and fibroblasts. This parallels the spectrum of the neoplasms with a well-established role for HHV-8 in their pathogenesis, including Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. HHV-8 infection of human fibroblasts is well documented in experimental studies.

It is known that the virus enters cells utilizing receptor-mediated endocytosis and displays activation of lytic and persistence of latent genes.

In light of these findings, inflammatory myofibroblast tumor appears to be a reasonable choice for HHV-8 testing.

Gómez-Román et al, reported HHV-8 deoxyribonucleic acid (DNA) sequences in seven cases of inflammatory myofibroblast tumor, and also identified viral transcripts from several open reading frames (ORF).

In the English language literature, only three additional cases of pulmonary inflammatory myofibroblastic tumor have been studied for HHV-8 by immunohistochemical and molecular methods.

One study has documented the absence of HHV-8 in pulmonary inflammatory myofibroblastic tumors, suggesting that further investigation is required to clarify the pathogenesis of this lesion. (17643094)

Molecular identification of HHV-8

Molecular identification of HHV-8 is known to produce both false-positive and false-negative results. The latter is thought, in part, to be related to HHV-8 sequence variation, which can range up to 35% in certain regions of the viral genome, as in ORFK1.

The use of a single primer set based on a sequence with a high level of sequence variation can lower the PCR sensitivity and, therefore, the rate of HHV-8 detection. Another potential source of false-negative results is targeting large fragments of viral DNA.

Based on our experience and data in the literature, 250 base pairs are often beyond the upper size limit of what can readily be amplified by PCR from formalin-fixed, paraffin-embedded tissue.

False-positive results are thought to be due to utilization of high cycle protocols and/or complimentary primer sets, as in nested PCR. Through a set of validation tests, Pan et al, demonstrated that nested PCR is readily contaminated, even in strictly controlled environments, and use of standard PCR with more than one set of primers is recommended. In their study, 6 of 16 negative controls tested positive for HHV-8 sequences in nested PCR using primers to ORF, but none were positive utilizing standard PCR.

The contamination by nucleic acids, particularly from previously amplified material (carry-over), is likely the main source of false-positive results.

References

- Seliem RM, Griffith RC, Harris NL, Beheshti J, Schiffman FJ, Longtine J, Kutok J, Ferry JA. HHV-8+, EBV+ multicentric plasmablastic microlymphoma in an HIV+ Man: the spectrum of HHV-8+ lymphoproliferative disorders expands. Am J Surg Pathol. 2007 Sep;31(9):1439-45. PMID: 17721201

Reviews

- Wang HW, Boshoff C. Linking Kaposi virus to cancer-associated cytokines. Trends Mol Med. 2005 Jul;11(7):309-12. PMID: 15967719

- Verschuren EW, Jones N, Evan GI. The cell cycle and how it is steered by Kaposi’s sarcoma-associated herpesvirus cyclin. J Gen Virol. 2004 Jun;85(Pt 6):1347-61. PMID: 15166416

- Ding Y, Saylors RL, Brown H, et al. Pulmonary inflammatory pseudotumor with HHV-8. Am J Surg Pathol 2002;26:1089–1091.