Non-neoplastic Histiocytic Proliferations of Lymph Nodes and Bone Marrow

Definition

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a rare, self-limited histiocytic disorder of unknown cause. It is typically characterized by massive bilateral enlargement of the cervical lymph nodes, often accompanied by fever and weight loss; extranodal presentations can occur, and lymph nodes in other sites may be involved (see Pearls and Pitfalls ).

Epidemiology

SHML can occur at any age but is most common in the first and second decades of life (median age, 20 years); there is a slight male preponderance. The disease has been found worldwide, with a slightly higher prevalence in Africans. It is thought to be a non-familial disorder, although one report described the presence of the disease in three brothers. Moreover, histologic features of SHML have been reported in lymph nodes of patients with autoimmune lymphoproliferative syndrome (ALPS).

Etiology

The cause and pathogenesis of SHML remain unclear. The indolent clinical course suggests a reactive rather than a neoplastic process. Studies of clonality indicate that it is polyclonal. It has been hypothesized that SHML is a reaction to an infectious agent, such as human herpesvirus 6, parvovirus B19, polyomavirus, or Epstein-Barr virus (EBV); however, no infectious agent has been definitively linked to SHML. An association with systemic lupus erythematosus has also been reported. Recent publications reported patients with SHML to have an increased number of immunoglobulin G4 (IgG4)–positive plasma cells and an increased IgG4/IgG ratio in affected tissues, suggesting that SHML may be a part of the spectrum of IgG4-related diseases. However, most studies concluded that whereas SHML patients may have increased IgG4-positive plasma cells, patients lack the criteria needed to belong in the spectrum of IgG4-related diseases.

Clinical Features

Patients with SHML typically have painless, massive bilateral cervical lymphadenopathy, accompanied by low-grade fever, weight loss, leukocytosis, polyclonal gammopathy, and elevated erythrocyte sedimentation rate. A mild normochromic normocytic anemia may also be present. Extranodal involvement occurs in 25% to 40% of patients and may be the initial manifestation of SHML in some cases. Cases with pure extranodal presentation have been reported, mainly within the central nervous system, nasal cavity, and paranasal sinuses. In general, the most common extranodal sites are skin, upper respiratory tract, soft tissue, orbit, bone, salivary gland, central nervous system, breast, and pancreas.

Morphology

SHML is characterized by the expansion of lymph node sinuses by large histiocytes accompanied by lymphocytes and plasma cells, causing pronounced sinusoidal dilation ( Fig. 52-1 ). Total effacement of the normal lymph node architecture may occur as the disease progresses. The histiocytes have large, round or oval nuclei with dispersed chromatin, often prominent nucleoli, and abundant pale cytoplasm. Within the histiocytes, the presence of lymphocytes and plasma cells in intracytoplasmic vacuoles that protect them from degradation by cytolytic enzymes, a process called emperipolesis, is characteristic but not specific for SHML ( Fig. 52-1 ). Erythrophagocytosis may also be observed. Plasma cells are typically numerous in the medullary cords. Granulomas may be seen in rare cases. In extranodal sites, where there are no sinuses, the histiocytes form aggregates that resemble dilated sinuses ( Fig. 52-2 ). Emperipolesis may be less conspicuous in extranodal sites and prominent loose fibrosis may be seen, often with a somewhat edematous-appearing background ( Fig. 52-2 ). Although the diagnosis of SHML can be made on fine-needle aspirates, which show the characteristic histiocytes exhibiting emperipolesis identified in a background of lymphocytes and plasma cells, limited sampling may lead to difficulty in establishing diagnosis.

Immunophenotype

The histiocytes in SHML express S100 (see Fig. 52-1 ) and other macrophage-associated markers, such as CD4, CD11c, CD14, CD64, CD33, and CD68. A variable number of cells express the macrophage-associated enzymes lysozyme, α ₁ -antitrypsin, and α ₁ -antichymotrypsin. CD30 is reportedly positive in half the cases, although the histiocytes show cytoplasmic staining and not true membranous staining, likely representing nonspecific staining. In contrast to Langerhans cell histiocytosis, CD1a positivity is seen in less than 10% of cases of SHML; cathepsin D and E are positive in both disorders.

Clinical Course

SHML typically has an indolent, protracted course with an excellent prognosis. The disease usually lasts between 3 and 9 months, followed by spontaneous remission. However, persistent disease lasting more than 5 years may infrequently be seen. On occasion, the disease is fatal, particularly in patients with immunologic abnormalities. Patients with an aggressive course and recurrences after complete remission tend to have multiple sites of lymph node involvement or involvement of multiple extranodal sites. Development of lymphoma in patients with SHML has been reported, as has focal SHML in lymph nodes involved by lymphoma, but an increased risk of lymphoma has not been documented. Complete surgical resection is the most effective treatment for recurring cases and for cases with an aggressive course. Several postoperative modalities, including chemotherapy, steroids, interferon, and radiotherapy, have been used but with variable results.

Differential Diagnosis

It is important to differentiate SHML from Langerhans cell histiocytosis. In contrast to the histiocytes of SHML, the characteristic cytologic features of Langerhans cells include elongated, grooved nuclei, inconspicuous nucleoli, and a smaller amount of pale cytoplasm. Eosinophils are typically numerous, plasma cells are absent, and emperipolesis does not occur in Langerhans cell histiocytosis. Other disorders in the differential diagnosis are reactive sinus histiocytosis and sinusoidal malignant tumors. Both of these lack the massive expansion of sinuses by histiocytes and lymphophagocytosis that occur in SHML. Although the prominent nucleoli of the histiocytes in SHML can give them an atypical appearance, the absence of mitotic activity is useful in ruling out malignancy. Hemophagocytic syndromes, especially the familial form that occurs in early life, can mimic SHML; however, these syndromes are characterized by disseminated disease and an aggressive clinical course. Infectious processes inducing the proliferation of histiocytes, such as tuberculosis, should also be considered in the differential diagnosis, but true granulomas and necrosis are uncommon in SHML.

Familial (Primary) Hemophagocytic Lymphohistiocytosis