REVIEW ARTICLE
Multinucleate Cell Angiohistiocytoma: Clinicopathological Correlation of 142 Cases With Insights Into Etiology and Pathogenesis John W. Frew, MBBS (Hons), MMed
Introduction: Multinucleate cell angiohistiocytoma (MCAH) is a peculiar dermatopathological entity described as asymptomatic grouped red-to-violaceous papules, developing over weeks to months without spontaneous regression. The histopathological findings comprise bizarre basophilic multinucleated cells (MC), small vessel inflammation, mild dermal fibrosis, and a sparse lymphohistiocytic infiltrate.
Aims and Methods: This study aimed to collate and analyze the clinical, histological, and immunohistochemical characteristics of all reported cases of MCAH from the international literature, and the presence or absence of concurrent chronic inflammatory or neoplastic phenomena to investigate any potential clinicopathological correlations, which may hint at the underlying pathophysiology of this condition. A systematic review of the literature was undertaken with information collected by a predeveloped pro forma. New case reports were also sourced from patient records at the Skin and Cancer Foundation Australia Database. Results: A total of 142 cases of MCAH were collated, including 8 new case reports. The average age of onset was 50.1 years, with 79% of all individuals being female. The most commonly affected areas were the hands (30%) and face (29%). Univariate analysis revealed a positive association between lesion size and MC staining for CD68 (R = 0.488; P = 0.004), and an inverse relationship between size and endothelial staining for CD34 (R = 20.530; P = 0.012). Multiple lesions were significantly associated with an inverse relationship to MC staining of CD68 (R = 20.519; P = 0.002). Moderate correlations were seen between specific sites of vascularity and sites in which MCs were identified (R = 0.734–0.741; P , 0.001), and dermal fibrosis was associated with an increased number of MCs (R = 0.522; P = 0.002) and decreased multinucleate cell immunohistochemical staining (R = 20.655; P = 0.003). An association was found between patients with chronic inflammatory conditions and endothelial staining for CD68 (R = 0.671; P = 0.012), and an inverse relationship with MC staining for factor XIIIa (20.481; P , 0.001). No statistically significant relationships between neoplasia and MCAH were found.
From the Dermatology Services, Skin and Cancer Foundation, University of New South Wales, Sydney, Australia. The author declares no conflicts of interest. Reprints: John W. Frew, MBBS (Hons), MMed, Dermatology Registrar, Skin and Cancer Foundation, 121 Crown St, Darlinghurst, New South Wales, Sydney, 2010, Australia (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Discussion and Conclusions: From the data examined, we hypothesize that although this condition may be inflammatory and vascular in initial origin, fibrosis and atrophy play a vital role in the pathogenesis, particularly regarding the progression to multiple lesions. A detailed hypothesis is described that may be amenable to more detailed investigations. Limitations in this study include the heterogeneity of results analyzed across case reports; however, our conclusions match those developed through the analysis of our case series. These hypotheses and proposals provide an experimental basis for further research into the pathogenesis and mechanisms underlying MCAH. Key Words: multinucleate cell angiohistiocytoma, dermatofibroma, systematic review, angiofibroma, Kaposi sarcoma, diagnosis, etiology, pathogenesis (Am J Dermatopathol 2015;37:222–228)
BACKGROUND Multinucleate cell angiohistiocytoma (MCAH) is a peculiar dermatopathological entity first identified by Smith and Wilson Jones in 1985.1 It was initially described as asymptomatic grouped red-to-violaceous papules, developing over weeks to months without spontaneous regression. The histopathological findings are described as unique, comprising bizarre basophilic multinucleated cells (MC), small vessel inflammation, mild dermal fibrosis, and a sparse lymphohistiocytic infiltrate.1,2 Since the initial cases in 1985, a total of 134 cases have been reported in the international literature until October 2012. Many of these cases show significant variation from the initial description of MCAH and include isolated papules on a wide variety of body surfaces, coexisting epidermal proliferation or atrophy, extensive fibrosis, and angiomatous changes. The main defining histological findings in MCAH have overlapped with many other fibromatous and angiomatous conditions, with the bizarre MC giving rise to this condition’s name being also seen in atrophic vascular histocytoma,3 fibrous papule of the nose,2 and other benign conditions questioning its status as an independent histopathological entity. Contention surrounds suggestions that MCAH is a reactive process to chronic inflammatory stimuli, with estrogen receptors (ERs) suggesting an explanation of its female preponderance.4 Zegler et al5 suggest that MCAH may lie within the spectrum of dermatofibromas because of the common histopathological overlaps with a number of other Am J Dermatopathol Volume 37, Number 3, March 2015
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entities; however, Cesarino et al4 refute this suggestion, stating that estrogen plays a crucial role in reactive vascularity that clearly distinguishes MCAH from dermatofibroma. In an effort to simplify the confusing nomenclature associated with such conditions, cytology and cytometry are proving useful classification tools.5 However, definitive classification has remained elusive in MCAH with conflicting results across different studies.2–4 Current consensus is that MCs are thought to represent degenerate fibroblasts. Opinion persists that it is a unique histopathological entity, despite the conclusion that it is likely a reactive process.2–4 To date, no systematic review of the MCAH literature has been undertaken to evaluate the breadth of clinical and histological manifestations of this condition and to assess the evidence whether this condition is likely to fall within the spectrum of dermatofibroma or is a unique histopathological entity. Revisiting the spectrum of presentations this disorder manifests holds great utility in identifying this unique benign entity clinically and histopathologically from other more concerning differential diagnoses including Kaposi sarcoma, sarcoidosis, lupus erythematosus, and granuloma annulare.6 We also present 8 additional cases of histologically confirmed MCAH to add to the spectrum of clinical and histological presentations of this rare condition.
AIMS FIGURE 1. Summary of search strategy.
1. To collate and analyze the clinical, histological, and immunohistochemical (IHC) characteristics of MCAH from all case reports in the international literature to explore the breadth of clinical presentations and histological manifestations of MCAH. 2. To explore any potential clinicopathological correlations, which may hint at the underlying pathophysiology of MCAH through univariate statistical analysis. 3. To compare the clinical, histological, and IHC characteristics of MCAH with coexisting inflammatory or neoplastic phenomena to quantify evidence pertaining to the hypothesis that MCAH is a reactive phenomenon and/or variant of preexisting phenomena such as dermatofibroma.
METHODS The methodology used in literature search is illustrated in Figure 1. Inclusion criteria were used to establish a consistent diagnostic definition for MCAH. These criteria were based on widely accepted histopathological descriptions7 that include (1) increased numbers of ecstatic or narrow vessels in the upper and mid dermis, (2) presence of multinucleated giant cells, and (3) scattered fibrohistiocytic cells between dermal collagen bundles. Because of the variation in antibodies and procedures in IHC staining in various case reports, our diagnostic definition did not include the IHC staining outcomes. A retrospective search of all patients presenting to the Skin and Cancer Foundation Darlinghurst between 2009 and 2012 yielded 8 cases of histologically confirmed MCAH. All Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
8 cases complied with the above established inclusion criteria. All patients were included, and demographic and histological details are presented in Table 1. Literature search involved systematic search of the MEDLINE, OvidSP, and EMBASE databases from 1985 to October 2012. Key words and search terms included “multinucleate cell angiohistiocytoma” and “MCAH.” One hundred two results were identified in the literature, and all articles were read fully. Five articles were duplicate entries. Twentyone of the remaining 97 articles were review articles describing cases published elsewhere, and hence excluded to avoid duplication of cases. The remaining 76 articles contained a total of 134 cases of MCAH. A detailed pro forma was used to collect clinical, histological, and IHC data on each case. Demographic information including age, sex, length of time with disease present before presentation, age at first onset, site of lesions, and histological descriptions of the epidermis, dermis, fibrotic changes, vascular changes, and site of MC were gathered. Reported IHC characteristics were also noted and included positive or negative staining for factor VIII, factor XIIIa, CD31, CD34, CD68, and vimentin staining of both vascular endothelia and MCs. Descriptions of histological changes were based on in-text descriptions in the published articles, and IHC markers were reported as either positive or negative.
Statistical Analysis All statistical analyses were undertaken with SPSS v20.0 (IBM). Descriptive items were converted to categorical www.amjdermatopathology.com |
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TABLE 1. Clinicopathological Details of Presented Cases
Case
Age, years
Size, mm
Gender Site
1
35
F
Nose
3
2 3 4
57 50 45
M M M
Face Back Arms
3 6 4
5
39
M
Arms
4
6 7 8
50 23 77
F F F
Hands Nose Hand
3 3 5
Epidermal Changes
Dermal Changes
Associated Conditions
Moderate fibrosis and vascularity Normal Mild vascularity Normal Moderate vascularity Hyperkeratotic Moderate fibrosis and spindle cells Hyperkeratotic Moderate fibrosis and vascularity Hyperkeratotic Mild vascularity Normal Mild vascularity Normal Moderate vascularity Acanthotic
Immunohistochemistry Endothelial Immunohistochemistry Cells MCs CD31
CD34
CD68
CD68
Factor XIIIa
None
+
+
2
2
2
None None None
+ + +
+ 2 +
+ 2 2
+ + 2
2 2 2
Actinic keratosis Dermatitis None None
+
+
2
+
+
+ + +
+ + +
+ + 2
2 + +
2 + +
F, Female; M, Male; NR, not reported; (+), positive; (2), negative.
variables to facilitate statistical comparison with continuous and binary variables. Descriptive statistical analyses were initially performed, and subsequent univariate correlation matrices measuring Spearman correlation coefficients were made to investigate relationships between the variables. Cases in which certain variables were recorded as “not reported” were excluded on a case-wise basis. Comparisons between continuous variables were made using Spearman correlation coefficients, and binary variables were compared using the x2 test. All statistically significant univariate correlations (defined as 20.5 , R . 0.5 with P , 0.05) were flagged for examination of clinical significance.
RESULTS Case Reports Searching the Skin and Cancer Foundation database, 8 new cases of MCAH were identified. The details of these cases are presented in Table 1. All cases involved single lesions that in 7 or 8 cases were treated definitively with excisional biopsy. The remaining case (case 7) was definitively treated after biopsy with intense pulsed light. Intense pulsed light and laser therapies for MCAH have been previously reported.8,9
results from all patients is presented in Figure 3. The most common epidermal pathology described was that of acanthosis (23.5%), with almost half of all cases reporting generalized, full-thickness dermal vascularity (43.7%) and one-third of the cases reporting generalized, full-thickness dermal fibrosis (38.7%). IHC studies demonstrated 60% of vascular endothelial cells stained for CD68, normally a macrophage or histiocytic marker. As expected, endothelial cells also expressed staining to factor VIII, CD31, and CD34. MCs expressed negative staining to endothelial markers factor VIII and CD34, with roughly half of all cases staining positive to macrophage/histiocytic markers factor XIIIa and CD68. Regarding the association with chronic inflammation or neoplastic processes, 10 cases were associated with concurrent neoplasia, with 48 cases specifically denying any incidence of neoplasia and 84 cases being unreported. Thirty cases had an associated inflammatory condition, with 45 cases denying any inflammatory diseases and 67 cases remaining unreported.
Univariate Correlation Analysis
Of the 142 cases analyzed, the average age of individuals with MCAH was 55 years, with 79% of all individuals being female. The average age of onset was 50.1 years with the average length of time until diagnosis being 4.2 years. The majority of individuals (73.9%) was afflicted with more than 1 lesion with the average size of lesions being 9.5 mm in diameter. The most commonly affected area was the hand (30%), followed by the face (29%), leg (20%), and abdomen (10%). Two cases demonstrated a generalized eruption, and only 1 case involved mucosal surfaces. Representative histology taken from case 1 is presented in Figure 2. A summary table of the descriptive histological and immunochemical
A table of significant univariate correlations is presented in Table 2. Univariate analysis revealed a positive association between the lesion size and the MC staining for CD68 (R = 0.488; P = 0.004), implying that increase in macrophage or histiocytic activity may be a driver in the growth of these lesions. The presence of multiple lesions was inversely associated with the MC staining of CD68 (R = 20.519; P = 0.002). No significant associations were found between age or gender and other variables. Regarding the histological outcomes, a normal epidermis was positively associated MC staining for CD68 (R = 0.645; P , 0.001). Site-specific dermal vascularity (upper dermis, mid dermis, etc) was positively associated with the presence of MCs at those specific sites (R = 0.734–0.741; P , 0.001). Moderate dermal fibrosis was associated with the presence of MCs (R = 0.564; P = 0.002) and inversely proportional to positive MC staining for CD68 (R = 20.522; P = 0.002). The presence of fibrosis (not otherwise specified)
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Descriptive Analysis
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Multinucleate Cell Angiohistiocytoma
FIGURE 2. Histological presentation of multinucleate cell angiohistiocytoma. Lesion biopsy from case 1 showing low power magnification of the lesion (·1) (A), dilated dermal vasculature and dense collagen in the upper dermis (·4) (B), and a large MC with the surrounding fibrosis, fibrohistiocytic cells, and dilated vasculature (·20) (C).
was found to correlate with positive endothelial staining for CD68 (R = 0.612; P = 0.008). Regarding the association with chronic inflammation or neoplasms, a positive association was found between patients with chronic inflammatory conditions and endothelial staining for CD68 (R = 0.671; P = 0.012), perhaps reflecting a high circulating number of monocytes and macrophages (which may be unrelated to MCAH), and an inverse relationship between chronic inflammation and MC staining for factor XIIIa (R = 20.481; P , 0.001). No significant relationships were found between the presence or absence of neoplasia and other analyzed variables.
DISCUSSION The results of our compiled data agree with the conclusions of previous reports that MCAH is a condition Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
with a propensity to middle-aged women and is commonly distributed on the extremeties.6 As this was a retrospective study, we were unable to accurately assess the rate of spontaneous regression in this condition, although some case reports have noted such occurences.10 A prospective follow-up study would be required to definitely determine the rate of spontaneous regression. The staining patterns in MCs are consistent with the suggestions by Sass et al11 that these cells are of a fibrohistiocytic origin, although our IHC staining results do not exclude MCs being of macrophage origin. There were no additional reports of ER/vascular endothelial growth factor or human herpes virus type 8 staining beside those included in the 2 original articles by Cesarino et al4 and Sass et al,11 respectively. As it stands currently, no association has been found between the human herpes virus type 8 infection and MCAH. ER-alpha positivity in MCAH suggests an www.amjdermatopathology.com |
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FIGURE 3. Summary of histological and IHC details of 142 MCAH cases.
explanation for its association with women and a possible mechanism for the vascular nature of lesions, questioning whether vascularity is the primary driver of this condition.4 The presence of chronic inflammatory conditions does correlate with IHC staining patterns, specifically positive CD68 staining in endothelial cells, which may represent intravascular and migrating monocytes or macrophages. There was no suggestion of the size or number of lesions correlating with the length of time with the disease, implying a varied natural course of the condition. The caveat that correlation (or the lack thereof) does not imply causation should be noted. The authors acknowledge that as a retrospective compilation of patient details (including published articles), there was no guarantee as to the standard of information provided in case reports. This review is therefore open to significant publication bias. We have attempted to standardize histological diagnosis through the use of diagnostic inclusion criteria in this study (to which all 142 cases met the aforementioned criteria), and through the stratification of the degree of fibrosis and vascularity based on the wording provided in the case reports examined. With regard to the IHC stains, a large amount of variation was noted between techniques and antibodies used for IHC stains between case reports; however, our 8 cases all used the same IHC stains and antibodies, performed in the same laboratory using identical techniques by the same staff. To verify our conclusions made from the histopathological and IHC analyses from examination of all 142 cases,
we examined our subset of 8 cases and were able to demonstrate the same general correlations, validating our broader conclusions despite the disparity in IHC antibodies and laboratory techniques across all 142 case reports. It is noted, however, that the reliability of such correlations is reduced because of the small size of the patient cohort with completed IHC staining and the variations between antibodies, techniques, and investigators reporting such results across the 142 reported cases. As a very rare condition, compiling a significant number of cases in a single institution is a considerable challenge and a review of published cases is the most effective method in ensuring a large patient sample to analyze data in this poorly understood condition. The results we have presented include a positive correlation between IHC staining for CD68 on endothelial cells and lesion size, and an inverse correlation between positive IHC staining for CD68 on MCs and the development of multiple lesions. We have also established correlation between site-specific dermal vascularity, the development of MCs, and site-specific fibrosis, as well as demonstrating a connection between increasing dermal fibrosis and negative CD68 MC staining. A hypothesis we propose regarding the mechanism of action behind MCAH is as follows: CD68 staining in endothelial cells and lesion size may possibly be related to an active inflammatory response with circulating and migrating macrophages associated with increased dermal vascularity. It is unclear whether this
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Multinucleate Cell Angiohistiocytoma
TABLE 2. Statistically Significant Univariate Correlations Across 142 MCAH Cases Primary Variable Female gender Lesion size Lesion size Multiple lesions Site of lesion(s): buccal mucosa Site of lesion(s): leg Site of lesion(s): arm Epidermal acanthosis Epidermal acanthosis Epidermal acanthosis Normal epidermis Hypertrophic epidermis Mid-dermal vascularity Mid-dermal vascularity Dermal vascularity Dermal vascularity Reticular dermal vascularity Superficial and mid vascularity Reticular dermal vascularity Dermal fibrosis Moderate dermal fibrosis Moderate dermal fibrosis Normal dermal fibrosis Normal dermal fibrosis Mild dermal fibrosis Mid dermal MCs MC staining positive for factor VIII Endothelial staining positive for vimentin Endothelial staining positive for factor VIII Endothelial staining positive for CD34 Dermal MCs Chronic inflammatory condition Chronic inflammatory condition
Correlating Variable
Correlation Coefficient
P
Endothelial staining positive for CD 34 Endothelial staining positive for CD 34 Endothelial staining positive for CD 68 MC staining positive for CD68 Endothelial staining positive for CD 34 Endothelial staining positive for CD31 Endothelial staining positive for CD34 MC staining positive for factor VIII Moderate dermal fibrosis MC staining positive for vimentin MC staining positive for CD68 The presence of perivascular MCs Endothelial staining positive for vimentin MC staining positive for factor VIII Endothelial staining positive for vimentin MC staining positive for factor XIIIa MC staining positive for factor VIII Presence of superficial and mid dermal MCs The presence of reticular dermis MCs MCs staining positive for CD68 MCs staining positive for factor VIII Endothelial staining positive for vimentin Endothelial staining positive for CD68 Endothelial staining positive for vimentin Endothelial staining positive for CD31 Moderate dermal fibrosis MCs staining positive for CD34 MCs staining positive for factor VIII MCs staining positive for CD68 Endothelial staining positive for vimentin MCs staining positive for CD68 MCs staining positive for factor XIIIa Endothelial staining positive for CD68
20.62 20.53 0.488 20.519 0.542 0.667 0.542 20.802 0.457 0.537 0.645 0.538 20.856 20.631 0.667 0.503 0.563 0.734 0.741 20.522 20.802 0.655 0.612 20.715 0.612 0.564 1.000 20.650 20.632 21.000 20.645 20.481 0.671
0.003 0.012 0.004 0.002 0.01 0.018 0.01 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.002 ,0.001 0.003 0.008 ,0.001 0.03 ,0.001 ,0.001 0.004 0.034 ,0.001 ,0.001 0.001 0.012
vascularity may be secondary to a systemic or chronic inflammatory stimulus. The development of MCs and dermal fibrosis follow the migration of CD68 positive cells from the intravascular space, with CD68 positive fibrohistiocytic cells remaining present in the area of, or adjacent to, the MCs. Epidermal changes would also be present at this stage. The natural history of the disease would then progress to an advanced stage with a reduction in CD68 positive cell activity and multiple lesions. The development of multiple lesions may be intertwined with cellular atrophy or dermal sclerotic changes. Atrophy and sclerosis have been associated with the loss of factor XIIIa IHC staining in dermatofibrosis,5 and a similar mechanism may possibly be at play in MCAH with the surrounding dermal and vascular changes precipitating further lesion development, possibly with hormonal receptor interplay. These observations and suggested mechanisms conform to the suggestion by previous authors that MCAH may be a reactive phenomenon.5,12 The role of ER-alpha and vascular endothelial growth factor as reported by Cesarino et al4 is still Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
uncertain at this point, and as suggested, it may an underlying inflammatory stimulus that precipitates the initial vascular changes. All these points are consistent with the Zegler et al5 interpretation of MCAH as a primarily fibrotic process, and also integrate the current general consensus of MCAH having a primarily vascular etiology.
CONCLUSIONS Statistical analysis of 142 cases of MCAH suggests that the pathogenesis of this condition is complex and may involve multiple mediators. From the data examined, we hypothesize that although this condition may be inflammatory and vascular in the initial origin, fibrosis and cellular atrophy play a vital role in understanding the pathogenesis, particularly regarding the progression to multiple lesions. Limitations in this study include the heterogeneity of results analyzed across case reports; however, our conclusions match those developed through a small subset of case reports analyzed by our team. These hypotheses and proposals www.amjdermatopathology.com |
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provide an experimental basis for further research into the pathogenesis and mechanisms underlying MCAH. REFERENCES 1. Smith NP, Wilson Jones E. Multinucleate cell angiohistiocytoma: a new entity. Br J Dermatol. 1985;113:15. 2. Smolle J, Auboeck I, Gogg-Retzer I, et al. Multinucleate cell angiohistiocytoma: a clinicopathological, immunohistochemical and ultrastructural study. Br J Dermatol. 1989;121:113–121. 3. Annessi G, Girolomoni G, Gianetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol. 1992;14:340–344. 4. Cesarino AM, Roncati L, Maiorana A. Estrogen receptor alpha overexpression in multinucleate cell angiohistocytoma: new insights into the pathogenesis of a reactive process. Am J Dermatopathol. 2010;32: 655–659. 5. Zegler B, Zegler BG, Burgdorf WHC. Dermatofibroma—a critical evaluation. Int J Surg Pathol. 2004;12:333–344.
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6. Wilson-Jones E, Cerio R, Smith NP. Multinucleate cell angiohistiocytoma: an acquired vascular anomaly to be distinguished from Kaposi sarcoma. Br J Dermatol. 1990;122:651–663. 7. Weedon D. Weedon’s Skin Pathology. 3rd ed. London, United Kingdom: Churchill Livingstone; 2010. 8. Fernandez-Jorge B, Del Pozo J, Garcia-Silva J, et al. Multinucleate cell angiohistiocytoma: treatment using intense pulsed light. Dermatol Surg. 2009;35:1141–1143. 9. Kopera D, Smolle J, Kerl H. Multiucleate cell Angiohistiocytom: Treatment with Argon laser. Br J Dermatol. 1995;133:308–310. 10. Cribier B, Gambini C, Rainero M, et al. Multinucleate cell angiohistiocytoma. Acta Derm Venereol. 1995;75:337–339. 11. Sass U, Jean-Christophe N, Josette A, et al. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of HHV-8 infection. J Cutan Pathol. 2000;27:258–261. 12. Requenca L, Sangueza OP. Cutaneous vascular proliferation. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38:143–175.
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Multinucleate Cell Angiohistiocytoma: Clinicopathological Correlation of 142 Cases With Insights Into Etiology and Pathogenesis John W. Frew, MBBS (Hons), MMed
Introduction: Multinucleate cell angiohistiocytoma (MCAH) is a peculiar dermatopathological entity described as asymptomatic grouped red-to-violaceous papules, developing over weeks to months without spontaneous regression. The histopathological findings comprise bizarre basophilic multinucleated cells (MC), small vessel inflammation, mild dermal fibrosis, and a sparse lymphohistiocytic infiltrate.
Aims and Methods: This study aimed to collate and analyze the clinical, histological, and immunohistochemical characteristics of all reported cases of MCAH from the international literature, and the presence or absence of concurrent chronic inflammatory or neoplastic phenomena to investigate any potential clinicopathological correlations, which may hint at the underlying pathophysiology of this condition. A systematic review of the literature was undertaken with information collected by a predeveloped pro forma. New case reports were also sourced from patient records at the Skin and Cancer Foundation Australia Database. Results: A total of 142 cases of MCAH were collated, including 8 new case reports. The average age of onset was 50.1 years, with 79% of all individuals being female. The most commonly affected areas were the hands (30%) and face (29%). Univariate analysis revealed a positive association between lesion size and MC staining for CD68 (R = 0.488; P = 0.004), and an inverse relationship between size and endothelial staining for CD34 (R = 20.530; P = 0.012). Multiple lesions were significantly associated with an inverse relationship to MC staining of CD68 (R = 20.519; P = 0.002). Moderate correlations were seen between specific sites of vascularity and sites in which MCs were identified (R = 0.734–0.741; P , 0.001), and dermal fibrosis was associated with an increased number of MCs (R = 0.522; P = 0.002) and decreased multinucleate cell immunohistochemical staining (R = 20.655; P = 0.003). An association was found between patients with chronic inflammatory conditions and endothelial staining for CD68 (R = 0.671; P = 0.012), and an inverse relationship with MC staining for factor XIIIa (20.481; P , 0.001). No statistically significant relationships between neoplasia and MCAH were found.
From the Dermatology Services, Skin and Cancer Foundation, University of New South Wales, Sydney, Australia. The author declares no conflicts of interest. Reprints: John W. Frew, MBBS (Hons), MMed, Dermatology Registrar, Skin and Cancer Foundation, 121 Crown St, Darlinghurst, New South Wales, Sydney, 2010, Australia (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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Discussion and Conclusions: From the data examined, we hypothesize that although this condition may be inflammatory and vascular in initial origin, fibrosis and atrophy play a vital role in the pathogenesis, particularly regarding the progression to multiple lesions. A detailed hypothesis is described that may be amenable to more detailed investigations. Limitations in this study include the heterogeneity of results analyzed across case reports; however, our conclusions match those developed through the analysis of our case series. These hypotheses and proposals provide an experimental basis for further research into the pathogenesis and mechanisms underlying MCAH. Key Words: multinucleate cell angiohistiocytoma, dermatofibroma, systematic review, angiofibroma, Kaposi sarcoma, diagnosis, etiology, pathogenesis (Am J Dermatopathol 2015;37:222–228)
BACKGROUND Multinucleate cell angiohistiocytoma (MCAH) is a peculiar dermatopathological entity first identified by Smith and Wilson Jones in 1985.1 It was initially described as asymptomatic grouped red-to-violaceous papules, developing over weeks to months without spontaneous regression. The histopathological findings are described as unique, comprising bizarre basophilic multinucleated cells (MC), small vessel inflammation, mild dermal fibrosis, and a sparse lymphohistiocytic infiltrate.1,2 Since the initial cases in 1985, a total of 134 cases have been reported in the international literature until October 2012. Many of these cases show significant variation from the initial description of MCAH and include isolated papules on a wide variety of body surfaces, coexisting epidermal proliferation or atrophy, extensive fibrosis, and angiomatous changes. The main defining histological findings in MCAH have overlapped with many other fibromatous and angiomatous conditions, with the bizarre MC giving rise to this condition’s name being also seen in atrophic vascular histocytoma,3 fibrous papule of the nose,2 and other benign conditions questioning its status as an independent histopathological entity. Contention surrounds suggestions that MCAH is a reactive process to chronic inflammatory stimuli, with estrogen receptors (ERs) suggesting an explanation of its female preponderance.4 Zegler et al5 suggest that MCAH may lie within the spectrum of dermatofibromas because of the common histopathological overlaps with a number of other Am J Dermatopathol Volume 37, Number 3, March 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
Multinucleate Cell Angiohistiocytoma
entities; however, Cesarino et al4 refute this suggestion, stating that estrogen plays a crucial role in reactive vascularity that clearly distinguishes MCAH from dermatofibroma. In an effort to simplify the confusing nomenclature associated with such conditions, cytology and cytometry are proving useful classification tools.5 However, definitive classification has remained elusive in MCAH with conflicting results across different studies.2–4 Current consensus is that MCs are thought to represent degenerate fibroblasts. Opinion persists that it is a unique histopathological entity, despite the conclusion that it is likely a reactive process.2–4 To date, no systematic review of the MCAH literature has been undertaken to evaluate the breadth of clinical and histological manifestations of this condition and to assess the evidence whether this condition is likely to fall within the spectrum of dermatofibroma or is a unique histopathological entity. Revisiting the spectrum of presentations this disorder manifests holds great utility in identifying this unique benign entity clinically and histopathologically from other more concerning differential diagnoses including Kaposi sarcoma, sarcoidosis, lupus erythematosus, and granuloma annulare.6 We also present 8 additional cases of histologically confirmed MCAH to add to the spectrum of clinical and histological presentations of this rare condition.
AIMS FIGURE 1. Summary of search strategy.
1. To collate and analyze the clinical, histological, and immunohistochemical (IHC) characteristics of MCAH from all case reports in the international literature to explore the breadth of clinical presentations and histological manifestations of MCAH. 2. To explore any potential clinicopathological correlations, which may hint at the underlying pathophysiology of MCAH through univariate statistical analysis. 3. To compare the clinical, histological, and IHC characteristics of MCAH with coexisting inflammatory or neoplastic phenomena to quantify evidence pertaining to the hypothesis that MCAH is a reactive phenomenon and/or variant of preexisting phenomena such as dermatofibroma.
METHODS The methodology used in literature search is illustrated in Figure 1. Inclusion criteria were used to establish a consistent diagnostic definition for MCAH. These criteria were based on widely accepted histopathological descriptions7 that include (1) increased numbers of ecstatic or narrow vessels in the upper and mid dermis, (2) presence of multinucleated giant cells, and (3) scattered fibrohistiocytic cells between dermal collagen bundles. Because of the variation in antibodies and procedures in IHC staining in various case reports, our diagnostic definition did not include the IHC staining outcomes. A retrospective search of all patients presenting to the Skin and Cancer Foundation Darlinghurst between 2009 and 2012 yielded 8 cases of histologically confirmed MCAH. All Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
8 cases complied with the above established inclusion criteria. All patients were included, and demographic and histological details are presented in Table 1. Literature search involved systematic search of the MEDLINE, OvidSP, and EMBASE databases from 1985 to October 2012. Key words and search terms included “multinucleate cell angiohistiocytoma” and “MCAH.” One hundred two results were identified in the literature, and all articles were read fully. Five articles were duplicate entries. Twentyone of the remaining 97 articles were review articles describing cases published elsewhere, and hence excluded to avoid duplication of cases. The remaining 76 articles contained a total of 134 cases of MCAH. A detailed pro forma was used to collect clinical, histological, and IHC data on each case. Demographic information including age, sex, length of time with disease present before presentation, age at first onset, site of lesions, and histological descriptions of the epidermis, dermis, fibrotic changes, vascular changes, and site of MC were gathered. Reported IHC characteristics were also noted and included positive or negative staining for factor VIII, factor XIIIa, CD31, CD34, CD68, and vimentin staining of both vascular endothelia and MCs. Descriptions of histological changes were based on in-text descriptions in the published articles, and IHC markers were reported as either positive or negative.
Statistical Analysis All statistical analyses were undertaken with SPSS v20.0 (IBM). Descriptive items were converted to categorical www.amjdermatopathology.com |
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TABLE 1. Clinicopathological Details of Presented Cases
Case
Age, years
Size, mm
Gender Site
1
35
F
Nose
3
2 3 4
57 50 45
M M M
Face Back Arms
3 6 4
5
39
M
Arms
4
6 7 8
50 23 77
F F F
Hands Nose Hand
3 3 5
Epidermal Changes
Dermal Changes
Associated Conditions
Moderate fibrosis and vascularity Normal Mild vascularity Normal Moderate vascularity Hyperkeratotic Moderate fibrosis and spindle cells Hyperkeratotic Moderate fibrosis and vascularity Hyperkeratotic Mild vascularity Normal Mild vascularity Normal Moderate vascularity Acanthotic
Immunohistochemistry Endothelial Immunohistochemistry Cells MCs CD31
CD34
CD68
CD68
Factor XIIIa
None
+
+
2
2
2
None None None
+ + +
+ 2 +
+ 2 2
+ + 2
2 2 2
Actinic keratosis Dermatitis None None
+
+
2
+
+
+ + +
+ + +
+ + 2
2 + +
2 + +
F, Female; M, Male; NR, not reported; (+), positive; (2), negative.
variables to facilitate statistical comparison with continuous and binary variables. Descriptive statistical analyses were initially performed, and subsequent univariate correlation matrices measuring Spearman correlation coefficients were made to investigate relationships between the variables. Cases in which certain variables were recorded as “not reported” were excluded on a case-wise basis. Comparisons between continuous variables were made using Spearman correlation coefficients, and binary variables were compared using the x2 test. All statistically significant univariate correlations (defined as 20.5 , R . 0.5 with P , 0.05) were flagged for examination of clinical significance.
RESULTS Case Reports Searching the Skin and Cancer Foundation database, 8 new cases of MCAH were identified. The details of these cases are presented in Table 1. All cases involved single lesions that in 7 or 8 cases were treated definitively with excisional biopsy. The remaining case (case 7) was definitively treated after biopsy with intense pulsed light. Intense pulsed light and laser therapies for MCAH have been previously reported.8,9
results from all patients is presented in Figure 3. The most common epidermal pathology described was that of acanthosis (23.5%), with almost half of all cases reporting generalized, full-thickness dermal vascularity (43.7%) and one-third of the cases reporting generalized, full-thickness dermal fibrosis (38.7%). IHC studies demonstrated 60% of vascular endothelial cells stained for CD68, normally a macrophage or histiocytic marker. As expected, endothelial cells also expressed staining to factor VIII, CD31, and CD34. MCs expressed negative staining to endothelial markers factor VIII and CD34, with roughly half of all cases staining positive to macrophage/histiocytic markers factor XIIIa and CD68. Regarding the association with chronic inflammation or neoplastic processes, 10 cases were associated with concurrent neoplasia, with 48 cases specifically denying any incidence of neoplasia and 84 cases being unreported. Thirty cases had an associated inflammatory condition, with 45 cases denying any inflammatory diseases and 67 cases remaining unreported.
Univariate Correlation Analysis
Of the 142 cases analyzed, the average age of individuals with MCAH was 55 years, with 79% of all individuals being female. The average age of onset was 50.1 years with the average length of time until diagnosis being 4.2 years. The majority of individuals (73.9%) was afflicted with more than 1 lesion with the average size of lesions being 9.5 mm in diameter. The most commonly affected area was the hand (30%), followed by the face (29%), leg (20%), and abdomen (10%). Two cases demonstrated a generalized eruption, and only 1 case involved mucosal surfaces. Representative histology taken from case 1 is presented in Figure 2. A summary table of the descriptive histological and immunochemical
A table of significant univariate correlations is presented in Table 2. Univariate analysis revealed a positive association between the lesion size and the MC staining for CD68 (R = 0.488; P = 0.004), implying that increase in macrophage or histiocytic activity may be a driver in the growth of these lesions. The presence of multiple lesions was inversely associated with the MC staining of CD68 (R = 20.519; P = 0.002). No significant associations were found between age or gender and other variables. Regarding the histological outcomes, a normal epidermis was positively associated MC staining for CD68 (R = 0.645; P , 0.001). Site-specific dermal vascularity (upper dermis, mid dermis, etc) was positively associated with the presence of MCs at those specific sites (R = 0.734–0.741; P , 0.001). Moderate dermal fibrosis was associated with the presence of MCs (R = 0.564; P = 0.002) and inversely proportional to positive MC staining for CD68 (R = 20.522; P = 0.002). The presence of fibrosis (not otherwise specified)
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Descriptive Analysis
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Multinucleate Cell Angiohistiocytoma
FIGURE 2. Histological presentation of multinucleate cell angiohistiocytoma. Lesion biopsy from case 1 showing low power magnification of the lesion (·1) (A), dilated dermal vasculature and dense collagen in the upper dermis (·4) (B), and a large MC with the surrounding fibrosis, fibrohistiocytic cells, and dilated vasculature (·20) (C).
was found to correlate with positive endothelial staining for CD68 (R = 0.612; P = 0.008). Regarding the association with chronic inflammation or neoplasms, a positive association was found between patients with chronic inflammatory conditions and endothelial staining for CD68 (R = 0.671; P = 0.012), perhaps reflecting a high circulating number of monocytes and macrophages (which may be unrelated to MCAH), and an inverse relationship between chronic inflammation and MC staining for factor XIIIa (R = 20.481; P , 0.001). No significant relationships were found between the presence or absence of neoplasia and other analyzed variables.
DISCUSSION The results of our compiled data agree with the conclusions of previous reports that MCAH is a condition Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
with a propensity to middle-aged women and is commonly distributed on the extremeties.6 As this was a retrospective study, we were unable to accurately assess the rate of spontaneous regression in this condition, although some case reports have noted such occurences.10 A prospective follow-up study would be required to definitely determine the rate of spontaneous regression. The staining patterns in MCs are consistent with the suggestions by Sass et al11 that these cells are of a fibrohistiocytic origin, although our IHC staining results do not exclude MCs being of macrophage origin. There were no additional reports of ER/vascular endothelial growth factor or human herpes virus type 8 staining beside those included in the 2 original articles by Cesarino et al4 and Sass et al,11 respectively. As it stands currently, no association has been found between the human herpes virus type 8 infection and MCAH. ER-alpha positivity in MCAH suggests an www.amjdermatopathology.com |
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FIGURE 3. Summary of histological and IHC details of 142 MCAH cases.
explanation for its association with women and a possible mechanism for the vascular nature of lesions, questioning whether vascularity is the primary driver of this condition.4 The presence of chronic inflammatory conditions does correlate with IHC staining patterns, specifically positive CD68 staining in endothelial cells, which may represent intravascular and migrating monocytes or macrophages. There was no suggestion of the size or number of lesions correlating with the length of time with the disease, implying a varied natural course of the condition. The caveat that correlation (or the lack thereof) does not imply causation should be noted. The authors acknowledge that as a retrospective compilation of patient details (including published articles), there was no guarantee as to the standard of information provided in case reports. This review is therefore open to significant publication bias. We have attempted to standardize histological diagnosis through the use of diagnostic inclusion criteria in this study (to which all 142 cases met the aforementioned criteria), and through the stratification of the degree of fibrosis and vascularity based on the wording provided in the case reports examined. With regard to the IHC stains, a large amount of variation was noted between techniques and antibodies used for IHC stains between case reports; however, our 8 cases all used the same IHC stains and antibodies, performed in the same laboratory using identical techniques by the same staff. To verify our conclusions made from the histopathological and IHC analyses from examination of all 142 cases,
we examined our subset of 8 cases and were able to demonstrate the same general correlations, validating our broader conclusions despite the disparity in IHC antibodies and laboratory techniques across all 142 case reports. It is noted, however, that the reliability of such correlations is reduced because of the small size of the patient cohort with completed IHC staining and the variations between antibodies, techniques, and investigators reporting such results across the 142 reported cases. As a very rare condition, compiling a significant number of cases in a single institution is a considerable challenge and a review of published cases is the most effective method in ensuring a large patient sample to analyze data in this poorly understood condition. The results we have presented include a positive correlation between IHC staining for CD68 on endothelial cells and lesion size, and an inverse correlation between positive IHC staining for CD68 on MCs and the development of multiple lesions. We have also established correlation between site-specific dermal vascularity, the development of MCs, and site-specific fibrosis, as well as demonstrating a connection between increasing dermal fibrosis and negative CD68 MC staining. A hypothesis we propose regarding the mechanism of action behind MCAH is as follows: CD68 staining in endothelial cells and lesion size may possibly be related to an active inflammatory response with circulating and migrating macrophages associated with increased dermal vascularity. It is unclear whether this
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Multinucleate Cell Angiohistiocytoma
TABLE 2. Statistically Significant Univariate Correlations Across 142 MCAH Cases Primary Variable Female gender Lesion size Lesion size Multiple lesions Site of lesion(s): buccal mucosa Site of lesion(s): leg Site of lesion(s): arm Epidermal acanthosis Epidermal acanthosis Epidermal acanthosis Normal epidermis Hypertrophic epidermis Mid-dermal vascularity Mid-dermal vascularity Dermal vascularity Dermal vascularity Reticular dermal vascularity Superficial and mid vascularity Reticular dermal vascularity Dermal fibrosis Moderate dermal fibrosis Moderate dermal fibrosis Normal dermal fibrosis Normal dermal fibrosis Mild dermal fibrosis Mid dermal MCs MC staining positive for factor VIII Endothelial staining positive for vimentin Endothelial staining positive for factor VIII Endothelial staining positive for CD34 Dermal MCs Chronic inflammatory condition Chronic inflammatory condition
Correlating Variable
Correlation Coefficient
P
Endothelial staining positive for CD 34 Endothelial staining positive for CD 34 Endothelial staining positive for CD 68 MC staining positive for CD68 Endothelial staining positive for CD 34 Endothelial staining positive for CD31 Endothelial staining positive for CD34 MC staining positive for factor VIII Moderate dermal fibrosis MC staining positive for vimentin MC staining positive for CD68 The presence of perivascular MCs Endothelial staining positive for vimentin MC staining positive for factor VIII Endothelial staining positive for vimentin MC staining positive for factor XIIIa MC staining positive for factor VIII Presence of superficial and mid dermal MCs The presence of reticular dermis MCs MCs staining positive for CD68 MCs staining positive for factor VIII Endothelial staining positive for vimentin Endothelial staining positive for CD68 Endothelial staining positive for vimentin Endothelial staining positive for CD31 Moderate dermal fibrosis MCs staining positive for CD34 MCs staining positive for factor VIII MCs staining positive for CD68 Endothelial staining positive for vimentin MCs staining positive for CD68 MCs staining positive for factor XIIIa Endothelial staining positive for CD68
20.62 20.53 0.488 20.519 0.542 0.667 0.542 20.802 0.457 0.537 0.645 0.538 20.856 20.631 0.667 0.503 0.563 0.734 0.741 20.522 20.802 0.655 0.612 20.715 0.612 0.564 1.000 20.650 20.632 21.000 20.645 20.481 0.671
0.003 0.012 0.004 0.002 0.01 0.018 0.01 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.002 ,0.001 0.003 0.008 ,0.001 0.03 ,0.001 ,0.001 0.004 0.034 ,0.001 ,0.001 0.001 0.012
vascularity may be secondary to a systemic or chronic inflammatory stimulus. The development of MCs and dermal fibrosis follow the migration of CD68 positive cells from the intravascular space, with CD68 positive fibrohistiocytic cells remaining present in the area of, or adjacent to, the MCs. Epidermal changes would also be present at this stage. The natural history of the disease would then progress to an advanced stage with a reduction in CD68 positive cell activity and multiple lesions. The development of multiple lesions may be intertwined with cellular atrophy or dermal sclerotic changes. Atrophy and sclerosis have been associated with the loss of factor XIIIa IHC staining in dermatofibrosis,5 and a similar mechanism may possibly be at play in MCAH with the surrounding dermal and vascular changes precipitating further lesion development, possibly with hormonal receptor interplay. These observations and suggested mechanisms conform to the suggestion by previous authors that MCAH may be a reactive phenomenon.5,12 The role of ER-alpha and vascular endothelial growth factor as reported by Cesarino et al4 is still Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
uncertain at this point, and as suggested, it may an underlying inflammatory stimulus that precipitates the initial vascular changes. All these points are consistent with the Zegler et al5 interpretation of MCAH as a primarily fibrotic process, and also integrate the current general consensus of MCAH having a primarily vascular etiology.
CONCLUSIONS Statistical analysis of 142 cases of MCAH suggests that the pathogenesis of this condition is complex and may involve multiple mediators. From the data examined, we hypothesize that although this condition may be inflammatory and vascular in the initial origin, fibrosis and cellular atrophy play a vital role in understanding the pathogenesis, particularly regarding the progression to multiple lesions. Limitations in this study include the heterogeneity of results analyzed across case reports; however, our conclusions match those developed through a small subset of case reports analyzed by our team. These hypotheses and proposals www.amjdermatopathology.com |
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provide an experimental basis for further research into the pathogenesis and mechanisms underlying MCAH. REFERENCES 1. Smith NP, Wilson Jones E. Multinucleate cell angiohistiocytoma: a new entity. Br J Dermatol. 1985;113:15. 2. Smolle J, Auboeck I, Gogg-Retzer I, et al. Multinucleate cell angiohistiocytoma: a clinicopathological, immunohistochemical and ultrastructural study. Br J Dermatol. 1989;121:113–121. 3. Annessi G, Girolomoni G, Gianetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol. 1992;14:340–344. 4. Cesarino AM, Roncati L, Maiorana A. Estrogen receptor alpha overexpression in multinucleate cell angiohistocytoma: new insights into the pathogenesis of a reactive process. Am J Dermatopathol. 2010;32: 655–659. 5. Zegler B, Zegler BG, Burgdorf WHC. Dermatofibroma—a critical evaluation. Int J Surg Pathol. 2004;12:333–344.
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6. Wilson-Jones E, Cerio R, Smith NP. Multinucleate cell angiohistiocytoma: an acquired vascular anomaly to be distinguished from Kaposi sarcoma. Br J Dermatol. 1990;122:651–663. 7. Weedon D. Weedon’s Skin Pathology. 3rd ed. London, United Kingdom: Churchill Livingstone; 2010. 8. Fernandez-Jorge B, Del Pozo J, Garcia-Silva J, et al. Multinucleate cell angiohistiocytoma: treatment using intense pulsed light. Dermatol Surg. 2009;35:1141–1143. 9. Kopera D, Smolle J, Kerl H. Multiucleate cell Angiohistiocytom: Treatment with Argon laser. Br J Dermatol. 1995;133:308–310. 10. Cribier B, Gambini C, Rainero M, et al. Multinucleate cell angiohistiocytoma. Acta Derm Venereol. 1995;75:337–339. 11. Sass U, Jean-Christophe N, Josette A, et al. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of HHV-8 infection. J Cutan Pathol. 2000;27:258–261. 12. Requenca L, Sangueza OP. Cutaneous vascular proliferation. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol. 1998;38:143–175.
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