Histopathology 2015, 67, 836–842. DOI: 10.1111/his.12716
Histopathological features of molluscum contagiosum other than molluscum bodies Martin K Ishikawa,1 David P Arps,1 Conroy Chow,2 Thomas L Hocker1 & Douglas R Fullen1,2 1
Department of Pathology, University of Michigan, Ann Arbor, MI, USA, and 2Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
Date of submission 7 March 2015 Accepted for publication 15 April 2015 Published online Article Accepted 17 April 2015
Ishikawa M K, Arps D P, Chow C, Hocker T L, & Fullen D R (2015) Histopathology 67, 836–842. DOI: 10.1111/his.12716
Histopathological features of molluscum contagiosum other than molluscum bodies Aims: Classic histopathological features of molluscum contagiosum (MC) include a crateriform, acanthotic epidermis containing intracytoplasmic molluscum bodies (MBs). In our experience, a subset of cases lack these features on initial haematoxylin and eosin-stained sections. We aimed to describe the histopathological features of MC other than those classically described. Methods and results: Sixty-seven biopsies diagnosed as MC from January 2011 to October 2012 were retrospectively reviewed. Keratinocytes peripheral to the diagnostic cells with MBs had prominent nucleoli (67; 100%), amphophilic cytoplasm (54; 81%), and in many instances clear cytoplasmic vacuolization (38; 57%). Stroma surrounding MC lesions showed
fibroedematous to fibromyxoid changes in many cases (36; 54%), with a subset (13; 19%) showing abundant dermal mucin. In eight of 67 cases (12%), initial sections did not possess MBs or crateriform epidermis of MC. In these cases, initial sections revealed only the epithelial and/or perilesional stromal changes described above. Additional sections contained MBs in all of these cases. Conclusions: Perilesional fibroedematous to fibromyxoid stroma and keratinocyte changes, including prominent nucleoli and amphophilic cytoplasm with clear vacuolization, are common in MC. Recognizing these features may prove helpful in reaching the diagnosis of MC in cases lacking classic histopathological features on initial sections.
Keywords: dermal mucin, fibroedematous stroma, fibromyxoid stroma, molluscum contagiosum, papular mucinosis, viral dermatoses
Introduction Molluscum contagiosum (MC) is a common cutaneous infection caused by the MC virus (MCV), a doublestranded DNA virus that exclusively infects humans. It is included in the Poxviridae family, and is the only member of the Molluscipoxvirus genus.1 Bateman first described the disease in 1817. Later, Henderson and Paterson described the characteristic intracytoplasmic inclusion bodies, and they demonstrated the infectious nature of MC in 1841. The virus is predominantly Address for correspondence: D R Fullen, 1301 Catherine St, M3261 Medical Science I, Ann Arbor, MI 48109-5602, USA. e-mail: [email protected] © 2015 John Wiley & Sons Ltd.
spread by direct skin contact or contaminated fomites, and primarily infects children, sexually active adults, and immunocompromised individuals.2 Typical lesions appear clinically as 2–5-mm flesh coloured, dome-shaped papules with central umbilication that contain a thick, whitish-yellow curd-like material. Lesions may occur in a variety of locations, but most commonly appear on the trunk, extremities, and axillae.3,4 Infection may also occur in the genital area when transmitted by sexual contact.5 The majority of MC cases can be diagnosed clinically. However, some lesions may have an atypical presentation, making clinical diagnosis difficult. In these cases, a biopsy may be required for definitive diagnosis. Clinical factors contributing to an atypical
Molluscum contagiosum
appearance include lesions with variant morphology (giant and pseudocystic MC), inflamed lesions, lesions surrounded by an eczematous reaction (‘molluscum dermatitis’), and MC secondarily involving another lesion. When these clinical factors are present, the rate of correct clinical diagnosis may drop significantly. Patient demographics and lesion location may also make clinical diagnosis challenging. MC occurring in immunocompromised individuals, older patients and patients with lesions on the head and neck may be more difficult to diagnose clinically.6 Atypical MC lesions may clinically mimic other neoplastic and inflammatory disorders, including basal cell carcinoma, keratoacanthoma, adnexal tumours, Darier’s disease, cutaneous cryptococcosis, cutaneous histoplasmosis, eruptive vellus hair cysts, acne vulgaris, histoid leprosy, and xanthomas.3,7–12 On histopathological evaluation, MC classically presents as a lobulated crateriform lesion with acanthotic epidermis containing intracytoplasmic viral inclusions known as molluscum bodies (MBs) or Henderson–Paterson bodies. These homogeneous ground-glass-like inclusions range from basophilic to eosinophilic, and peripherally displace the cell nucleus, resulting in a signet-ring appearance.2,13,14 MC has a tendency to infect follicular epithelium, and viral cores are first demonstrated in the basal layers of the epidermis.15 After inoculation, MCV regulates host cell transcription and replicates within the cytoplasm. As virusladen cells mature, they grow larger and move towards the surface. Eventually, viral particles displace the host cell organelles and nucleus, and infected cells develop the characteristic MBs, which are typically identified three to four layers above the basal cell layer.2 When the classic histopathological features of MC are present, reaching the correct diagnosis is straightforward. However, in our experience, a subset of biopsies of MC lack the classically described histopathological features on initial sections. We sought to characterize the histopathological changes of MC other than the classically described crateriform acanthotic epithelium and MBs, and to determine the frequency with which these features occur. We also attempted to determine whether these features were present on initial sections in cases that were initially non-diagnostic.
Materials and methods Upon approval from the Institutional Review Board (HUM00064315; current approval dates 27 May 2014 to 26 May 2015), the surgical pathology © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
837
database at the University of Michigan was searched for the keyword ‘molluscum’ over a 21-month period (January 2011 to October 2012). This search resulted in 67 cases, among 61 patients, with slides available for histopathological review. Clinical data, including patient age, gender, lesion site, clinical impression, and immune status, were obtained from the electronic medical records for all cases. Haematoxylin and eosin-stained sections were reviewed for all 67 cases. The diagnosis of MC was confirmed by the presence of characteristic intracytoplasmic MBs in all cases. Slides were reviewed to identify additional histological features. Epithelial and stromal changes were characterized, and their frequencies were recorded. Epithelial changes included the following: (i) basal keratinocyte prominent nucleoli; (ii) peripheral keratinocyte pale amphophilic cytoplasm; and (iii) clear cytoplasmic vacuoles within peripheral keratinocytes rimming lesions. Perilesional stromal changes included: (i) fibromyxoid changes with mucin; (ii) fibroedematous changes lacking prominent mucin; (iii) acute inflammation; and (iv) mixed (acute and chronic) inflammation. Cases that required deeper sectioning to reveal diagnostic MBs were recorded, and the presence of any histopathological features on initial sections was noted. Selected cases were stained with colloidal iron to highlight dermal mucin (four cases).
Results A total of 67 MC cases were reviewed. The average age of the patients was 27.6 years (range 7 months to 92 years), and the male/female ratio was 1:1. The most common site of involvement was the head and neck area (21/67; 31%), followed by the trunk (18/ 67; 27%), genitocrural region (14/67; 21%), lower extremities (11/67; 16%), perianal area (2/67; 3%), and upper extremities (1/67; 2%). In 32 of the 67 cases (48%), the leading clinical diagnosis was MC. Among the remaining 35 cases, MC was included in the clinical differential diagnosis in six cases. In the cases where MC was not suspected (29/67; 43%), the most common leading clinical diagnoses included sebaceous neoplasms (sebaceous hyperplasia or Fordyce spots), xanthomas, nevi, acrochordons, cysts, viral verrucae, and non-melanoma skin cancers. Ten cases (15%) occurred in immunocompromised patients, and in five of these cases MC was the leading clinical diagnosis. The leading clinical diagnoses in the other five cases included viral verruca,
838
M K Ishikawa et al.
Table 1. Histopathological features identified in molluscum contagiosum
Histopathological feature
Number of cases (n = 67), no. (%)
Epithelial changes Prominent nucleoli
67 (100)
Pale amphophilic cytoplasm
54 (81)
Clear cytoplasmic vacuolization
38 (57)
Perilesional stromal changes Fibromyxoid stroma with mucin
13 (19)
Fibroedematous changes without mucin
23 (34)
Acute inflammation
9 (13)
Mixed inflammation
15 (22)
intradermal nevus, xanthoma, non-melanoma skin cancer, and sebaceous hyperplasia; in only two of these five cases was MC included in the differential diagnosis. In all cases, basal keratinocytes immediately surrounding the MBs had prominent nucleoli (67/67; 100%). Other epithelial changes variably present in keratinocytes peripherally rimming the MBs included pale amphophilic cytoplasm in 54 cases (81%) and clear cytoplasmic vacuolization in 38 cases (57%) (Table 1; Figure 1). The stroma directly adjacent to MC lesions showed fibroedematous or fibromyxoid stromal changes in a majority of cases (36/67; 54%), with a subset (13/67; 19%) showing abundant dermal mucin (Figures 2 and 3). Epithelial and stromal changes were not associated with a specific site or immune status. A subset of MC cases showed signifi-
A
cant perilesional dermal inflammation (24/67; 36%). The inflammatory infiltrate was predominantly composed of neutrophils, and was categorized as acute inflammation in nine cases (13%). In 15 cases (22%), the infiltrate was composed of a polymorphous population with variable numbers of neutrophils, small lymphocytes, plasma cells, and histiocytes, and was categorized as mixed inflammation. Stromal changes (fibromyxoid or fibroedematous) and inflammation (acute or mixed) were infrequently seen together (3/ 67, 4%). No cases showed large atypical lymphocytes that would be consistent with activated CD30-positive lymphocytes and potentially confused with a CD30positive lymphoproliferative disorder. In two cases, MC occurred in association with other lesions (one compound melanocytic nevus; one lipofibroma), and in one case MC was found incidentally in a biopsy with inflammatory changes consistent with connective tissue disease. In eight of 67 cases (12%), initial sections did not possess MBs or the crateriform acanthotic epithelium classically seen in MC. In all of these cases, either the epithelial or the perilesional stromal changes described in this study were present on initial sections. Subsequent deeper sectioning in all of these cases showed cells containing MBs in all of these initially non-diagnostic specimens (Figure 4).
Discussion In this study, we retrospectively evaluated clinical data and histopathological findings among a cohort of patients with MC. There have only been a few large series that have investigated the histological spectrum observed in MC.6,16 Our study adds to this literature, characterizing histological changes not previously reported, including some features in basal
B
Figure 1. Molluscum contagiosum (MC): epithelial changes observed in MC. A, Basal keratinocytes show prominent nucleoli, amphophilic cytoplasm, and clear cytoplasmic vacuoles. Well-formed molluscum bodies are present within the central portion of the lesion. B, Epithelial changes present on initial sections, in the absence of diagnostic molluscum bodies. © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Molluscum contagiosum
839
A
B
C
Figure 2. Molluscum contagiosum (MC): fibromyxoid stromal changes present in MC. A, At scanning magnification, pale-staining stroma surrounds and extends well beyond the infected epithelium. B, At higher power, stromal changes are characterized as fibromyxoid, with abundant dermal mucin. C, Mowry’s colloidal iron stain highlights dermal mucin.
keratinocytes located along the periphery of MC lesions and perilesional stromal changes. The majority of MC cases (57/67, 85%) in our study had significant accompanying stromal changes. We categorized these changes broadly into inflammatory changes (acute and mixed inflammation) and changes in surrounding dermal fibroblasts with associated oedema or mucin deposition. The secondary stromal changes associated with MC reported in the literature are predominantly focused on the pattern of inflammation that may accompany © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Figure 3. Molluscum contagiosum (MC): fibroedematous stromal changes seen in MC. Pale-staining stroma surrounds infected epithelium. In this example, the stromal changes are quite prominent, comprising more than twice the area of the infected epithelium.
the lesion. It is known that lesions may become secondarily inflamed when ulceration, trauma or secondary infection occurs. A foreign body-type reaction can also be elicited when lesions rupture and extrude MBs into the surrounding dermis.17 Some authors have suggested that the accompanying inflammation may represent a cell-mediated immune response to infection, heralding clearance of the lesion, and that this pattern of inflammation can be observed during immune reconstitution in immunocompromised individuals.18 Rarely, the inflammatory infiltrate may include atypical large CD30-positive cells mimicking CD30-positive lymphoproliferative disorders, including cutaneous lymphoma.19,20 The presence of accompanying dermal inflammation was observed in 36% of cases. Cases showed a spectrum of inflammatory cells, including both acute and chronic inflammation, and some cases appeared to represent ruptured MC. Interestingly, no cases with large atypical cells mimicking lymphoma were identified histopathologically in this series. Non-inflammatory stromal changes accompanying MC are not well documented in the literature. In our study, we observed changes in the surrounding dermal stroma in the majority of cases (54%). These cases showed a spectrum of histopathological changes. Some cases were characterized by loose oedematous stroma with thin collagen bands and elongated fibroblasts. In contrast, a minor subset of cases (19%) had a slightly basophilic fibromyxoid appearance and increased dermal mucin. In many cases, these stromal changes were prominent and extended well beyond the lesional epithelium into the underlying dermis. Interestingly, these changes were only appreciated rarely (4%) in combination with dermal inflammation, possibly suggesting that secondary
840
M K Ishikawa et al.
A
B
C
Figure 4. Molluscum contagiosum: sections of an initially nondiagnostic biopsy. A, The initial section contains fibromyxoid alteration of the dermal collagen, without any epithelial changes. B, Deeper sections contain an island of epithelium with altered keratinocytes characterized by prominent nucleoli, amphophilic cytoplasm, and occasional clear cytoplasmic vacuoles (inset). C, Additional deeper sections ultimately revealed epithelium with molluscum bodies.
inflammation involving lesions can obscure or precede the stromal changes. Cribier et al.6 previously reviewed the histopathological findings of 578 MC cases, and noted in their study the presence of loose collagen fibres in the underlying dermis of nine pedunculated MC cases. Additionally, Smith et al.16 described stromal changes resembling retraction artefact that surrounded all non-verrucous MC lesions lacking inflammation. The presumed artefactual stromal change was described as a split between the infected follicular infundibulum
and the surrounding stroma resulting in three to six surrounding layers of CD34-positive spindled stromal cells. We hypothesize that the observations described in both of these previous studies represent the same spectrum of non-inflammatory dermal stromal changes described in our study. Our findings suggest that these changes are probably underreported, and are present in many MC cases. Various epithelial changes were observed in basally located keratinocytes at the periphery of MC lesions. These changes included prominent nucleoli, pale amphophilic cytoplasm, and clear cytoplasmic vacuoles. The epithelial changes occurred in the majority of cases, and appeared to be distinct from classic welldeveloped MBs. The presence of prominent nucleoli in keratinocytes was the most consistent finding (100%); however, cytoplasmic amphophilia (81%) and vacuolization (57%) were present in the majority of cases. In 2007, a case report by Calder et al.21 described a violaceous hue of the squamous epithelium in proximity to MC, and underscored its potential to be confused with bowenoid papulosis. In our series of cases, the keratinocytes showed a more amphophilic than violaceous hue, although this may be influenced by variability in staining between individual laboratories. Cytoplasmic vacuolization has been previously noted as a feature of MCV-infected keratinocytes; however, the prevalence and localization of this finding have not been previously described.3 Overall, the histopathological appearance of these peripherally rimming keratinocytes is consistent with a reactive viropathic process, probably representing the early cytopathological changes of MCV infection before well-developed MBs form. Ultrastructural studies have demonstrated that follicular epithelium infected with MCV first shows viral cores in the basal keratinocytes,15 and histopathological studies have shown that the characteristic MC cytoplasmic inclusions progressively enlarge as they rise through the epidermis before developing into true MBs.2,17 Immunohistochemical studies have shown that the basal keratinocytes of MC lesions have a higher Ki67 proliferative index than normal skin-matched controls.22 These prior studies suggest that the basal keratinocytes in MC lesions probably reflect the earliest-infected cells, and our findings confirm the distinct histopathological changes observed in these cells. A significant minority of cases (12%) did not show MBs or classic architectural features of MC on initial haematoxylin and eosin-stained sections. In all of these cases, either the non-inflammatory stromal changes or peripheral keratinocyte changes described in this study were noted on initial sections, and © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Molluscum contagiosum
prompted further evaluation with deeper sectioning. In all of these initially non-diagnostic cases, deeper sectioning revealed MBs. However, as we queried the pathology database for MC, we do not know how many, if any, cases of MC were misdiagnosed as other conditions or as non-specific diagnoses, especially cases not clinically suspected to be MC. This finding underscores the importance of pathologists appreciating the non-inflammatory stromal and peripheral epithelial changes described in this study in order to maximize diagnostic accuracy. Cases with prominent fibromyxoid stromal changes and increased dermal mucin, but that do not show lesional epithelium on initial sections, represent a potential diagnostic pitfall. These cases may be mistakenly diagnosed as some form of cutaneous mucinosis. Interestingly, Feliciani et al.23 reported a case of a 34-year-old male presenting with small (2–3mm) skin-coloured umbilicated papules on genital skin. The clinical diagnosis was atypical MC. The authors made a diagnosis of papular mucinosis on the biopsy, based on the presence of dermal mucin in pools and infiltrating collagen bundles, which were positive for alcian blue and periodic acid–Schiff stains. A mild inflammatory infiltrate and a moderately increased number of fibroblasts were also present. Clinically, the lesions disappeared in several weeks without treatment, leaving a few hypopigmented macules. Empirically, the findings were interpreted as being consistent with the rare form of adult self-healing papular mucinosis, despite occurring in an unusual location. The histopathological description reported in this case is similar to the perilesional stromal changes present in our study. MC is often selfresolving in immunocompetent patients, and it seems to be a more likely diagnosis than self-healing papular mucinosis, according to the clinical information provided. In conclusion, this series of MCs expands the histopathological features commonly seen in MC, and provides helpful clues for an accurate diagnosis in cases where MC is not suspected clinically and/or classic histopathological features are not seen in the initial tissue sections. Cytomorphological changes of the peripherally located keratinocytes are common, and include prominent nucleoli, clear cytoplasmic vacuoles, and amphophilic cytoplasm. Fibroedematous to fibromyxoid stromal changes are also frequent, and in some instances the extent of mucin deposition can be confused with a cutaneous mucinosis. Although failure to diagnose MC does not pose a serious health risk to the patient, it can result in the potential for sexual transmission to a partner, patient anxiety © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
841
because of the appearance of the lesions, and uncertainty about the diagnosis for the clinician, resulting in the need for a repeat biopsy to establish the correct diagnosis.
Acknowledgement There was no funding for this study.
Author contributions M. Ishikawa performed the research, analysed data, and wrote the manuscript. D. Arps assisted with analysis of data and writing of the manuscript. C. Chow assisted with the research, analysis of data, and writing of the manuscript. T. Hocker assisted with the study design, research, analysis of data, and reviewing and writing of the manuscript. D. Fullen initiated and designed the study, reviewed the data, wrote a portion of the manuscript, and revised the final manuscript.
Conflicts of interest The authors state that they have no conflicts of interest.
References 1. Moss B. Poxviridae: the viruses and their replication. In Knipe DM, Howley PM eds. Fields virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007; 2905. 2. Chen X, Anstey AV, Bugert JJ. Molluscum contagiosum virus infection. Lancet Infect. Dis. 2013; 13; 877–888. 3. Diven DG. An overview of poxviruses. J. Am. Acad. Dermatol. 2001; 44; 1–16. 4. S aez M, Rodrıguez-Martın M, Carnerero A et al. Atypical molluscum contagiosum. J. Eur. Acad. Dermatol. Venereol. 2006; 20; 465–466. 5. Lynch PJ, Minkin W. Molluscum contagiosum of the adult: probable venereal transmission. Arch. Dermatol. 1968; 98; 141–143. 6. Cribier B, Scrivener Y, Grosshans E. Molluscum contagiosum: histologic patterns and associated lesions. A study of 578 cases. Am. J. Dermatopathol. 2001; 23; 99–103. 7. Filo-Rogulska M, Pindycka-Piaszczy nska M, Januszewski K, Jarzaz b J. Disseminated atypical molluscum contagiosum as a presenting symptom of HIV infection. Postepy Dermatol. Alergol. 2013; 30; 56–58. 8. Mansur AT, G€ oktay F, G€ und€ uz S, Serdar ZA. Multiple giant molluscum contagiosum in a renal transplant recipient. Transpl. Infect Dis. 2004; 6; 120–123. 9. Ghorpade A. Molluscoid skin lesions in histoid leprosy with pseudo-isomorphic Koebner phenomenon. Int. J. Dermatol. 2008; 47; 1278–1280.
842
M K Ishikawa et al.
10. Digby M, Belli R, McGraw T, Lee A. Eruptive xanthomas as a cutaneous manifestation of hypertriglyceridemia: a case report. J. Clin. Aesthet. Dermatol. 2011; 4; 44–46. 11. Alfaro-Castell on P, Mejıa-Rodrıguez SA, Valencia-Herrera A, Ramırez S, Mena-Cedillos C. Dermoscopy distinction of eruptive vellus hair cysts with molluscum contagiosum and acne lesions. Pediatr. Dermatol. 2012; 29; 772–773. 12. Ramdial PK, Calonje E, Sing Y, Chotey NA, Aboobaker J. Molluscum-like cutaneous cryptococcosis: a histopathological and pathogenetic appraisal. J. Cutan. Pathol. 2008; 35; 1007–1013. 13. Nelson BL, Thompson LD. Molluscum contagiosum. Ear Nose Throat J. 2003; 82; 560. 14. Rao K, Priya N, Umadevi H, Smitha T. Molluscum contagiosum. J. Oral Maxillofac. Pathol. 2013; 17; 146–147. 15. Vreeswijk J, Leene W, Kalsbeek GL. Early interactions of the virus molluscum contagiosum with its host cell virus-induced alterations in the basal and suprabasal layers of the epidermis. J. Ultrastruct. Res. 1976; 54; 37–52. 16. Smith KJ, Yeager J, Skelton H. Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum. Int. J. Dermatol. 1999; 38; 664–672.
17. Weedon D. Viral diseases: molluscum contagiosum. In Weedon’s skin pathology, 3rd ed. London: Churchill Livingstone Elsevier, 2010; 609–610. 18. de Carvalho VO, Cruz CR, Noronha L, Abagge KT, Lima HC. An inflammatory reaction surrounding molluscum contagiosum as possible manifestation of immune reconstitution inflammatory syndrome in HIV infection. Pediatr. Dermatol. 2010; 27; 631–634. 19. de Diego J, Berridi D, Saracibar N, Requena L. Cutaneous pseudolymphoma in association with molluscum contagiosum. Am. J. Dermatopathol. 1998; 20; 518–521. 20. Guitart J, Hurt M. Pleomorphic T-cell infiltrate associated with molluscum contagiosum. Am. J. Dermatopathol. 1999; 21; 178–180. 21. Calder KB, Mathew R, Morgan MB. Purple penile papules. Am. J. Dermatopathol. 2007; 29; 417–418. 22. Simonart T, Fayt I, Noel JC. An immunohistochemical study of abnormal keratinocyte proliferation in molluscum contagiosum. Br. J. Dermatol. 2002; 146; 609–614. 23. Feliciani C, Pennacchia I, Massi G. Adult self-healing papular mucinosis on genital skin. Clin. Exp. Dermatol. 2009; 34; e760–e762.
© 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Histopathological features of molluscum contagiosum other than molluscum bodies Martin K Ishikawa,1 David P Arps,1 Conroy Chow,2 Thomas L Hocker1 & Douglas R Fullen1,2 1
Department of Pathology, University of Michigan, Ann Arbor, MI, USA, and 2Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
Date of submission 7 March 2015 Accepted for publication 15 April 2015 Published online Article Accepted 17 April 2015
Ishikawa M K, Arps D P, Chow C, Hocker T L, & Fullen D R (2015) Histopathology 67, 836–842. DOI: 10.1111/his.12716
Histopathological features of molluscum contagiosum other than molluscum bodies Aims: Classic histopathological features of molluscum contagiosum (MC) include a crateriform, acanthotic epidermis containing intracytoplasmic molluscum bodies (MBs). In our experience, a subset of cases lack these features on initial haematoxylin and eosin-stained sections. We aimed to describe the histopathological features of MC other than those classically described. Methods and results: Sixty-seven biopsies diagnosed as MC from January 2011 to October 2012 were retrospectively reviewed. Keratinocytes peripheral to the diagnostic cells with MBs had prominent nucleoli (67; 100%), amphophilic cytoplasm (54; 81%), and in many instances clear cytoplasmic vacuolization (38; 57%). Stroma surrounding MC lesions showed
fibroedematous to fibromyxoid changes in many cases (36; 54%), with a subset (13; 19%) showing abundant dermal mucin. In eight of 67 cases (12%), initial sections did not possess MBs or crateriform epidermis of MC. In these cases, initial sections revealed only the epithelial and/or perilesional stromal changes described above. Additional sections contained MBs in all of these cases. Conclusions: Perilesional fibroedematous to fibromyxoid stroma and keratinocyte changes, including prominent nucleoli and amphophilic cytoplasm with clear vacuolization, are common in MC. Recognizing these features may prove helpful in reaching the diagnosis of MC in cases lacking classic histopathological features on initial sections.
Keywords: dermal mucin, fibroedematous stroma, fibromyxoid stroma, molluscum contagiosum, papular mucinosis, viral dermatoses
Introduction Molluscum contagiosum (MC) is a common cutaneous infection caused by the MC virus (MCV), a doublestranded DNA virus that exclusively infects humans. It is included in the Poxviridae family, and is the only member of the Molluscipoxvirus genus.1 Bateman first described the disease in 1817. Later, Henderson and Paterson described the characteristic intracytoplasmic inclusion bodies, and they demonstrated the infectious nature of MC in 1841. The virus is predominantly Address for correspondence: D R Fullen, 1301 Catherine St, M3261 Medical Science I, Ann Arbor, MI 48109-5602, USA. e-mail: [email protected] © 2015 John Wiley & Sons Ltd.
spread by direct skin contact or contaminated fomites, and primarily infects children, sexually active adults, and immunocompromised individuals.2 Typical lesions appear clinically as 2–5-mm flesh coloured, dome-shaped papules with central umbilication that contain a thick, whitish-yellow curd-like material. Lesions may occur in a variety of locations, but most commonly appear on the trunk, extremities, and axillae.3,4 Infection may also occur in the genital area when transmitted by sexual contact.5 The majority of MC cases can be diagnosed clinically. However, some lesions may have an atypical presentation, making clinical diagnosis difficult. In these cases, a biopsy may be required for definitive diagnosis. Clinical factors contributing to an atypical
Molluscum contagiosum
appearance include lesions with variant morphology (giant and pseudocystic MC), inflamed lesions, lesions surrounded by an eczematous reaction (‘molluscum dermatitis’), and MC secondarily involving another lesion. When these clinical factors are present, the rate of correct clinical diagnosis may drop significantly. Patient demographics and lesion location may also make clinical diagnosis challenging. MC occurring in immunocompromised individuals, older patients and patients with lesions on the head and neck may be more difficult to diagnose clinically.6 Atypical MC lesions may clinically mimic other neoplastic and inflammatory disorders, including basal cell carcinoma, keratoacanthoma, adnexal tumours, Darier’s disease, cutaneous cryptococcosis, cutaneous histoplasmosis, eruptive vellus hair cysts, acne vulgaris, histoid leprosy, and xanthomas.3,7–12 On histopathological evaluation, MC classically presents as a lobulated crateriform lesion with acanthotic epidermis containing intracytoplasmic viral inclusions known as molluscum bodies (MBs) or Henderson–Paterson bodies. These homogeneous ground-glass-like inclusions range from basophilic to eosinophilic, and peripherally displace the cell nucleus, resulting in a signet-ring appearance.2,13,14 MC has a tendency to infect follicular epithelium, and viral cores are first demonstrated in the basal layers of the epidermis.15 After inoculation, MCV regulates host cell transcription and replicates within the cytoplasm. As virusladen cells mature, they grow larger and move towards the surface. Eventually, viral particles displace the host cell organelles and nucleus, and infected cells develop the characteristic MBs, which are typically identified three to four layers above the basal cell layer.2 When the classic histopathological features of MC are present, reaching the correct diagnosis is straightforward. However, in our experience, a subset of biopsies of MC lack the classically described histopathological features on initial sections. We sought to characterize the histopathological changes of MC other than the classically described crateriform acanthotic epithelium and MBs, and to determine the frequency with which these features occur. We also attempted to determine whether these features were present on initial sections in cases that were initially non-diagnostic.
Materials and methods Upon approval from the Institutional Review Board (HUM00064315; current approval dates 27 May 2014 to 26 May 2015), the surgical pathology © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
837
database at the University of Michigan was searched for the keyword ‘molluscum’ over a 21-month period (January 2011 to October 2012). This search resulted in 67 cases, among 61 patients, with slides available for histopathological review. Clinical data, including patient age, gender, lesion site, clinical impression, and immune status, were obtained from the electronic medical records for all cases. Haematoxylin and eosin-stained sections were reviewed for all 67 cases. The diagnosis of MC was confirmed by the presence of characteristic intracytoplasmic MBs in all cases. Slides were reviewed to identify additional histological features. Epithelial and stromal changes were characterized, and their frequencies were recorded. Epithelial changes included the following: (i) basal keratinocyte prominent nucleoli; (ii) peripheral keratinocyte pale amphophilic cytoplasm; and (iii) clear cytoplasmic vacuoles within peripheral keratinocytes rimming lesions. Perilesional stromal changes included: (i) fibromyxoid changes with mucin; (ii) fibroedematous changes lacking prominent mucin; (iii) acute inflammation; and (iv) mixed (acute and chronic) inflammation. Cases that required deeper sectioning to reveal diagnostic MBs were recorded, and the presence of any histopathological features on initial sections was noted. Selected cases were stained with colloidal iron to highlight dermal mucin (four cases).
Results A total of 67 MC cases were reviewed. The average age of the patients was 27.6 years (range 7 months to 92 years), and the male/female ratio was 1:1. The most common site of involvement was the head and neck area (21/67; 31%), followed by the trunk (18/ 67; 27%), genitocrural region (14/67; 21%), lower extremities (11/67; 16%), perianal area (2/67; 3%), and upper extremities (1/67; 2%). In 32 of the 67 cases (48%), the leading clinical diagnosis was MC. Among the remaining 35 cases, MC was included in the clinical differential diagnosis in six cases. In the cases where MC was not suspected (29/67; 43%), the most common leading clinical diagnoses included sebaceous neoplasms (sebaceous hyperplasia or Fordyce spots), xanthomas, nevi, acrochordons, cysts, viral verrucae, and non-melanoma skin cancers. Ten cases (15%) occurred in immunocompromised patients, and in five of these cases MC was the leading clinical diagnosis. The leading clinical diagnoses in the other five cases included viral verruca,
838
M K Ishikawa et al.
Table 1. Histopathological features identified in molluscum contagiosum
Histopathological feature
Number of cases (n = 67), no. (%)
Epithelial changes Prominent nucleoli
67 (100)
Pale amphophilic cytoplasm
54 (81)
Clear cytoplasmic vacuolization
38 (57)
Perilesional stromal changes Fibromyxoid stroma with mucin
13 (19)
Fibroedematous changes without mucin
23 (34)
Acute inflammation
9 (13)
Mixed inflammation
15 (22)
intradermal nevus, xanthoma, non-melanoma skin cancer, and sebaceous hyperplasia; in only two of these five cases was MC included in the differential diagnosis. In all cases, basal keratinocytes immediately surrounding the MBs had prominent nucleoli (67/67; 100%). Other epithelial changes variably present in keratinocytes peripherally rimming the MBs included pale amphophilic cytoplasm in 54 cases (81%) and clear cytoplasmic vacuolization in 38 cases (57%) (Table 1; Figure 1). The stroma directly adjacent to MC lesions showed fibroedematous or fibromyxoid stromal changes in a majority of cases (36/67; 54%), with a subset (13/67; 19%) showing abundant dermal mucin (Figures 2 and 3). Epithelial and stromal changes were not associated with a specific site or immune status. A subset of MC cases showed signifi-
A
cant perilesional dermal inflammation (24/67; 36%). The inflammatory infiltrate was predominantly composed of neutrophils, and was categorized as acute inflammation in nine cases (13%). In 15 cases (22%), the infiltrate was composed of a polymorphous population with variable numbers of neutrophils, small lymphocytes, plasma cells, and histiocytes, and was categorized as mixed inflammation. Stromal changes (fibromyxoid or fibroedematous) and inflammation (acute or mixed) were infrequently seen together (3/ 67, 4%). No cases showed large atypical lymphocytes that would be consistent with activated CD30-positive lymphocytes and potentially confused with a CD30positive lymphoproliferative disorder. In two cases, MC occurred in association with other lesions (one compound melanocytic nevus; one lipofibroma), and in one case MC was found incidentally in a biopsy with inflammatory changes consistent with connective tissue disease. In eight of 67 cases (12%), initial sections did not possess MBs or the crateriform acanthotic epithelium classically seen in MC. In all of these cases, either the epithelial or the perilesional stromal changes described in this study were present on initial sections. Subsequent deeper sectioning in all of these cases showed cells containing MBs in all of these initially non-diagnostic specimens (Figure 4).
Discussion In this study, we retrospectively evaluated clinical data and histopathological findings among a cohort of patients with MC. There have only been a few large series that have investigated the histological spectrum observed in MC.6,16 Our study adds to this literature, characterizing histological changes not previously reported, including some features in basal
B
Figure 1. Molluscum contagiosum (MC): epithelial changes observed in MC. A, Basal keratinocytes show prominent nucleoli, amphophilic cytoplasm, and clear cytoplasmic vacuoles. Well-formed molluscum bodies are present within the central portion of the lesion. B, Epithelial changes present on initial sections, in the absence of diagnostic molluscum bodies. © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Molluscum contagiosum
839
A
B
C
Figure 2. Molluscum contagiosum (MC): fibromyxoid stromal changes present in MC. A, At scanning magnification, pale-staining stroma surrounds and extends well beyond the infected epithelium. B, At higher power, stromal changes are characterized as fibromyxoid, with abundant dermal mucin. C, Mowry’s colloidal iron stain highlights dermal mucin.
keratinocytes located along the periphery of MC lesions and perilesional stromal changes. The majority of MC cases (57/67, 85%) in our study had significant accompanying stromal changes. We categorized these changes broadly into inflammatory changes (acute and mixed inflammation) and changes in surrounding dermal fibroblasts with associated oedema or mucin deposition. The secondary stromal changes associated with MC reported in the literature are predominantly focused on the pattern of inflammation that may accompany © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Figure 3. Molluscum contagiosum (MC): fibroedematous stromal changes seen in MC. Pale-staining stroma surrounds infected epithelium. In this example, the stromal changes are quite prominent, comprising more than twice the area of the infected epithelium.
the lesion. It is known that lesions may become secondarily inflamed when ulceration, trauma or secondary infection occurs. A foreign body-type reaction can also be elicited when lesions rupture and extrude MBs into the surrounding dermis.17 Some authors have suggested that the accompanying inflammation may represent a cell-mediated immune response to infection, heralding clearance of the lesion, and that this pattern of inflammation can be observed during immune reconstitution in immunocompromised individuals.18 Rarely, the inflammatory infiltrate may include atypical large CD30-positive cells mimicking CD30-positive lymphoproliferative disorders, including cutaneous lymphoma.19,20 The presence of accompanying dermal inflammation was observed in 36% of cases. Cases showed a spectrum of inflammatory cells, including both acute and chronic inflammation, and some cases appeared to represent ruptured MC. Interestingly, no cases with large atypical cells mimicking lymphoma were identified histopathologically in this series. Non-inflammatory stromal changes accompanying MC are not well documented in the literature. In our study, we observed changes in the surrounding dermal stroma in the majority of cases (54%). These cases showed a spectrum of histopathological changes. Some cases were characterized by loose oedematous stroma with thin collagen bands and elongated fibroblasts. In contrast, a minor subset of cases (19%) had a slightly basophilic fibromyxoid appearance and increased dermal mucin. In many cases, these stromal changes were prominent and extended well beyond the lesional epithelium into the underlying dermis. Interestingly, these changes were only appreciated rarely (4%) in combination with dermal inflammation, possibly suggesting that secondary
840
M K Ishikawa et al.
A
B
C
Figure 4. Molluscum contagiosum: sections of an initially nondiagnostic biopsy. A, The initial section contains fibromyxoid alteration of the dermal collagen, without any epithelial changes. B, Deeper sections contain an island of epithelium with altered keratinocytes characterized by prominent nucleoli, amphophilic cytoplasm, and occasional clear cytoplasmic vacuoles (inset). C, Additional deeper sections ultimately revealed epithelium with molluscum bodies.
inflammation involving lesions can obscure or precede the stromal changes. Cribier et al.6 previously reviewed the histopathological findings of 578 MC cases, and noted in their study the presence of loose collagen fibres in the underlying dermis of nine pedunculated MC cases. Additionally, Smith et al.16 described stromal changes resembling retraction artefact that surrounded all non-verrucous MC lesions lacking inflammation. The presumed artefactual stromal change was described as a split between the infected follicular infundibulum
and the surrounding stroma resulting in three to six surrounding layers of CD34-positive spindled stromal cells. We hypothesize that the observations described in both of these previous studies represent the same spectrum of non-inflammatory dermal stromal changes described in our study. Our findings suggest that these changes are probably underreported, and are present in many MC cases. Various epithelial changes were observed in basally located keratinocytes at the periphery of MC lesions. These changes included prominent nucleoli, pale amphophilic cytoplasm, and clear cytoplasmic vacuoles. The epithelial changes occurred in the majority of cases, and appeared to be distinct from classic welldeveloped MBs. The presence of prominent nucleoli in keratinocytes was the most consistent finding (100%); however, cytoplasmic amphophilia (81%) and vacuolization (57%) were present in the majority of cases. In 2007, a case report by Calder et al.21 described a violaceous hue of the squamous epithelium in proximity to MC, and underscored its potential to be confused with bowenoid papulosis. In our series of cases, the keratinocytes showed a more amphophilic than violaceous hue, although this may be influenced by variability in staining between individual laboratories. Cytoplasmic vacuolization has been previously noted as a feature of MCV-infected keratinocytes; however, the prevalence and localization of this finding have not been previously described.3 Overall, the histopathological appearance of these peripherally rimming keratinocytes is consistent with a reactive viropathic process, probably representing the early cytopathological changes of MCV infection before well-developed MBs form. Ultrastructural studies have demonstrated that follicular epithelium infected with MCV first shows viral cores in the basal keratinocytes,15 and histopathological studies have shown that the characteristic MC cytoplasmic inclusions progressively enlarge as they rise through the epidermis before developing into true MBs.2,17 Immunohistochemical studies have shown that the basal keratinocytes of MC lesions have a higher Ki67 proliferative index than normal skin-matched controls.22 These prior studies suggest that the basal keratinocytes in MC lesions probably reflect the earliest-infected cells, and our findings confirm the distinct histopathological changes observed in these cells. A significant minority of cases (12%) did not show MBs or classic architectural features of MC on initial haematoxylin and eosin-stained sections. In all of these cases, either the non-inflammatory stromal changes or peripheral keratinocyte changes described in this study were noted on initial sections, and © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
Molluscum contagiosum
prompted further evaluation with deeper sectioning. In all of these initially non-diagnostic cases, deeper sectioning revealed MBs. However, as we queried the pathology database for MC, we do not know how many, if any, cases of MC were misdiagnosed as other conditions or as non-specific diagnoses, especially cases not clinically suspected to be MC. This finding underscores the importance of pathologists appreciating the non-inflammatory stromal and peripheral epithelial changes described in this study in order to maximize diagnostic accuracy. Cases with prominent fibromyxoid stromal changes and increased dermal mucin, but that do not show lesional epithelium on initial sections, represent a potential diagnostic pitfall. These cases may be mistakenly diagnosed as some form of cutaneous mucinosis. Interestingly, Feliciani et al.23 reported a case of a 34-year-old male presenting with small (2–3mm) skin-coloured umbilicated papules on genital skin. The clinical diagnosis was atypical MC. The authors made a diagnosis of papular mucinosis on the biopsy, based on the presence of dermal mucin in pools and infiltrating collagen bundles, which were positive for alcian blue and periodic acid–Schiff stains. A mild inflammatory infiltrate and a moderately increased number of fibroblasts were also present. Clinically, the lesions disappeared in several weeks without treatment, leaving a few hypopigmented macules. Empirically, the findings were interpreted as being consistent with the rare form of adult self-healing papular mucinosis, despite occurring in an unusual location. The histopathological description reported in this case is similar to the perilesional stromal changes present in our study. MC is often selfresolving in immunocompetent patients, and it seems to be a more likely diagnosis than self-healing papular mucinosis, according to the clinical information provided. In conclusion, this series of MCs expands the histopathological features commonly seen in MC, and provides helpful clues for an accurate diagnosis in cases where MC is not suspected clinically and/or classic histopathological features are not seen in the initial tissue sections. Cytomorphological changes of the peripherally located keratinocytes are common, and include prominent nucleoli, clear cytoplasmic vacuoles, and amphophilic cytoplasm. Fibroedematous to fibromyxoid stromal changes are also frequent, and in some instances the extent of mucin deposition can be confused with a cutaneous mucinosis. Although failure to diagnose MC does not pose a serious health risk to the patient, it can result in the potential for sexual transmission to a partner, patient anxiety © 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
841
because of the appearance of the lesions, and uncertainty about the diagnosis for the clinician, resulting in the need for a repeat biopsy to establish the correct diagnosis.
Acknowledgement There was no funding for this study.
Author contributions M. Ishikawa performed the research, analysed data, and wrote the manuscript. D. Arps assisted with analysis of data and writing of the manuscript. C. Chow assisted with the research, analysis of data, and writing of the manuscript. T. Hocker assisted with the study design, research, analysis of data, and reviewing and writing of the manuscript. D. Fullen initiated and designed the study, reviewed the data, wrote a portion of the manuscript, and revised the final manuscript.
Conflicts of interest The authors state that they have no conflicts of interest.
References 1. Moss B. Poxviridae: the viruses and their replication. In Knipe DM, Howley PM eds. Fields virology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2007; 2905. 2. Chen X, Anstey AV, Bugert JJ. Molluscum contagiosum virus infection. Lancet Infect. Dis. 2013; 13; 877–888. 3. Diven DG. An overview of poxviruses. J. Am. Acad. Dermatol. 2001; 44; 1–16. 4. S aez M, Rodrıguez-Martın M, Carnerero A et al. Atypical molluscum contagiosum. J. Eur. Acad. Dermatol. Venereol. 2006; 20; 465–466. 5. Lynch PJ, Minkin W. Molluscum contagiosum of the adult: probable venereal transmission. Arch. Dermatol. 1968; 98; 141–143. 6. Cribier B, Scrivener Y, Grosshans E. Molluscum contagiosum: histologic patterns and associated lesions. A study of 578 cases. Am. J. Dermatopathol. 2001; 23; 99–103. 7. Filo-Rogulska M, Pindycka-Piaszczy nska M, Januszewski K, Jarzaz b J. Disseminated atypical molluscum contagiosum as a presenting symptom of HIV infection. Postepy Dermatol. Alergol. 2013; 30; 56–58. 8. Mansur AT, G€ oktay F, G€ und€ uz S, Serdar ZA. Multiple giant molluscum contagiosum in a renal transplant recipient. Transpl. Infect Dis. 2004; 6; 120–123. 9. Ghorpade A. Molluscoid skin lesions in histoid leprosy with pseudo-isomorphic Koebner phenomenon. Int. J. Dermatol. 2008; 47; 1278–1280.
842
M K Ishikawa et al.
10. Digby M, Belli R, McGraw T, Lee A. Eruptive xanthomas as a cutaneous manifestation of hypertriglyceridemia: a case report. J. Clin. Aesthet. Dermatol. 2011; 4; 44–46. 11. Alfaro-Castell on P, Mejıa-Rodrıguez SA, Valencia-Herrera A, Ramırez S, Mena-Cedillos C. Dermoscopy distinction of eruptive vellus hair cysts with molluscum contagiosum and acne lesions. Pediatr. Dermatol. 2012; 29; 772–773. 12. Ramdial PK, Calonje E, Sing Y, Chotey NA, Aboobaker J. Molluscum-like cutaneous cryptococcosis: a histopathological and pathogenetic appraisal. J. Cutan. Pathol. 2008; 35; 1007–1013. 13. Nelson BL, Thompson LD. Molluscum contagiosum. Ear Nose Throat J. 2003; 82; 560. 14. Rao K, Priya N, Umadevi H, Smitha T. Molluscum contagiosum. J. Oral Maxillofac. Pathol. 2013; 17; 146–147. 15. Vreeswijk J, Leene W, Kalsbeek GL. Early interactions of the virus molluscum contagiosum with its host cell virus-induced alterations in the basal and suprabasal layers of the epidermis. J. Ultrastruct. Res. 1976; 54; 37–52. 16. Smith KJ, Yeager J, Skelton H. Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum. Int. J. Dermatol. 1999; 38; 664–672.
17. Weedon D. Viral diseases: molluscum contagiosum. In Weedon’s skin pathology, 3rd ed. London: Churchill Livingstone Elsevier, 2010; 609–610. 18. de Carvalho VO, Cruz CR, Noronha L, Abagge KT, Lima HC. An inflammatory reaction surrounding molluscum contagiosum as possible manifestation of immune reconstitution inflammatory syndrome in HIV infection. Pediatr. Dermatol. 2010; 27; 631–634. 19. de Diego J, Berridi D, Saracibar N, Requena L. Cutaneous pseudolymphoma in association with molluscum contagiosum. Am. J. Dermatopathol. 1998; 20; 518–521. 20. Guitart J, Hurt M. Pleomorphic T-cell infiltrate associated with molluscum contagiosum. Am. J. Dermatopathol. 1999; 21; 178–180. 21. Calder KB, Mathew R, Morgan MB. Purple penile papules. Am. J. Dermatopathol. 2007; 29; 417–418. 22. Simonart T, Fayt I, Noel JC. An immunohistochemical study of abnormal keratinocyte proliferation in molluscum contagiosum. Br. J. Dermatol. 2002; 146; 609–614. 23. Feliciani C, Pennacchia I, Massi G. Adult self-healing papular mucinosis on genital skin. Clin. Exp. Dermatol. 2009; 34; e760–e762.
© 2015 John Wiley & Sons Ltd, Histopathology, 67, 836–842.
