Hereditary progressive mucinous histiocytosis

Hereditary progressive mucinous histiocytosis Kathrin Schr6der, MD, U w e Hettmannsperger, MD, Matthias Schmuth, MD, Constantin E. Orfanos, MD, and Sergij Goerdt, MD Berlin, Germany We describe hereditary progressive mucinons histiocytosis, a rare autosomal dominant nonLangerhans cell histiocytosis, in a mother and daughter. Both had similar, progressive eruptions of skin-colored to red-brown papules on the nose, hands, forearms, and thighs. Light microscopy showed small collections of epithelioid histiocytes and telangiectatic vessels in the upper dermis of early lesions. In the mid dermis of early and well-developed lesions, nodular aggregates of tightly packed spindle-shaped cells were seen. Moderate to extensive mucin production was demonstrated in epithelioid histiocytes and spindle-shaped cells. Electron microscopy of spindle-shaped cells revealed many dendritic histiocytes with abundant lysosomal storage organelles such as myelin bodies and zebra bodies. Immunohistochemistry showed expression of macrophage antigens (CD68; MS-1 high-molecularweight protein) in epithelioid histiocytes and in some of the spindle-shaped cells. The histologic and immunohistochemical features of hereditary progressive mucinous histiocytosis most closely resemble solitary histiocytoma/cellular-type dennatofibroma. (J Am Acad Dermatol 1996;35:298-303.)

Hereditary progressive mucinous histiocytosis (HPMH) was fu'st described in 1988 by Bork and Hoede. 1 A total of seven patients in three families have been described; all of them were women. 1-3 In addition, six female and two male members in two of these families 1' 2 were reported not to be affected. Clinically, H P M H is characterized by few to numerous skin-colored to red-brown, pinhead to peasized papules with a predilection to localize on the face, hands, forearms, and legs. Lesions are confined to the skin, usually appear in the second decade of life, and show slow progression without spontaneous resolution. Microscopic examination shows a histiocytic infiltrate in the upper and mid dermis, producing considerable amounts of metachromatic mucinous material. A moderately increased number of dilated vessels and mast cells are seen. Ultrastmcturally, the large, oval, or spindle-shaped histiocytes contain numerous myelin bodies and zebra bodies

This article is made possible through an educational grant from the Dermatological Division, O t t o Pharmaceutical Corporation. From the Hautldinik und Polfldinik, Universit~tsk3inikqmaBenjamin Franklin, Freie Universit~t Berlin. Reprint requests: Priv.-Doz. Dr. S. Goerdt, Hautlinik nnd Poliklinik, Universitgtsklinikatm Benjamin Franklin, Freie Universit~t Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0 16/4/70833 ORTHO

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and an enlarged and dilated rough endoplasmatic reticulum. No lipid vacuoles or Birbeck granules are present. Biochemical analysis of lysosomal enzymes in serum and tissue extracts failed to demonstrate lysosomal enzyme deficiency. Immunohistochemical detection of chymotrypsin, trypsin, and lysozyme and a lack of CD 1a and S 100 antigens in the lesional cells suggest the macrophage nature of the disease. Thus H P M H is viewed as an autosomal dominant or, less probably, an X-linked inherited, nonlipidizing, cutaneous non-Langerhans cell histiocytosis. However, positive expression of monocyte/macrophagespecific antigens in t t P M H cells has not yet been reported. We describe two female members of a fourth family with HPMH. In addition, we discuss the classification and histogenesis of H P M H on the basis of immunohistochemical studies with a panel of monoclonal antibodies to monocyte/macrophagespecific antigens. 4, 5 CASE REPORT

A 20-year-old woman had a 3-year history of small (2 mm) papules on the nose and small-to-large (up to 8 mm) papules on the dorsal aspect of the hands, the forearms (Fig. 1, A), and the thighs (Fig. 1, C). The asymptomatic lesions slowly but progressively increased in number and did not show any tendency to resolve spontaneously. Examination showed numerous skin-colored to red-brown, finn papules. The mucous membranes were not affected.

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General examination revealed no abnormalities. The results of routine laboratory studies, including a serum lipid panel (after a 12-hour fasting period) and thyroid fraction, were normal. Biopsy specimens of a small nasal papule (Fig. 2, A and B) and of a larger papule from the forearm (Fig. 2 C and D) showed essentially the same features in the mid derlifts, whereas differences were noted in the upper dermis. The mid-dermal lesions consisted of dendritic, spindleshaped cells with an elongated nucleus but little cytoplasm (Fig. 2, A and C). These cells lay between bundles of collagen fibers. Alcian blue staining detected abundant mucinous material (Fig. 2, D). Toluidine blue staining revealed only weak metachromasia, but numerous mast cells were identified. In the upper dermis of the small nasal papule (Fig. 2, A), small aggregates of epithelioid histiocytes were found in close proximity to dilated, telangiectatic blood vessels. Around the cell membrane of these epithelioid histiocytes, a small rim of alcian blue-positive mucinous material was seen (Fig. 2, B). Electron microscopy (Fig. 3,A and B) of a larger papule on the forearm demonstrated that the tumor was composed of fibroblasts, mast cells, small vessels, and a considerable admixture of unique histiocytic cells. The histiocytic cells occurred as two types. Small histiocytic ceils were often highly dendritic (Fig. 3,A) whereas larger histiocytes displayed extensive rough endoplasmic reticulum with widely dilated vacuoles. Histiocytic cells occasionally phagocytized collagen fibers and contained large numbers of zebra and myelin bodies (Fig. 3,/3). Birbeck granules, cytoplasmic laminated bodies, or pleomorphic inclusion bodies were not observed. Immunohistochemical studies were performed on formatin-fixed paraffin-embedded (S-100, CD34, CD68, Mac-387, and von Willebrand factor)6 or on fresh-frozen (all other antigens) tissue sections by the APAAP or direct immunoperoxidase techniques, respectively. On fresh-frozen tissue sections, quenching of endogenous peroxidase was achieved with hydrogen peroxide and sodium azide. Sources and specificity of the antibodies used and the results of immunostaining are presented in Table I. Unfortunately, a frozen biopsy specimen of a nasal papule was not available. Immunohistochemistry grossly reflected the differences in the hematoxylin-eosin findings. Most lesional ceils in the mid dermis expressed the fibroblast-related antigen CD34 in the larger papules, whereas the epithelioid histiocytes and the spindle-shaped ceils in the nasal lesion were negative. In contrast, most epithelioid histiocytes and spindle-shaped cells of the small nasal papule expressed the macrophage-related antigen CD68 strongly ( 10% ) or moderately (70%), but they did not express the CD34 antigen. MS- 1-HMWP and RM 3/1 antigen were positive in 15% of the spindle-shaped cells in the mid dermis in the larger forearm lesion. Because these two latter monoclonal antibodies can be used

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Fig. 1. Small skin-colored papules on nose and dorsal aspect of hands, and larger red-to-brown papules on forearms (A) and thighs (B).

only on fresh-frozen sections, we were not able to assess their expression in the nasal lesions. Monoclonal antibody 1F10 and antiserum against the von Willebrand factor revealed a moderately increased vascularity in the lesions. S-100, CDla, CDllc, MRP-14 (monoclonal antibody MAC 387), and a marker for follicular dendritic cells were not expressed by the epithefioid histiocytes or the mid-dermal spindle-shaped cells. The 46-year-old mother of this patient had similar clinical fmdings, with fewer papules than her daughter on the nose and the forearms. The lesions had first appeared when she was 20 years old and had been slowly progressive. No new lesions had occurred in the last 10 years. Hematoxylin and eosin and alcian blue staining of one forearm lesion showed findings similar to the forearm lesion of her daughter. Another daughter of this woman was also reported to be affected, and a son was reported to be tmaffected. These children were not available for examination. DISCUSSION Unlike reactive processes such as granulomatous diseases, histiocytoses are primary diseases o f the monocyte/macrophage and dendritic cell systems. The histiocytoses are divided into Langerhans cell

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Fig. 2. Light micrographs. Hematoxylin-eosin (A and C) and alcian blue (B and D) staining of small (A and B) and large (C and D) papules. In the upper dermis of the small nasal papule (A), small aggregates of epithelioid histiocytes are found in close proximity to dilated, telangiectatic blood vessels. Around the cell membrane of these epithefioid histiocytes, a small rim of alcian blue-positive mucinous material is seen (B). The mid-dermal lesions consist of dendritic, spindle-shaped cells with an elongated nucleus but little cytoplasm (A and C). Alcian blue staining shows abundant mucinous material in these lesions (D). (class I) and non-Langerhans cell (class II) groups. It is a matter of debate whether truly malignant Langerhans cell and non-Langerhans cell histiocyroses (class III) exist.7 The non-Langerhans cell histiocytoses are subdivided into cutaneous8-1° and systemic11-13 forms. Langerhans cell histiocytoses are characterized by the presence of Birbeck granules and by expression of C D l a and S100 antigens, whereas non-Langerhans cell histiocytoses lack these

features. In contrast, the cutaneous non-Langerhans cell histiocytoses are defined by expression of MS1 high-molecular-weight protein (MS-1-HMWp)4, 6, 13-17

Cutaneous non-Langerhans cell histiocytoses represent a heterogeneous group of diseases that are subclassifiable by their tendency to store lipids. Lipidizing cutaneous non-Langerhans cell histiocytoses include juvenile xanthogranuloma, is xanth-

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oma disseminatum] 9-2a multicentric reticulohistiocytosis, 22 and necrobiotic xanthogranuloma. 23 The classification of normolipemic plane z4 or papular 25 xanthomatosis remains controversial. Nonlipidizing cutaneous non-Langerhans cell histiocytoses include generalized eruptive histiocytoma17,26 and benign cephalic histiocytoma.27 Hereditary progressive mucinous histiocytosis (HPMH) 1,2 is a nonlipidizing cutaneous non-Langerhans cell histiocytosis. Of the other nonlipidizing cutaneous non-Langerhans cell histiocytoses, none is a genodermatosis. Although generalized eruptive histiocytoma bears some resemblance to HPMH, it can be differentiated by onset late in life, by the tendency of the lesions to resolve spontaneously, by the predominance of epithelioid histiocytes in the lesions, and by the lack of mucin production. Benign cephalic histiocytosis may be a localized childhood variant of generalized eruptive histiocytoma or of juvenile xanthogranuloma. Progressive nodular histiocytoma2s-3° is characterized by the slowly progressive development of widespread papules and nodules that may reach a diameter of up to 5 cm and contain a central depression or painful ulceration. The lesions tend to coalesce to plaques and may finally give the patient' s face a leonine appearance. As in HPMH, the histology may show spindle-shaped histiocytes in progressive nodular histiocytoma. However, lesional cells in progressive nodular histiocytoma may lipidize, contain pleomorphic inclusion bodies, and do not produce mucin. Apart from the nonlipidizing cutaneous non-Langerhans cell histiocytosis, other diagnoses have to be considered. Of the mucinoses, acral persistent papular mucinosis is similar to HPMH in that, mostly in female patients, bilateral papules develop on the dorsal aspects of the hands and the forearms; papules may develop on the medial aspects of the knees. Acral persistent papular mucinosis differs from HPMH in that it is not hereditary, children are not affected, and the lesions show mucinous degeneration without a histiocytic infiltrate or even lack enhanced cellularity.31 Cutaneous focal mucinosis 32 and superficial angiomyxomas 33 usually are solitary lesions. With regard to a single lesion in HPMH, histiocytoma/dermatoflbroma is the most difficult to distinguish. Multiple ordinary dermatofibromas34 or multiple dermal dendrocytomas35 have been reported, so that inheritance and mucin production in HPMH become essential diagnostic features. However, the histogenesis of histiocytoma/dermatofi-

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Fig. 3. Electron micrograph of larger papule on forearm shows two types of histiocytes. Small histiocyfic cells with little cytoplasm were often highly dendritic (A). Larger histiocytes displayed enlarged rough endoplasmatic reticulum with widely dilated vacuoles (A) and a large number of lysosomal bodies, such as myelin and zebra bodies (B).

broma and its relation to the diverse cutaneous nonLangerhans cell histiocytoses have not been clarified. It has been reported in the older literature that most cellular elements in histiocytoma/dermatofibroma are able to phagocytize. 36 Electron microscopy, however, has revealed ultrastmcmral features ascribed to fibroblasts rather than macrophages. 37 Recently, we have shown that a high percentage of cells in histiocytoma/cellular-type dermatofibroma express macrophage-specific antigens such as RM 3/1 antigen and MS-1-HMWP 4, whereas CD34 as a fibroblast marker is expressed only at the border of the lesion. In contrast, the cells in fibrous-type dermatofibroma lack RM 3/1 antigen and MS-1HMWP. MS-1-HMWP + macrophages in histiocy-

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T a b l e

I. Antigenic phenotype of lesional cells in HPMH. Result Antibodies

MS- 1FS

RM 3 / 1 F s BU15Fs 25F9Fs KD1P Dako-T6Fs antiserump Qbendl0P MAC 387P 27E10Fs DRC1-R3/24Fs antiserumP 1F10Fs

Specificity

Nose

Arm

Source

sinusoidal endothelia, dendritic macrophages, non-Langerhans cell histiocytoses monocytes/macrophages CD1 lc, monocytes/macrophages macrophages, late differentiation antigen CD68, macrophages, mast cells, others CDla, thymocytes, Langerhans cells S 100 CD34, hemopoietic precursor cells, endothefium, fibroblasts MRP-14, myeloid cells MRP-8/-14, myeloid cells follicular dendritic cells von Willebrand factor, endothelial cells endothelial cells

nd

+*

Goerdt et al. 14

lad nd

+* -

Zwadlo et al.39 Immunotech$

nd

-

Zwadlo et al.40

+++~

+$

Dakopatts§

nd

-

-

(+)/+§ -

Dakopatts Dakopatts Irnmtmotech

nd rid -II

-II

Dakopatts Zwadlo et al.41 Dakopatts Behring&

nd

-II

Goerdt et al.42

-

*Positive staining of 15% of lesional spindle-shaped cells. j-Strong staining of 10% and moderate staining of 70% of lesional cells. :~Fifteen percent of lesional cells with a rounded contour are strongly stained; spindle-shaped cells are negative. §Ten percent of the lesional cells are strongly stained, 80% are weakly stained. IIModerately increased degree of vascularization in part with teleangiectasia in the upper dermis. ~{Dako Corp., Glostrup, Denmark. #Immunotech SA, Marseille, Frmlce. **Behring Diagnostika, Marburg, Germany. FSFor use on frozen sections only. eFor use on paraffin-embedded, formalin-fixed tissue.

toma/cellular-type dermatofibroma, in contrast to MS-1-HMWP + macrophages in typical cutaneous non-Langerhans cell histiocytoses, are spindleshaped dendritic cells that resemble the MS-1-HMWP + perivascular dendritic cells in normal human skin.4, 15 Immunohistochemistry of the H P M H lesions showed a pattern similar to that of histiocytomaJcellular-type dermatofibroma with regard to the spindie-shaped cells in the mid dermis. These cells contained a reasonable percentage of MS-1-HMWP +, RM 3/1 + dendritic macrophages. On the other hand, the spindle-shaped cells that predominated in these lesions did not express any macrophage-specific antigens but expressed the fibroblast-related CD34 antigen. In contrast, the nasal lesion in our younger patient with H P M H showed small aggregates of histi-

ocytes with a high percentage of CD68 +, CD34macrophages in the upper dermis. We hypothesize that these epithelioid histiocytes are MS-1-HMWP + macrophages similar to those found in other nonLangerhans cell histiocytoses. These MS-1-HMWP + macrophages may secrete cytokines inducing fibroblast proliferation and angiogenesis, an essential function of alternatively activated macrophages. 13 During further development of the lesion, MS- 1-HMWP + macrophages may undergo progressive mucinous degeneration with loss of macrophage-specific antigens because of inborn apoptotic mechanisms. 38 Macrophage apoptosis may thus explain the phenotypic shift from macrophage to fibroblast during development of H P M H lesions and may also shed some fight on the histogenesis of reactive histiocytoma/dermatofibroma.

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