POEMS syndrome

* We report a case of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome in a 55-year-old African American woman in which human herpesvirus-8 (HHV-8) was demonstrated within rare lymphocytes in a Castleman disease lymph node biopsy and numerous endothelial cells and lymphocytes in a microvenular hemangioma skin biopsy. Initial symptoms and findings of night sweats, weight loss, anorexia, generalized lymphadenopathy, and hemangiomas improved after chemotherapy with cyclophosphamide and prednisone. However, in the year following the initial diagnosis, the patient suffered from recurrent bouts of night sweats, gastroparesis, and lymphadenopathy, which required further treatment with plasmapheresis, cyclophosphamide, prednisone, and rituximab. One year later, the patient is asymptomatic but has persistent gammopathy. Although HHV-8 has previously been detected in POEMS-associated Castleman disease tissue, to our knowledge, this is the first case report in which HHV-8 has been directly demonstrated within the endothelial cells of a POEMS-associated hemangioma.

POEMS syndrome is a rare multisystem complex characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes and is often associated with multicentric Castleman disease. Recent data indicate that POEMS-associated Castleman disease is often associated with human herpesvirus 8 (HHV-8 [KSHV]) infection. HHV-8 is also nearly always found in the angioproliferative lesions of Kaposi sarcoma (KS) but rarely in non-KS angioproliferative lesions. POEMS syndrome is often associated with the development of multiple hemangiomas. We report a case of POEMS syndrome in which HHV-8 is found not only in the lymphoid cells of Castleman disease, but also, to our knowledge, for the first time within the endothelial cells of microvenular hemangioma.

REPORT OF A CASE

A 55-year-old African American woman with a medical history of hypothyroidism and idiopathic hepatitis first presented in June 2000 with night sweats, dyspepsia, anorexia, and a 15-kg weight loss. Examination revealed edematous facies, diffuse lymphadenopathy, numerous hemangiomas, hyperpigmentation of the chest and lower extremities, thickened skin and hypertrichosis of the lower extremities, and peripheral neuropathy. Laboratory tests demonstrated triclonal gammopathy with 1 immunoglobulin M (IgM) and 2 IgA [lambda] spikes. A magnetic resonance imaging bone survey demonstrated a decreased T1 signal within the calvarium consistent with a marrow-replacing lesion but without osteolytic or osteosclerotic lesions. A computed tomographic scan of the chest and abdomen demonstrated a small pericardial effusion, interstitial pulmonary infiltrates, a slightly enlarged spleen, and bilateral axillary lymphadenopathy. A skin biopsy showed a focal benign microvenular proliferation within the upper dermis. Such findings are consistent with microvenular hemangioma (Figure, a). In some areas, a reactive perivascular lymphocytic infiltrate was noted (Figure, b). HHV-8-positive endothelial cells and lymphocytes (Figure, c and d) were detected within the hemangioma by immunoperoxidase staining with an affinity-purified rabbit polyclonal anti-HHV-8 latent nuclear antigen antibody (PA1-73N, gift of Drs Tetsutaro Sata and Harutaka Katano, Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan).1 An axillary lymph node biopsy showed angiofollicular hyperplasia with hyaline vascular transformation of the lymphoid follicles characteristic of hyaline vascular Castleman disease (Figure, e). A few small HHV-8 latent nuclear antigen-positive lymphocytes within the interfollicular zone and subcapsular sinus were detected within the lymph node (Figure, f). A bone marrow biopsy showed only mild hypercellularity. A gastric biopsy showed only a mild infiltration of lamina propria by plasma cells. A sural nerve biopsy was consistent with a demyelinating neuropathy with an ischemic component. A previously described indirect immunofluorescence assay for detection of serum antibody to HHV-8 lytic antigens was positive at a titer of 1:80.2 Initial treatment with cyclophosphamide and prednisone led to decreased lymphadenopathy, pericardial effusion, and night sweats. One year later, recurrent bouts of lymphadenopathy, neuropathy, pericardial effusion, and night sweats were treated with a course of rituximab; partial improvement followed.

COMMENT

POEMS syndrome, also known as Crow-Fukase syndrome, was first described in Japan as a curious multisystem complex of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.3,4 The polyneuropathy is often severe, progressive, and sensorimotor. Electromyography and nerve biopsies show a variety of abnormalities ranging from demyelination to axonal degeneration, with no antibody or amyloid deposition. Organomegaly may include hepatomegaly, lymphadenopathy, and, less commonly, splenomegaly. The lymphadenopathy is frequently consistent with Castleman disease (angiofollicular lymphoid hyperplasia). Endocrine abnormalities are protean and may include amenorrhea, male impotence and gynecomastia, hyperprolactinemia with papilledema and elevated cerebrospinal fluid pressure, type 2 diabetes mellitus, hypothyroidism, and adrenal insufficiency. Monoclonal [lambda] light chain gammopathy (often biclonal or triclonal) is often due to osteosclerotic myeloma.5 Skin changes may include hyperpigmentation, hypertrichosis, skin thickening, digital clubbing, and hemangiomas. Other manifestations may include peripheral edema, ascites, pleural effusions, fever, and thrombocytosis.

The pathogenesis of POEMS syndrome remains unclear, but many manifestations may be cytokine mediated. Elevated levels of the proinflammatory cytokines interleukin-1, interleukin-6, tumor necrosis factor [beta], and vascular endothelial growth factor and low levels of the anti-inflammatory cytokine transforming growth factor [beta] suggest a strong proinflammatory bias.6 Vascular endothelial growth factor likely contributes to the growth of POEMS-associated hemangiomas.7

HHV-8 has been associated not only with KS but also with Castleman disease.8 The plasma cell proliferation of Castleman disease is likely due at least in part to the actions of the HHV-8-derived cytokine viral interleukin-6.6 More recently, an association of POEMS syndrome with HHV-8 has been suggested. Belec et al9,10 described 7 of 13 (54%) POEMS patients with HHV-8 DNA sequences in their tissues and 9 of 18 (50%) with circulating anti-HHV-8 antibody. Kim et al11 described a case of POEMS with HHV-8-positive Castleman disease.

The ability of HHV-8 to infect and transform primary human microvascular endothelial cells has been demonstrated in vitro.12 Despite the near-universal presence of HHV-8 in KS, the virus is rarely if ever detected in non-KS angioproliferative skin lesions.13,14 We report the clinicopathologic findings of an unusual case of HHV-8-sero-positive POEMS syndrome with multiple microvenular hemangiomas containing HHV-8-positive tumor endothelial cells. This finding suggests that HHV-8 indeed resides within non-KS endothelial cells and lends support to the findings of HHV-8 PCR positivity from non-KS skin biopsies.15

The authors wish to express their gratitude to Tetsutaro Sata, MD, PhD, and Harutaka Katano, DDS, PhD (Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan) for their generous supply of the anti-HHV-8 latent nuclear antigen antibody used in this study.

References

1. Katano H, Sato Y, Kurata T, Mori S, Sata T. Expression and localization of human herpesvirus 8-encoded proteins in primary effusion lymphoma, Kaposi's sarcoma, and multicentric Castleman's disease. Virology. 2000;269:335-344.

2. Hudnall SD, Rady PL, Tyring SK, Fish JC. Serologic and molecular evidence of human herpesvirus 8 activation in renal transplant recipients. J Infect Dis. 1998;178:1791-1794.

3. Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology. 1984;34:712.

4. Soubrier MJ, Dubost JJ, Sauvezie BJ. POEMS syndrome: study of 25 cases and a review of the literature. Am J Med. 1994;97:543.

5. Schey S. Osteosclerotic myeloma and POEMS syndrome. Blood Rev. 1996;2:75.

6. Gherardi RK, Belec L, Soubrier M, et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood. 1996;87:1458-1465.

7. Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet. 1996;347:702.

8. Parravinci C, Corbellino M, Paulli M, et al. Expression of a virus-derived cytokine, KSHV vIL-6, in HIV-seronegative Castleman's disease. Am J Pathol. 1997;151:1517.

9. Belec L, Mohamed AS, Authier FJ, et al. Human herpesvirus 8 infection in patients with POEMS syndrome-associated multicentric Castleman's disease. Blood. 1999;93:3643.

10. Belec L, Authier FJ, Mohamed AS, Soubrier M, Gherardi RK. Antibodies to human herpesvirus 8 in POEMS syndrome with multicentric Castleman's disease. Clin Infect Dis. 1999;28:678-679.

11. Kim DE, Kim HJ, Kim YA, Lee KW. Kaposi's sarcoma herpesvirus-associated Castleman's disease with POEMS syndrome. Muscle Nerve. 2000;23:436-439.

12. Flore O, Rafii S, Ely S, O'Leary JJ, Hyjek EM, Cesarman E. Transformation of primary human endothelial cells by Kaposi's sarcoma-associated herpesvirus. Nature. 1998;394:588-592.

13. Viviano E, Romano N, Sorce M, Castelli E, Marasa L. Absence of human herpesvirus 8 DNA in benign and malignant endothelial lesions. J Clin Microbiol. 1997;35:3010.

14. McMenamin ME, Fletcher CD. Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum. Am J Surg Pathol. 2002;26:685-697.

15. Nishimoto S, Inagi R, Yamanishi K, Hosokawa K, Kakibuchi M, Yoshikawa K. Prevalence of human herpesvirus-8 in skin lesions. Br J Dermatol. 1997;137:179-184.

S. David Hudnall, MD; Tiansheng Chen, MD, PhD; Kelty Brown, MD; Tiffany Angel, MD; Mary R. Schwanz, MD; Steven K. Tyring, MD, PhD

Accepted for publication March 20, 2003.

From the Departments of Pathology (Drs Hudnall and Chen) and Dermatology (Dr Tyring), University of Texas Medical Branch, Galveston; and the Departments of Medicine (Dr Brown), Dermatology (Dr Angel), and Pathology (Dr Schwartz), Baylor College of Medicine, Houston, Tex.

Reprints: S. David Hudnall, MD, UTMB Department of Pathology, 301 University Blvd, Galveston, TX 77555-0741 (e-mail: shudnall@utmb.edu).

Copyright College of American Pathologists Aug 2003
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