PATHOLOGICA 2017;109:143-147

Case report

Kaposiform hemangioendothelioma in an adult with rheumatoid arthritis

M. FILOTICO1, R. FILOTICO2

1 Department of Anatomic Pathology, Ospedale Fond. Card. Panico, Tricase (LE), Italy; 2 Dermatology Unit, Ospedale “Perrino”, Brindisi, Italy

Key words

Vascular tumors • Kaposiform hemangioendothelioms

Summary

Correspondence Marcello Filotico, Department of Anatomic Pathology, Ospedale Fond. Card. Panico, Tricase (LE), Italy - E-mail: mfilotico@libero.it

This report describes a case of kaposiform hemangioendothelioma arising in an adult man during the course of rheumatoid arthritis treated with steroids and methotrexate. The vascular proliferation began in the terminal phase of the disease, which culminated in acute

renal failure and death. We discuss the possible relationship between rheumatoid arthritis, its treatment, and the onset of vascular prolif-eration, as well as the role of kaposiform hemangioendothelioma in aggravating the autoimmune disease and leading to its fatal outcome.

Ackowledgements The authors thank Dr. Valerie Matarese for having made editorially acceptable their work.

Introduction

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of intermediate (borderline) malignancy that occurs mainly in infants and children. KHE is char-acterized by infiltrating nodules and sheets of spindle cells, affecting the skin and soft tissues of the extremi-ties. Morphologically, it is highly similar to Kaposi’s sarcoma, although the biologic behavior of KHE is not fully characterized. KHE patients die as a result of ex-tensive local disease or from a frequent complication called Kasabach-Merritt phenomenon (thrombocytope-nia, microangiopathic hemolytic anemia, and consump-tive coagulopathy). KHE is even more rare in adults. The occurrence of this lesion in an adult, in association with an autoimmune disease treated with steroids and methotrexate and lead-ing to a quick lethal outcome, makes this case worthy of interest.

Case presentation

A 48-year-old Italian man presented to the Dermatology Unit with skin rashes of purplish-brown color, mainly on the limbs, which he had had for about 6 months. He reported that, since the age of 30, he had recurrent epi-sodes of joint pain accompanied by fever. He had been

diagnosed with serum-negative rheumatoid arthritis (RA) and had been under treatment with steroids and methotrexate. The patient also reported that, at the age of 46 years, he had been hospitalized for glaucoma of the right eye. On that occasion, laboratory testing revealed neutrophilic leukocytosis (12,000/mm3) and high plasma fibrinogen (520 mg/dl), confirming the diagnosis of RA.Based on the features of the rash and the patient’s im-munosuppressive therapy, we suspected Kaposi’s sarco-ma. Therefore, a biopsy of skin and subcutaneous tissue (3x2x1 cm3) was taken from an affected area on the left leg; it was fixed in formalin and embedded in paraffin for routine and immunohistochemical analyses. Hematoxilin-eosin staining revealed a brisk microvas-cular proliferation at the dermal and hypodermal levels (Fig. 1a). The vascular component consisted of well-formed capillaries whose endothelium was voluminous and prominent (Fig. 1c). The vascular lumen was en-gulfed by thrombotic material (Fig. 1c-d). The stromal elements were globoid and spindled, arranged disorderly (Fig. 1b). Mitotic activity was not seen. There was a glomeruloid pattern of capillary prolifera-tion (Fig. 2a-b). Gomori’s silver stain also revealed glo-meruloid dermal and hypodermal nodules (Fig. 2c-d). These observations excluded Kaposi’s sarcoma. Immunohistochemical analysis showed strong positivity for CD34 (Fig. 3a-b) and CD31 (Fig. 3c) in the endothe-lial elements, while stromal cells were negative for these

M. FILOTICO, R. FILOTICO144

antigens. Pericytes were positive for smooth muscle ac-tin (Fig. 3d). The sample was negative for human herpes virus 8 (HHV8), ruling out Kaposi’s sarcoma (Fig. 3e). The Ki-67 labeling index was < 1%, indicating a low level of proliferation. Altogether, these findings sup-ported a diagnosis of KHE.Three months later, the patient was hospitalized be-cause of the collapse of several vertebral bodies due to osteoporosis. A few days later he developed acute renal failure with normal values of platelets (268,000 cells/mm3), RBCs (5,200,000 cells/mm3) and WBCs (8,500 cells/mm3). Prothrombin time was 74% and the partial thromboplastin time (33 s) was in the normal range. In contrast, there was high serum fibrinogen (535 mg/dl) and D-dimer (7,004 ng/ml), indicating an aggravation of RA, high serum myoglobin (3,532 ng/ml) indicating muscle damage, and hyperkalemia (7.3 mEq/l). The patient died within a few hours. Testing for HIV was not carried out nor was an autopsy performed.

Discussion

This report illustrates the case of a middle-aged man who developed KHE in the context of immunosuppres-sive treatment for RA. The diagnosis of KHE was es-

tablished on the basis of the histologic and immunohis-tochemical findings that, together with the HHV8 nega-tivity, excluded Kaposi’s sarcoma. The patient’s death

Fig. 1. Diffuse proliferation of dermal capillaries (a), proliferation of interstitial elements (b), microthrombi in the capillary lumen (c), and venular thrombosis (d). Hematoxylin and eosin staining; original magnification 40x (a, d) or 100x (b, c).

A B

C D

Tab. I.

Author Yr. N. CasesMentzel T et al. 1 1997 3Zámecník M et al. 2 2000 1Zámecník M et al. 3 2001 1 Mac Moune Lai F et al. 4 2001 1/5Hardisson D et al. 5 2002 1Bienaimé A et al. 6 2006 1Senturk N et al. 7 2006 1Vetter-Kauczok CS et al. 8 2008 1White JB et al. 9 2009 1Karnes JC et al. 10 2009 1Kim MG et al. 11 2011 1Yu L et al. 12 2011 1Costa FD, Folpe AL 13 2013 2Wu CH et al. 14 2013 1Fernandez AP et al. 15 2013 1Wong BL et al. 16 2014 1Wang Z et al. 17 2014 1TOTAL 20

145KAPOSIFORM HEMANGIOENDOTHELIOMA IN AN ADULT WITH RHEUMATOID ARTHRITIS

was attributed to a rapid aggravation of RA, with signs of muscle damage and electrolyte imbalance, in the ab-sence of Kasabach-Merritt phenomenon.The first record in PubMed of KHE in adults dates back to 1997. From that date, 16 other reports have appeared in the literature. These are mostly reports of single cases or miniseries of no more than three cases, for a total of 20 cases as indicated in Table I.In the same period, two series of 33 and 107 cases con-cerning childhood KHE have also been published 18 19. The appearance of KHE at an early age in association with other malformative vascular lesions (e.g. lymph-angiomatosis) suggests a congenital etiology. An onset of KHE in adulthood, instead, suggests a pathogenetic mechanism of an acquired type. Indeed, several cases of KHE developed in the context of other diseases, such as osteomyelitis treated with repeated surgeries 4, lupus erythematosus disseminatus with chronic renal failure 9, hepatitis C and trauma 10, hepatitis C with cirrhosis  15, and RA (this case). Based on these observations, we sus-pect that even other reported cases of adult KHE may have arisen in the context of another disease, that how-ever, was not described.The clinical presentation of KHE mimics very closely that of Kaposi’s sarcoma. In contrast, the histopathology of the lesions differs substantially from classic Kaposi’s

sarcoma, in both architecture and cytology. The vascu-lar proliferation in KHE always consists of well-formed capillaries with an evident peripheral argyrophylic re-ticulin and a pericytic component; it can be diffuse or produce nodular aggregates that are glomeruloid and that affect the dermis and hypodermis. The differential diagnosis is also supported by immunohistochemical analyses: in KHE expression of CD34 and CD31 is re-stricted to endothelial cells and does not affect stromal cells, whereas in Kaposi’s sarcoma the stromal cells are also positive. In KHE, staining for smooth muscle actin highlights pericytes that are absent from classic Kapo-si’s sarcoma lesions. The constant negativity for HHV-8 in KHE is discriminating in the differential diagnosis.Our patient did not develop Kasabach-Merritt phenom-enon, which is a frequent complication of KHE in child-hood that often leads to death. In the two case series of childhood KHE, the incidence of Kasabach-Merritt phe-nomenon was 56% 18 19. In the 20 cases of adult KHE, this deadly complication was reported only once, in a patient with hepatitis C cirrhosis 15. The HIV status of our patient was not tested. None of the 20 reported cases of KH in adulthood were associated with HIV, although a retrospective survey of 52 HIV-positive patients (ages not reported) in a Mexico City hospital found one as-sociation with KHE 20. In the opinion of the authors of

Fig. 2. Glomeruloid pattern of capillary proliferation shown with hematoxylin and eosin (a, 100x) and Masson’s trichrome stain (b, 100x). Glomeruloid dermal (c) and hypodermal nodules (d)(Gomori’s silver stain, 40x).

A B

C D

M. FILOTICO, R. FILOTICO146

that report, the case of KHE had “no relation with HIV infection” 20. Histologically, KHE presents evident similarities with juvenile hemangioma [6]. KHE is even more similar to tufted angioma (angioblastoma of Nakagawa), a benign vascular tumor that presents as a macule or nodule. In-deed, some have proposed that KHE is the disseminated form of tufted angioma and, therefore, a benign lesion itself 6 15. In conclusion, on the basis of this case and the literature, it seems that the onset of KHE in adults, more than an autonomous phenomenon as happens in childhood, is an epiphenomenon accompanying another pathology . This etiology could explain the low incidence of Kasabach-Merritt phenomenon and the more severe course of the disease. That the appearance of KHE may be iatrogenic, in our case, seems unlikely since the same drugs admin-istered to patients with RA (e.g. steroids, antineoplastic agents) are used also to control this disease 21. It is to be noted, also, that the beginning of the worsening of the underlying disease coincided with the onset of the manifestations of KHE. The present state of knowledge does not allow one to know if the appearance of KHE in the course of a morbid process is the cause or the conse-quence of its worsening.

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Fig. 3. Immunohistochemical analyses of the biopsy specimen. (a) CD34, 40x, (b) CD34, 100x, (c) CD31, 100x, (d) smooth muscle actin (100x), and (e) HHV8 (100x).

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