Richard J. Reed, M.D.
New Orleans, La. Feb 2000
Whenever a pathologist encounters a relatively cell-poor histologic pattern with little evidence of disease, he is inclined to include mastocytosis in the differential diagnosis. A pathologist is likely to consider mast cell disease whenever mast cells are easily recognized on H&E stained sections. Whenever the mast cells are few in number but large, spindle shaped, and dendritic, a variant of mastocytosis should be considered in the differential diagnosis.
Some of the manifestations of mast cell disease have a temporal relevance. The clinical and histologic characteristics of mast cell lesions sometimes change as the host ages. On the other hand, some examples are relatively constant in clinical and histologic qualities over periods of years.
Clinical Keys and Specific Histologic Features
Case 1 clinically was a fairly typical example of urticaria pigmentosa (maculo-papular cutaneous mastocytosis). Clinically, Darierís sign was positive. Mast cells are loosely spaced in the upper portion of the dermis. The cells are polygonal in outline and have short dendrites. The nuclear grade is low (fig 3). Involvement of the upper portion of the dermis is characteristic of lesions of mastocytosis (fig 1).
For Case 2, Darierís sign was positive. The first biosy specimen shows the scanty perivascular infiltrates often associated with lesions of adult mastocytosis. In addition, adult mastocytosis is often equated with telangiectasia macularis eruptive perstans. The lesions have evolved clinically. Losing the qualities of urticaria pigmentosa, they have become macular and telangiectatic, particularly about the eyes and mouth. Histologically, they have acquired micronodular, fibroangiomatous qualities (fig 7). The vascular changes might easily be given priority in the histologic assessments (fig 8), but there is a distinctive pattern of lamellar fibrosis associated with the tortuous, dilated small vessels in the widened papillary dermis (fig 7). The mast cell infiltrates apparently have the potential to promote fibrogenesis.
In Case 3, the lesions often would swell and acquire the qualities of hives in response to pressure, heat, and/or trauma. The first biopsy specimen showed diffuse dermal infiltrates in a classic papulo-nodular pattern (fig 9). Nuclear grade was low (fig 11). In the second specimen a year later, the patterns in part were papulo-nodular and solid but there was a rich component of eosinophils. Nuclear grade was intermediate (fig 16). In areas on the second biopsy, there was a distinctive pattern of fibrogenesis and the associated mast cells tended to be plump and spindle shaped (fig 15) (spindle cell configurations are characteristic for many fibrogenic cells). The fibroangiomatous patterns as seen in Case 2 are not a feature of the spindle cell component in Case 3, but the differences may in part relate to the environment in each case. In Case 2, the changes affect the papillary dermis and in Case 3, they are a feature of the reticular dermis.
In Case 4, Darierís sign was positive. The histologic changes are those of a nodular infiltrate of mast cells. There are no patterns of fibrogenesis, at least in the upper portion of the dermis where the infiltrates are solid. This case has shown the signs of systematized mastocytosis and the severity of the disease has been little changed over several years of observation. The nuclear changes are prominent in this case (fig 22). If the degrees of atypia in this small series were to be divided into 3 grades, the nuclear changes of Case 4 would be grade III. It would however be a mistake to translate such a division into either a general guide for the grading of human mastocytoses or a guide to prognostications.
See Pertinent references: 2,3, & 7. Then scroll back up to here.
Mast cells are native to mesenchyme. The mastocytoses are diseases of mast cells. The clinical classification of cutaneous mast cell disease includes a maculo-papular variant, a nodular variant, a systemic variant, and an adult variant (telangiectasia macularis eruptiva perstans).
Histologically, some examples are perivenular processes with sparse interstitial infiltrates, some are plaque-like with interstitial infiltrates limited to the upper portion of the dermis, some are tumorous and may involve the subcutis as well as the dermis, and some are associated with clinically evident visceral infiltrates with hepatosplenomegaly as a prominent feature. Bone lesions are variable but may be both lytic and sclerotic.
It is difficult to conceptualize mast cell disease. Mast cells have their origin in the bone marrow and circulate in the blood. They are residents of mesenchyme and are easily identified in perivascular spaces of normal skin.
In resting mesenchyme, mast cells are generally rounded in outline and have oval nuclei with uniformly distributed chromatin. They may be found in the perivascular spaces and among collagen bundles of the reticular dermis. They are common residents of perifollicular connective tissue sheaths.
In the reactions of mesenchyme, particularly in lesions associated with an increased prominence of myxoid matrix, mast cells are increased in number in the affected tissue. Mast cells and dendritic histiocytes have an association with myxoid matrices.
It is possible to make distinctions between the small rounded mast cells of resting mesenchyme and the larger, dendritic mast cells encountered in some examples of cutaneous mast cell hyperplasia. Mast cell hyperplasias are poorly characterized but in part may represent a response of mast cells to the phenomena of cell mediated immunity.
In solid infiltrates of the skin, mast cells tend to be rounded or polygonal and closely packed with little histologic evidence of intercellular fibrous matrix. Near the dermal-epidermal interface the cells of mast cell infiltrates tend to be closely aggregated in solid patterns. In the deeper portion of the dermis, the cells may be arranged in files or individually among collagen bundles of the reticular dermis. Mast cell infiltrates have a homing (ecotaxic) quality. They most densely populate the sites which are naturally favored in resting mesenchyme.
If comparisons of lesions from different cases are made, it is possible to define cytologic distinctions based on nuclear and nucleolar size, chromatin patterns, and nuclear outlines. If attention is given solely to cytoplasmic qualities, then at least a small, rounded cell and a larger, elongated dendritic cell are options. As a variation in the small round cell category, some or many of the nuclei are notched or idented and the features are histiocytoid. Some mast cells show prominent perinuclear halos and this feature in combination with lavender cytoplasm may provide plasmacytoid qualities.
Like melanocytic processes, the prominence of dendrites at the periphery of mast cells depends in part on the density of the infiltrates. Cytoplasmic processes are more easily identified if cells are loosely spaced than if they are closely spaced.
Infiltrates of mast cells are variably associated with eosinophils and in the face of a high component of eosinophils in cutaneous lesions, these relationships are often assumed to be a response to the degranulation of mast cells in response to trauma or stimulation.
The common papular or nodular, solitary or sparsely distributed mastocytomas of infancy are histologically likely to be localized, solid infiltrates of mast cells, and to be most prominent in the upper portion of the reticular dermis. The component cells are likely to be rounded in outline and their nuclei are oval, uniform, and small. Cell membranes are well defined and often the cells show a perinuclear halo. Nuclear chromatin is diffusely distributed and nucleoli are inconspicuous (see figs , Case 1 & Case 2).
In some examples the nuclei show delicate chromatin patterns with notched or indented nuclei. These cells tend to have pale, somewhat vacuolated cytoplasm and indistinct cell membranes. They are histiocytoid mast cells (see figs , Case 3 & Case 4).
In some lesions, the mast cells focally are spindle shaped and are associated with a fine reticulum. In foci in some of the lesions, fibers outline individual cells. The mast cells in these fibrous areas have pale cytoplasm and enlarged nuclei. Nuclear chromatin is distributed in an open pattern and nucleoli are prominent and central. Many of the mast cells in these areas of fibrosis appear to be spindle shaped on H&E stained sections. Eosinophils may be a prominent feature of lesions showing this pattern of fibroplasia. The fibrous tissue is loosely laminated and in areas the lamellae are stacked. Such patterns have a poorly defined storiform or starburst quality. In this small collection, the changes were encountered in a long-standing case (Case 3).
Finally, some of the tumoral lesions with non-fibrogenic round cells in solid aggregates are composed of plump, pale cells with enlarged nuclei and prominent nucleoli. The nuclei are irregular in outline and chromatin is speckled. In this small series, these nuclear changes were encountered in the case of systemic mastocytosis (case 4).
In adult mastocytosis, the mast cells of the skin tend to be loosely spaced in non-tumoral patterns. They are elongated, enlarged and dendritic in both the perivascular spaces and in the mesenchyme of the reticular dermis. The cytologic features differ from those of the mast cells of resting mesenchyme. The designations, adult mastocytosis and telangiectasia macularis eruptiva pertans, are commonly used as if they are synonyms. Telangiectasia MEP is basically a clinical designation and should be restricted to such usage. Adult mastocytosis is a variant of dendritic cell mastocytosis. The mast cells of adult mastocytosis generally do not form tumoral aggregates. The infiltrates are mostly perivascular in the upper portion of the reticular dermis (Fig 24). On an H&E stained section, the spindle shaped mast cells may be inconspicuous at the periphery of the perivascular spaces (Fig 25). With a giemsa stain, the cells are sparsely arranged in the interstitium of the reticular dermis (Fig 26).
As a complication of mastocytosis, the upper portion of the dermis may show small lobular aggregates of small dilated vessels with symmetrically rounded lumens and thickened membranous walls. In addition, fibers in laminated patterns encircle the altered vessels (see the figs in Case 2 and Case 1). Perhaps, this fibrovascular lesion of mastocytosis is the closest histologic correlate of what is properly characterized clinically as telangiectasia MEP but in practice, the designation usually gives recognition to non-tumorous infiltrates in which the component cells are large, spindle shaped and dendritic.
Two patterns in this collection can be characterized as fibrogenic (Case 2 and Case 3). In Case 3, many of the cells are also spindle shaped. The spindle or dendritic mast cell may represent a fixed mesenchymal cell with fibrogenic properties.
In the spindle cell and fibrogenic components of Case 3, there is a plexus of small dilated vessels with thick walls. In the papillary dermal component of Case 2, the basic pattern has angioplastic qualities with thickened, vascular basement membranes. There is in addition a fibrogenic component with lamellae of fibrous tissue partially encircling the microlobular aggregates of vessels. The vascular changes are reminiscent of acral angiodermatitis but clinically the distribution of lesions would not suggest a role for venous stasis. Perhaps the fibroangioplastic components in the papillary dermis in Case 2 are merely a modification of the fibrogenic components of the reticular dermis in Case 3.
The fibrogenic components of Case 3 might be compared to the eosinophilic fibrohistiocytic lesion first described by the late Arkadi Rywlinref. 6.Only later was the lesion appreciated as being a manifestation of mast cell disease.
c-kit protooncogene encodes stem cell factor (KIT)ref. 1. The ligand of the stem cell factor is a cytokine that stimulates mast cell growth and differentiation. Reguera, et alref. 5, in a study of canine mast cell lesions defined 3 grades of mast cell tumors ( see Patnaikís grading systemref. 4: the system was characterized as having prognostic significance). Grade I lesions would correspond to the common lesions of urticaria pigmentosa in the human. The survival was shortest for the cases with grade III lesions. In our small series, there are cytologic variations from case to case with the most atypical cells (most irregular nuclear outlines) in the systemic variant (Case 4). The changes in Case3 might be characterized as intermediate between the lesions of Case 1, Case 2, and Case 4. In one study, all human mast cell disorders that were investigated also expressed KITref. 1.
1. Arber D, Tamayo R, Weiss L: Paraffin section detection of the c-kit gene product (CD117) in human tissues: value in the diagnosis of mast cell disorders. Hum Pathol 1998;29:498-504.
2. Kettelhut BV, Metcalfe DD: Pediatric mastocytosis. J Invest Dermatol 1991;96:155
3. Klaus SN, Winkleman RK: Course of urticaria pigmentosa in children. Arch Dermatol 1962;86:116-119.
4. Patnaik AK, Ehler WJ, MacEwen Eg: Canine cutaneous mast cell tumor: morphologic grading and survival time in 83 dogs. Vet Pathol 1984;21:469-74.
5. Reguera MJ, Rabanal Rm, Puigdemont A, Ferrer L: Canine mast cell tumors express stem cell factor receptor. Am J Dermatopathol 2000;22:49-54.
6. Rywlin AM: Histopathology of the Bone Marrow. Little, Brown & Co., Boston, pp 174-76, 1976.
7. Soter N: The skin in mastocytosis. J Invest Dermatol 1991;96:325
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