Progressive nodular histiocytosis (PNH) represents a very rare type of non-Langerhans cell histiocytosis (NLCH). It can be distinguished from other types by the occurrence of yellow to red-brown papules and nodules measuring a few centimeters in size. Histologically the nodules represent spindle-cell xanthogranulomas. We report on two new cases of PNH with novel clinical symptoms. In the first case, the patient had microcytic anemia due to massive iron deposition in the nodules and a progressively worsening limp due to involvement of the soles. The complex therapeutic challenge was effectively managed by successive surgical ablation of all visible lesions. The second patient had epibulbar infiltrates. The clinical variability of PNH leads to considerable overlap with other forms of NLCH.
Non-Langerhans cell histiocytosis (NLCH) is a group of clinically heterogeneous diseases. Histologically they are characterized by dermal collections of cells that are derived from macrophages as well as some cells with dendritic differentiation. Most of these diseases are very rare. A totally satisfactory classification for NLCH is still being sought.
One or the rarest and most impressive forms of NLCH is progressive nodular histiocytosis. It is characterized by the clinical appearance of yellow papules and larger nodules on the head, trunk, and extremities; mucous membrane involvement can occur on occasion as well . There have been reports of severe and disfiguring forms of disease, but not of involvement of internal organs or systemic complications. We describe two patients with unusual symptoms. The first had extensive widespread cutaneous disease, as well as difficulty walking. Due to massive tumoral iron depositions, the patient also developed microcytic anemia. The second patient is unique because of his peculiar ocular involvement.
A 29-year-old Armenian man had a more than 10-year history of firm nodules appearing all over his skin. The nodules steadily grew in size and number. On the basis of histological examinations, the patient was advised to follow a low-fat diet. This led to a loss of 15 kilograms in 3 months. After excision of solitary nodules, they often recurred. Other nodules resolved spontaneously. The patient had no medical problems. His mobility was limited by large nodules on the soles of his feet.
The patient's skin was pale. On his head, trunk, and extremities were hundreds of firm, red-purple nodules, some as large as a plum, coalescing primarily on the legs and buttocks, and often pedunculated (Figure 1). A few large tumors exhibited superficial necrosis. Smaller nodules, especially on the face, were yellow while others, as on the arms, were gray-brown; there were also atrophic scars (Figure 2). A yellow tumor was found on the epiglottis.
The dermis contained abundant histotiocytes, some with a foamy cytoplasm. The cell nuclei were uniformly shaped. In addition, there were abundant hemosiderin-laden macrophages (Figure 3). Berlin blue stain revealed dense dermal accumulations of hemosiderin-laden macrophages (Figure 4). Sudan staining detected lipid deposits. Immunohistology was positive for CD68, CD163, vimentin, and fascin, while it was negative for CD1a and S100. This confirmed the presence of NLCD.
Severe microcytic anemia: Hb 3.7 g/dl (normal values: 14.0–18.0), MCV 62.8 fl (80–96). Serum iron was low at 21 μg/dl (59–158) as was transferrin saturation at 6% (16–45); -ferritin was elevated at 468 ng/ml (30–400) as was haptoglobin at 348 mg/dl (30–200); transferrin was within normal ranges at 223 mg/dl (200–400) as was vitamin B12 at 205 pg/dl (191–663). Serum electrophoresis: IgG hypergammaglobulinemia with no detection of monoclonal immunoglobulin fractions. Other routine laboratory tests were unremarkable.
Hematological consultation: severe hypoproductive microcytic anemia, morphologically resembling iron deficiency. Bone marrow cytology: severely hypercellular bone marrow with reactive plasmacytosis and no evidence of iron storage. No infiltration of histiocytes. In balance, a mixed picture of iron deficiency and tumor anemia.
Ultrasound: enlarged, most likely reactive, benign confluent lymph nodes in inguinal, axillary and cervical regions.
CT thorax/abdomen, MRI head/neck: enlarged peripheral and abdominal lymph nodes, hepatosplenomegaly. Cutaneous nodules, but no other space-occupying masses.
Treatment and outcome
The patient was perfused with packed erythrocytes. The ulcerated nodules and erosions were treated with a topical antiseptic. Based on an analysis of histological and hematological findings, we decided to perform radical surgery with the intention of eliminating all nodules which were causing disfigurement or impairment. At the same time, the removal of iron-storing nodules was intended to ensure long-term stabilization of the patient's hematological status. Over a period of 11 months (7 treatment sessions), we removed all visible nodules, or about 1,000 lesions, from the patient's head, trunk, and extremities using a flat excision without wound closure. Follow-up treatment consisted of application of hydrocellular and antiseptic wound dressings and temporary antibiotic coverage. The majority of the wounds healed with flat or atrophic scars (Figure 5). The aesthetic results were good, and on the face in particular the cosmetic outcome was excellent (Figure 6). Physical therapy succeeded in eliminating functional impairment. After completing treatment, the patient's hemoglobin levels were stable at 9–10 g/dl. He gained weight and reported that his quality of life had improved dramatically. The epiglottal tumor showed a tendency to grow and was removed with laser surgery. Over time, new nodules developed, especially on the extremities, making several follow-up surgeries necessary. A particular concern is the rapidly-developing new nodules on the soles of the feet which could impair walking again. Regular follow-up visits have been planned.
A 55-year-old man presented with a 4-year history of spreading papules and nodules, some of which were painful. The lesions first appeared on the abdomen as small papules. These steadily grew in size, however, and then spread to the remainder of the skin. One year ago, ocular changes had occurred. The patient reported a feeling of ocular pressure and -dryness. Some of the skin lesions had reportedly regressed while others had progressed. The patient had begun treatment in the summer of 2006 at another institution for suspected Rosai-Dorfman syndrome (sinus histiocytosis) and was given systemic corticosteroids and chemotherapy, albeit without any positive effect. Since 2007 the patient has had heparin-induced thrombocytopenia following a leg thrombosis.
Multiple superficial yellow-brown densely-packed papules, as well as nodules and plaques, were disseminated mainly on the trunk, arms, thighs, margins of the feet, and face. Some were atrophic with a wrinkled surface. Several of the lesions were superficially quite yellow. There were also a few 1–3 cm deep, firm, red-brown, shiny smooth dome-shaped tumors with superficial telangiectases (Figure 7, 8). Epibulbar yellow plaques were found on the eyes (Figure 9).
The dermis was filled by a nodular infiltrate producing a dome-shaped profile. The infiltrate consisted cells with abundant pale eosinophilic cytoplasm and large nuclei. In some areas the cells were spindled and arranged in fascicles. The tumor cells were positive for CD4, and some were positive for CD68; they were negative for CD1a and langerin. There were also scattered giant cells, mainly Touton cells. In the center there was a zone of severe necrosis. There was also an associated focal lymphocytic infiltrate.
Elevated: neutrophils 80.0% (40–70), C-reactive protein 2.37 mg/dl (< 0.5), triglycerides (fasting while on simvastatin) 314 mg/dl (50–200), gamma gt 89 U/l (< 55).
Within reference range: all remaining parameters of blood differential and serum chemistry including cholesterol, HDL, LDL, Apo A1, Apo B, HbA1c and coagulation parameters.
CT of thorax/abdomen: multifocal cutaneous and subcutaneous densities in the chest and abdominal walls.
Cranial MRI: no evidence for space-occupying masses.
Bilateral firm yellow epibulbar deposits and bilateral conjunctival swelling.
Histopathology (subconjunctival excision biopsy from right eye): fibrosed soft tissue with histiocytic infiltrates with a positive reaction for CD68, low proliferation index (≤1%) and lacking CD1a. Occasional cells are positive for PAS.
Diagnosis: focal histiocytic infiltration in the scleral region.
Treatment and outcome
Systemic therapy with prednisone 10 mg/daily, which had been started elsewhere, was continued. Staging with positron emission tomography and bone marrow biopsy showed no evidence of involvement of the bone marrow or internal organs. The patient has not yet returned for his scheduled follow-up.
The various forms of the xanthogranuloma group of NLCH (disseminated juvenile xanthogranuloma based on the current WHO classification ) are generally believed to most likely be variants of a disease spectrum rather than independent entities (Table 1). There is considerable overlap between types, and hence they sometimes evade clear classification. Mucosal involvement is primarily seen in xanthoma disseminatum, but can occur in any of the forms. All types are permanent, with the exception of generalized eruptive histiocytosis, which by definition comes and goes. The presence of histiocytic infiltrates occurs in all forms and is characterized by spindle-shaped, vacuolated, stellate, oncocytic (ground-glass) and foamy cells, all of which express immunohistochemical macrophage markers such as CD68 and CD163. Dendritic cells are also occasionally involved [3-11].
Table 1. Xanthogranuloma group of non-Langerhans cell histiocytoses (based on ).
· Juvenile xanthogranuloma
· Papular xanthoma
· Xanthoma disseminatum
· Multicentric reticulohistiocytosis
· Spindle-cell xanthogranuloma
· Progressive nodular histiocytosis
· Benign cephalic histiocytosis
· Generalized eruptive histiocytomas
Within this spectrum, PNH is characterized by the simultaneous presence of two different lesions, namely yellow papules, which are almost always normolipemic xanthomas, and dermal nodules measuring several centimeters in size, which are always spindle-cell xanthogranulomas. The latter may also occur sporadically [1, 12]. In our patients, the nodules were the predominant clinical feature. There have been no reports of involvement of internal organs. The disease can also affect children [1, 13, 14]. Except for one patient with an association with leukemia , there seems to be no association with malignancies or chronic inflammatory diseases. Distinction from generalized eruptive histiocytomas in particular may be difficult . In patient 2, the initially diagnosed Rosai-Dorfman syndrome is usually associated with massive swelling of the cervical lymph nodes, mainly affects young adults, and appears with multiple, red-brown nodules and a histiocytic infiltrate which is S100-positive, but does not have other features of Langerhans cell histiocytosis .
A typical feature of PNH is disease progression spanning several decades. There have been only two reports of spontaneous regression of nodules [17, 18]. Although some of the lesions in our patients also regressed spontaneously, most seem to be characterized by unlimited growth. Patient 1 had incomparably extensive dissemination and increased density of the nodules. The lesions seemed to spread in a cranial to caudal fashion, something not previously noted. Unlike other patients in the literature [15, 18-20] our patients fortunately did not have large or severely disfiguring facial nodules. They did have involvement of the joint flexures, which has been uncommon in other reports [5, 21]. Only one other patient had involvement of the palms and soles . Mucosal involvement has been occasionally reported, including the publication by Taunton and colleagues , who were the first to describe this disease. In one patient, extensive laryngeal involvement led to respiratory difficulty and resulted in laser removal of the nodular infiltrates, which was also necessary in patient 1 . Taunton and colleagues also described conjunctival involvement as seen in our patient 2. A unique finding in patient 2 was ocular involvement with epibulbar infiltrates, which has only been reported once thus far . An association with retinitis pigmentosa, without an evident causal relationship has been reported in one patient .
Taunton's patient also had mild anemia, which is not generally associated with PNH, as well as iron storage in the nodules, which has only been reported a few times [12, 19]. Patient 1 had massive iron deposits with severe iron-deficiency anemia, which may be explained by cutaneous nodules weighing several kilograms heavily laden with iron. All hematological findings support this causal relationship. Iron deposition has previously been cited in xanthosiderohistiocytosis, a variant of xanthoma disseminatum which also belongs to the xanthogranuloma group of NLCH, but does not resemble PNH clinically .
The overall clinical situation with patient 1 presented a treatment challenge due to his reduced general health as a -result of anemia, the presence of disfiguring skin lesions, and his impaired walking. Iron substitution was not considered a long-term option, given the persistence of the nodules and their anticipated growth. Nor would selective excision of nodules, based on aesthetic considerations, have remedied the patient's anemia. The remaining option was thus radical removal of the iron-containing nodules as a means of addressing these problems simultaneously. Although the chosen procedure was rather more complex and also presented a greater burden for the patient, it fulfilled its purpose. Given that there is no curative therapy available at present, as well as a tendency toward nodule proliferation, periodic monitoring and further procedures will be necessary.
These two patients show that new and unexpected features of NLCH are possible despite – or because of – its rarity. On occasion, creative approaches to treatment may be necessary.