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History

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  2. What is your diagnosis?
  3. History
  4. Diagnosis
  5. Discussion
  6. References

A 5-month-old female infant presented with generalized yellow xanthomatous nodules and plaques over the face, scalp, back, and trunk, some confluent with a cobblestone-like appearance (Fig. 1), which were combined with brown macules and plaques over the upper and lower limbs since she was two weeks old (Fig. 2). The lesions swell and urticate on the back of the scalp, at the site of rubbing or after bathing.

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Figure 1. Diffuse, multiple yellow xanthomatous nodules some with cobblestone-like appearance over the face (a), scalp and back of neck (b), and trunk (back) (c). Note the lesions on the left arm for comparison. The bandage corresponds to the site of the skin biopsy.

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Figure 2. Red–brown pigmented macules, patches, and plaques scattered over the lower limbs (a) and hand (b)

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Diagnosis

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  3. History
  4. Diagnosis
  5. Discussion
  6. References

Cutaneous mastocytosis (CM): combined central xanthelasmoid and peripheral urticaria pigmentosa.

Discussion

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  2. What is your diagnosis?
  3. History
  4. Diagnosis
  5. Discussion
  6. References

Mastocytosis is a disorder characterized by mast cell proliferation and accumulation within various organs, most commonly the skin.[1-3] CM shows a variety of clinical manifestations. Cutaneous lesions include urticaria pigmentosa, mastocytoma, diffuse CM, and telangiectasia macularis eruptive perstans.[2, 3] These most commonly present as macules, papules, plaques, or nodules.[2, 3] Other unusual clinical presentations include telangiectatic and xanthelasmoid lesions.[4-6] Three cases were reported as xanthomatous small yellow papules that initially involved the vulvar and groin regions and then spread to the rest of the body.[4-6] A combination of these lesions might occur in the same patient.[5] Coexistence of two or more different types in the same patient, particularly with distinct anatomic distribution, might impose diagnostic difficulties for pediatricians and dermatologists.[5-7]

Our case was unusual compared to other reported cases. First, it developed two different lesions in different anatomical distribution with two different outcomes. One pattern was regular red–brown macules and plaques typical of urticaria pigmentosa with a positive Darier sign that were exclusively limited to the extremities; they dramatically improved after treatment. The other pattern was xanthomatous nodules over the trunk, back, head, and neck. These xanthomatous lesions were still active with a positive Darier sign and were still severe enough to become bullous even after treatment. Second, the xanthelasmoid lesions showed paradoxically superficial dense mast cell infiltrate (Fig. 3). This is in contrast to the typical deep dermal infiltrate common in xanthelasmoid CM.[6] However, this is not necessarily a requirement for diagnosis, because well-documented cases of xanthelasmoid CM involved the superficial dermis.[7] Finally, the mast cell dermal infiltrate was accompanied by a conspicuous CD68-positive histiocytic infiltrate (Fig. 3).

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Figure 3. (a) The dermis shows marked and diffuse infiltrate of monotonous neoplastic cells composed of round to oval cells with central round nuclei and granular cytoplasm. Scattered eosinophils are present. The overlying epidermis was intact (hematoxylin and eosin stain: original magnification, × 400). (b) Giemsa special stain highlights the positive pale blue to purple granular cytoplasm of the infiltrating cells (Giemsa stain, × 400). (c) CD117 immunomarker shows the strongly positive dense subepidermal cellular infiltrate with sparse infiltrate in the deeper dermis (CD117; Dako, Glostrup, Denmark; × 400). (d) CD68 shows less dense staining than CD117. Some of the neoplastic cells are positive, but most of the CD68-positive cells are larger dendritic cells probably reflecting an element of mononuclear histiocytic infiltrate (KP-1 clone; Cell Marque, Rocklin, CA, USA; × 400). Inset shows diffuse and strong staining for calretinin

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Our initial differential diagnosis of the central lesions was disseminated or eruptive xanthomas and non-Langerhans/Langerhans histiocytosis. Urticaria pigmentosa was our impression of the peripheral lesions. We thought of the possibilities of two different diseases. Diffuse CM, which is a very rare variant, could be a differential, but the radiologic studies showed no evidence of bone lesions, lymphadenopathy, or organomegaly. The bone marrow biopsy showed trilineage hematopoiesis with no evidence of abnormal cellular infiltrate in both the aspirate and trephine. The baby had no generalized symptoms, and the skin was not erythrodermic or thickened. Her blood tests showed raised serum tryptase (> 137 μg/l). A urine test for histamine and its metabolites was not performed. The blood film, full blood count, and ferritin showed microcytic hypochromic, iron deficiency anemia with reactive lymphocytosis. Hemoglobin was 10.4 g/dl, mean corpuscular volume 61.5 fl, and mean corpuscular hemoglobin 19.8 pg. The white blood count differential showed 21% neutrophils, 72% lymphocytes, and 1% eosinophils. Other parameters were within normal limits. The skin biopsy from the xanthomatous lesion revealed diffuse infiltration of the upper dermis by large number of monotonous neoplastic cells with granular cytoplasm and central round nuclei. These cells were strongly and diffusely positive for CD117 (Fig. 3), CD45, and calretinin. The cells were focally and moderately positive for CD68, which also stained larger probably histiocytic cells. However, we used the CD68-KP1 clone, which is less specific for histiocytes than CD68-PGM1 or CD163, but it can be positive in mast cells.[5] The cells were negative for CD2, MPO, CD1a, and S-100 protein. This ruled out leukemic and Langerhans histiocytic infiltrate, respectively. Mast cell tryptase, CD25, CD68-PGM1 clone, and CD163 markers are not available in our laboratory. Mast cell tryptase is a specific confirmatory marker for mast cells, and positive CD25 and CD2 markers would have suggested mast cell leukemia. Because CD68-PGM1 and CD163 are more specific for histiocytes, a negative result would have been useful in excluding histiocytic lesions. Nevertheless, the overall histomorphologic and immunohistochemical findings in our case were consistent with mast cell origin of the cellular dermal infiltrate (Fig. 3).

H1 and H2 antagonists were prescribed. The parents were advised to avoid certain medications commonly given to children but known to be mast cell degranulators, for example codeine. We followed up the patient for eight months to rule out any internal organ involvement and to observe the response of cutaneous lesions to treatment. The urticaria pigmentosa lesions on limbs resolved, and the Darier sign was negative. The central xanthomatous lesions, however, persisted with little or no improvement. No systemic lesions were detected, and the baby was well.

The xanthelasmoid lesions of CM are usually yellow xanthoma-like papules, macules, plaques, or nodules,[4-7] which might look like other xanthomatous lesions. Differential diagnosis might include xanthogranulomas, Langerhans and non-Langerhans cell histiocytosis, pseudoxanthoma elasticum, and xanthomas.[5, 7] Dermatologists should be aware of this clinical variation and different cutaneous manifestations of CM, particularly the xanthelasmoid type, either alone or in combination with other lesions to avoid misdiagnosis and confusion with other diseases. Serology and urine tests might help. However, in difficult cases, a skin biopsy with immunohistochemistry study should help differentiate between these cutaneous lesions and confirm CM. The variations in the clinical symptoms and cutaneous signs of CM are caused by either the dermal infiltration of mast cells, the release of certain chemicals from the mast cells, or both.[1] The density and distribution of the mast cell infiltrate within the dermis, and the presence of other inflammatory cells, for example histiocytes and eosinophils, might change the cutaneous manifestations. In addition, the presence of dermal edema, fibrosis, myxoid changes, and induced alterations in the overlying epidermis, which are caused by the released chemical mediators might change the clinical presentation.[1, 2, 5] Others consider the variation of the cutaneous manifestations of CM as well as the coexistence of different clinical lesions in the same patient might reflect the wide clinical spectrum of CM.[5] The deep solid dermal mast cell infiltrate explains the yellow xanthoma-like lesions of xanthelasmoid CM.[6] However, cases of xanthelasmoid CM with superficial or mid-dermis mast cell infiltrate were reported.[5, 7] We think that the presence of accompanying histiocytic infiltrate (Fig. 3) might explain the yellow hue of these lesions as well.

Therapy is conservative and aimed at symptoms.[6] It includes H1 and H2 antagonists, oral disodium cromoglycate, psoralens plus ultraviolet A phototherapy, and topical steroids.[2] However, none of the currently available therapeutic measures induce permanent involution of the cutaneous or visceral lesions.[3] Patients or their parents should be advised to avoid mast cell degranulators such as aspirin, nonsteroidal anti-inflammatory drugs, codeine, morphine, and alcohol.[2, 3] Regular periodic follow-ups are recommended to monitor systemic involvement and because some lesions might resolve spontaneously.[5, 6] In our case, the peripheral urticaria pigmentosa lesions showed responses to the medical treatment, but the central xanthelasmoid lesions were resistant and did not resolve. This peculiar and different response of the same disease in the same patient to the same treatment might reflect different biologic behavior of the mast cell infiltrate in various lesions. However, it is known that the xanthelasmoid lesions could persist longer than the conventional urticaria pigmentosa lesions, and gradual albeit slow improvement is expected.[6]

In conclusion, our case presented a clinically challenging diagnosis with central lesions of the rare xanthelasmoid variant of CM that were confused with other xanthomatous lesions. They were also combined with, but distinct from, the peripheral more common urticaria pigmentosa lesions. Dermatologists should be aware of the different cutaneous manifestations of CM as well as their variable natural history and different response to treatment. The unusual combination of two or more different cutaneous lesions, particularly with the rare xanthelasmoid types in the same patient is challenging. Skin biopsy should resolve this difficulty.

References

  1. Top of page
  2. What is your diagnosis?
  3. History
  4. Diagnosis
  5. Discussion
  6. References