O’Grady et al.¹ first described the disorder in 1994 in regards to a 77-year-old woman with a nontender, erythematous rash on her lower extremities; as histopathologic examination revealed dilated factor VIII-positive dermal vessels containing macrophages expressing Mac387 and CD68, the condition was named “intravascular histiocytosis.” Rieger et al.² described two cases with similar microscopic findings, which initially were thought to represent reactive angioendotheliomatosis; however, immunohistochemical and ultrastructural studies confirmed the histiocytic nature of the intraluminal proliferation. The authors speculated that intravascular histiocytosis might be associated with organizing intravascular microthrombi and the subsequent development of an endothelial cell proliferation, which is recognized as angioendotheliomatosis.²

In 2000, Pruim et al.³ reported two patients with rheumatoid arthritis with intravascular histiocytes manifesting as erythematous plaques on the upper extremities; based on histopathologic findings, the authors suggested that the involved vessels were lymphatic channels. Takiwaki et al.⁴ proposed the terminology “rheumatoid intravascular or intralymphatic histiocytosis of the skin” as the nature of the vessels remained unclear at the time. However, Okazaki et al.⁵ used immunohistochemistry for D240 to show that the implicated vessels were, in fact, lymphatics. In the largest series published, Requena et al.⁶ confirmed that the vessels involved are lymphatic vessels and suggested that, as such, intralymphatic histiocytosis and intravascular reactive angioendotheliomatosis are distinct disorders.

Intralymphatic histiocytosis likely represents a nonspecific inflammatory reaction pattern, and it has been associated with various clinical conditions. Multiple reports have demonstrated an association with rheumatoid arthritis, such that about half of cases occur in the setting of rheumatoid arthritis.^4,6,7,8,9,10 Rare cases have been reported in association with tonsillitis,¹¹ vulvar necrosis,¹² and Crohn disease.¹³ Other cases have been associated with orthopedic surgical procedures^{14,15,16,17,18} or surgery in the setting of malignancy, such as breast carcinoma, colonic carcinoma, melanoma in situ, and Merkel cell carcinoma.^6,19 Despite the multiple associations, intralymphatic histiocytosis has also been reported in a subset of patients without any known underlying inflammatory condition.¹³

It has been speculated that the histiocytes that are present within the vascular spaces have drained via lymphatics from joints involved by an inflammatory process. Lymphatic obstruction secondary to abnormal vessel development or damage from inflammation, infection, trauma, or surgery may cause lymphangiectasia and lymph stasis.^3,6 Requena et al.⁶ hypothesized that lymph stasis can lead to poor antigen clearance, subsequent localized immune dysfunction, and persistent inflammation with intraluminal accumulation of histiocytes. Okamoto et al.²⁰ implicated the release of cytokines, including tumor necrosis factor-alpha (TNF-α), from inflamed joints, such as in rheumatoid arthritis, in the development of the histiocytic aggregates. Clinical response following treatment with TNF-α inhibition with infliximab supports this hypothesis.²¹ Although the activity of skin disease in intralymphatic histiocytosis does not seem to directly correlate with severity of rheumatoid arthritis, the treatment of known associated conditions may lead to regression of skin lesions.^6,13

Intralymphatic histiocytosis is rare with few cases reported in the literature. It is more common in females than males and typically affects middle-aged to elderly patients, with a mean age of 62 and 70 years in two studies.^6,13 One reported case, associated with tonsillitis and scrotal lesions, occurred in a teenager.¹¹

Skin lesions are ill-defined, erythematous, or violaceous patches or plaques and may have a livedo reticularis-like appearance. The extremities are usually involved, and skin near an inflamed joint is often affected in the cases associated with rheumatoid arthritis.^5,6,9,10 Less commonly, the trunk or head and neck is involved.⁶ One case involving the vulva has been reported.¹² Most recently, a case involving the oral mucosa, clinically mimicking oral lymphangioma circumscriptum, and two cases of laryngeal involvement presenting as breathing difficulties in patients without any evidence of systemic disease have been reported.^22,23

Histopathologic examination shows dilated, irregularly shaped, thin-walled lymphatic vessels within the reticular dermis (Fig. 72-1). Variably cohesive aggregates of epithelioid mononuclear histiocytes with pale, finely granular cytoplasm, and vesicular, oval and uniform nuclei are present within the vascular spaces (Figs. 72-2, 72-3 and 72-4). Cytologic atypia or mitotic figures are typically absent.^6,8,13 The vascular channels are lined by a single layer of flat cells without nuclear pleomorphism or atypia (Fig. 72-5). In some cases, these lining cells may be hyperplastic with tufting of cells into the luminal space. Intraluminal lymphocytes and/or neutrophils may be present.⁶ Thrombosis or vasculitis is typically not seen; however, vessel thrombosis was reported in one case involving the scrotum.¹¹ The surrounding dermis may contain a patchy mixed inflammatory infiltrate composed of lymphocytes, histiocytes, plasma cells, and/or neutrophils. The overlying epidermis and papillary dermis are unremarkable.

The endothelial cells lining the vascular spaces are positive for D240, Lyve-1, and Prox-1. The intravascular lesional cells express CD68, CD163, PGM-1, Mac387, and HLA-DR and are negative for S100 and CD1a (Fig. 72-6)¹³; they may occasionally be positive for myeloperoxidase, podoplanin, and CD31.⁶ The Ki67 proliferative index of the histiocytes is low. Few admixed CD3⁺ T cells may be seen within the lymphatic lumina. CD3⁺ T cells, CD20⁺ B cells, and CD79a⁺ plasma cells may be present with an associated dermal inflammatory infiltrate.

Reactive angioendotheliomatosis and intralymphatic histiocytosis are proposed to be part of a continuous spectrum of disease.^2,24 However, this contention remains controversial. Angioendotheliomatosis was initially thought to be a neoplastic proliferation of endothelial cells.²⁵ However, subsequent reports described two subtypes of angioendotheliomatosis, a benign (or hyperplastic) form and a malignant form; these entities are now regarded as entirely different diseases as further studies have demonstrated that malignant angioendotheliomatosis actually represents intravascular lymphoma.²⁶

Reactive angioendotheliomatosis is a benign, self-limited proliferation of endothelial cells within previously formed blood vessels. This proliferation may occlude the vascular lumen and result in the formation of new vascular channels. While the etiology of reactive angioendotheliomatosis is unknown, it has been described in association with many other disorders, including systemic infections (e.g., tuberculosis, subacute bacterial endocarditis),^{27,28,29,30,31} microvascular occlusive disorders (e.g., cryoglobulinemia, antiphospholipid syndrome),^32,33,34,35 vascular diseases (e.g., peripheral vascular disease, hypertensive portal gastropathy),^36,37 and hematologic disorders (e.g., Castleman disease).³⁸ Additionally, reactive angioendotheliomatosis has also been associated with rheumatoid arthritis.^24,39 As discussed previously, some have speculated that the organization of microthrombi within vascular spaces can lead to the accumulation of intraluminal histiocytes and subsequent proliferation of endothelial cells manifesting as intralymphatic histiocytosis or angioendotheliomatosis.² Clinically, there is significant overlap between these two conditions in the range of physical exam findings seen in patients.⁴⁰ Interestingly, a recent report described the presence of both intravascular histiocytosis and reactive angioendotheliomatosis in a wide re-excision for malignant melanoma; the authors suggest that these histologic findings support prior reports that these entities are related phenomenon.⁴¹ However, other authors believe that these entities are distinctly different processes—one occurring within blood vessels and the other within lymphatic vessels.⁶