J Cutan Pathol 2015: 42: 632–638 doi: 10.1111/cup.12529 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Follicular necrotic keratinocytes – a helpful clue to the diagnosis of measles A skin specimen taken from the exanthem of a 22-year-old man with measles infection was examined by light microscopy. The most characteristic changes were foci of multiple necrotic keratinocytes, partially confluent and partially isolated, strictly within follicles and sebaceous glands. Serial sections revealed occasional necrotic and none-necrotic syncytial-type multinucleated epithelial cells in some infundibula. Neither nuclear nor cytoplasmic viral inclusions were present.
Mariantonieta Tirado1 , Karoline Adamzik2 and Almut Böer-Auer3
Keywords: dermatopathology, exanthema, follicular necrotic keratinocytes, measles, syncytial-type multinucleated epithelial cell
Mariantonieta Tirado, MD, Dermatology Diagnostics, Histologie Labor 1. Stock, Drehbahn 1–3, 20354, Hamburg, Germany Tel: +049 152 0433 1088 Fax: +049 40 350 17714 e-mail: [email protected]
Tirado M, Adamzik K, Böer-Auer A. Follicular necrotic keratinocytes – a helpful clue to the diagnosis of measles. J Cutan Pathol 2015; 42: 632–638. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Measles is a highly contagious viral disease caused by a virus belonging to the Paramyxoviridae family, genus Morbillivirus. The maculopapular rash of measles occurs three or four days after the onset of fever, malaise and headache in conjunction with cough, coryza and conjunctivitis. Measles virus is transmitted by aerosols entering the respiratory tract or by direct contact with respiratory secretions.1 The disease is largely self-limiting in immunocompetent and immunized individuals, but may be severe and even deadly in immunocompromised patients.2 Those who survive the virus can suffer respiratory and neurological complications.3 The exanthem of measles infection is clinically distinctive but clinicians may confuse it with other infectious or allergic exanthems because of a lack of experience with the disease or an unusual presentation.4 In such cases, biopsies may be submitted to a dermatopathology service to rule out an infectious cause. Often, exanthems of infectious diseases are not
632
1
Department of Pathology, Marienkrankenhaus Hamburg/Dermatology Diagnostics, Hamburg, Germany, 2 Department of Dermatology, University of Kiel, Kiel, Germany , and 3 Department of Dermatology, Dermatologikum Hamburg, Hamburg, Germany
Accepted for publication May 7, 2015
distinctive on histopathology and difficult to tell from allergic reactions. Case report A 22-year-old complaining of hallucinations under alcohol influence was presented by a social worker to the psychiatric department. The patient was admitted to the psychiatric ward and treatment with clorazepate dipotassium and vitamin B was initiated. After 12 days of hospitalization, he developed a skin rash. Cutaneous examination revealed an exanthem on the face and chest with mild pruritus. Palms and soles were uninvolved. There was no documentation of mucosal involvement. The patient also had 39 ∘ C fever, dry cough, odynophagia, back pain and diarrhea. Laboratory studies were significant for a white blood cell count of 7.2 nl with 74.9% of neutrophils, 13.3% of lymphocytes and 11.2% of monocytes. Toxicology screen was positive
Follicular necrotic keratinocytes
Fig. 1. Right shoulder. A) Orthokeratosis, focal parakeratosis, focal dyskeratotic cells and mild vacuolar change of the epidermal-dermal junction, HE 100× (B) 400× (C) Fourth serial section showing focal dyskeratotic cells strictly within the follicle, HE 100× and (D) 400×.
for Cannabis, Diclofenac and Paracetamol. Two skin biopsies were obtained from the exanthem, one from the right shoulder, the other from the right temple. Histopathology revealed basket-woven orthokeratosis with superimposed parakeratosis. Circumscribed-basal vacuolar change was seen with associated lymphocytes (Fig. 1A,B). Multiple dyskeratotic keratinocytes, partially confluent and partially isolated, were present within follicles and sebaceous glands (Figs. 1C,D and 2A,B,D,E,F,G). Serial sections revealed occasional multinucleated keratinocytes, necrotic and none-necrotic, in some infundibula. The multinucleated keratinocytes showed moderately eosinophilic cytoplasm and three to six irregularly shaped nuclei with indistinct nucleoli packed together (Fig. 2C,H). No cytoplasmic or nuclear inclusions, no abnormal chromatin distribution nor atypia was seen within epithelial cells or lymphocytes. No ballooning or acantholysis were encountered. The dermis showed a mild superficial and deep perivascular lymphohistiocytic infiltrate and some extravasated erythrocytes. Polymerase chain reaction assessment of the biopsy for Herpes simplex (HSV-1/2), Varicella zoster and Treponema pallidum was negative. With the combined clinical presentation and histologic findings, a viral infection including measles and coxsackie infections were
considered as differential diagnoses. Shortly thereafter, the results of serology testing arrived reavealing measles IgM-antibodies of 504 U/ml and IgG-antibodies of 230mlU/ml. Additional laboratory studies included negative testing for syphilis (rapid plasma regain test), human immunodeficiency virus (HIV), hepatitis B and hepatitis C. Antibody profiles of ParvoB19, Varicella and Rubella were negative. Additional history taking revealed that patient had had contact with a measles infected neighbor at his home. Immunization history, however, remained unknown. The patient was discharged on day 21 and was lost for follow-up. Discussion In 2011, 30 567 cases of measles were reported by the countries in the European Region of the World Health Organization (WHO). Suboptimal vaccination coverage over a period of time leads to the accumulation of susceptible individuals.3 In the United States of America and Europe, measles recent cases have been linked to families who opted out of having their children vaccinated highly influenced by anti-vaccination movements. Anti-vaccination attitudes are often supported by religious or philosophical beliefs. These religious minorities represent pockets of under-immunized populations.3 Suboptimal
633
Tirado et al.
Fig. 2. Right temple. A) Multiple dyskeratotic keratinocytes, partially confluent and partially isolated, restricted within follicles and sebaceous glands (circles), HE 40×. B) Dyskeratotic keratinocytes and necrosis within a sebaceous gland, HE 400×. C) None necrotic syncytial-type multinucleated epithelial cell showed moderately eosinophilic cytoplasm and three to five irregularly shaped nuclei with indistinct nucleoli packed together (circle), HE 400×. D) Second follicle showing multiple dyskeratotic keratinocytes, partially confluent and partially isolated, HE 100× and (E) 400×. (F) Third and fourth follicle showing multiple dyskeratotic keratinocytes, partially confluent and partially isolated, HE 100×. G) Third follicle, 400×. H) Fourth follicle showing a necrotic syncytial-type multinucleated epithelial cell.
vaccination coverage over a period of time and reduction in herd immunity leads to the accumulation of susceptible individuals that increases the risk of developing measles.5 Also, immunity is often incomplete after a single dose. This is particularly true if the vaccine was administered during the first year of life. In the early 1990s, it was recommended that patients receive a booster dose of the combined measles-mump-rubella vaccine.6 Even in the context of vaccination, it is possible to contract measles after having had the appropriate vaccinations as reported for 15% of cases in the European outbreaks.5 Pregnant women might be at high risk for severe measles and complications. The disease may also be associated with increased rates of spontaneous abortion, premature labor and preterm delivery and low birthweight.7
634
Few descriptions of histopathologic findings in lesions of the measles exanthem have been published. A summary of cutaneous and noncutaneous histopathologic features described in various reports can be found in Table 1. Ackerman et al. emphasized the syncytial-type multinucleate epithelial cell as the most specific finding of skin lesions in measles infection.9 The multinucleate cells, have been found associated to areas of spongiosis with or without necrotic keratinocytes and parakeratosis within the epidermis9,12 or strictly within follicular epithelium.14,15 The number of nuclei within syncytial-type multinucleate ranges from 3 to 26, it usually being about 5,9 irregular in shape, tightly packed-like pieces of a jigsaw puzzle and with indistinct nuclei.18 The chromatin pattern of nuclei in epidermal multinucleate
Year
1970
1971
1975
1992
1994
1998
2005
2011
2012
Author
Cutaneous Suringa8
Ackerman9
Kimura10
McNutt11
Makino12
Yanagihara13
Yoshida14
Scrivener15
Sheikine2
Focal Follicle Focal Strictly follicle (outer root sheath and sebaceous gland) Epidermis Follicle Acrosyringium
Focal Acrosyringium and follicle
Epidermal upper and basal layers HIV+ patient Focal Epidermal Follicular
Epidermal
Focal Upper epidermis Primarily around adnexae
Focal Epidermis
Area involved
Yes Single and clusters
Yes
No
Yes Associated to other epidermal changes
Yes Associated to other epidermal changes
Yes Single
Yes Single
Yes Associated to other epidermal changes
Yes
Necrotic cells
Yes Serial sections necessary to discover
Yes
Yes
Yes Associated to necrotic cells
Yes Associated to other epidermal changes
Yes
Yes Always among spongiosis No. of nuclei 3–26 Serial sections necessary to discover Normal chromatin pattern Yes
Yes No. of nuclei 3–26
Syncytial multinucleated giant cells
Table 1. Summary of reported histologic findings in patients diagnosed with measles infection
Possible epithelial inclusions
Yes Epithelial
No
Yes Epithelial Cytoplasmic and nuclear Pink-staining No
Yes Nuclear
Epidermal inclusion-like eosinophilic bodies
Yes Epithelial Cytoplasmic and nuclear Pink-staining
Yes Epithelial Cytoplasmic and nuclear Pink-staining
Intracellular inclusions
Focal spongiosis associated to eosinophils Vacuolar change
Spongiosis with eosinophilic bodies IHC: + measles virus antigen in necrotic cells, cells of acrosyringium and infundibular cells EM: nuclear microtubule aggregates in acrosyringial cells IHC: + measles virus antigen in giant cells of the follicles Spongiosis of the follicle
Hyperkeratosis Parakeratosis Spongiosis
Spongiosis, hyperkeratosis, focal parakeratosis, dermal edema EM: cytoplasmic microtubule aggregates in endothelial cells and rarely lymphocytes Psoriasiform hyperplasia Focal parakeratosis
Focal parakeratosis, spongiosis associated with a few lymphocytes. Electron microscopy EM: nuclear and cytoplasmic microtubule aggregates in epidermal cells Focal parakeratosis, spongiosis associated with lymphocytes
Additional findings
Dermal perifollicular Lymphocytes, eosinophils and some neutrophils
Dermal perifollicular lymphocytic and some neutrophils
Dermal perifollicular lymphocytic
Dermal superficial, perivascular, lymphocytes and neutrophils
Dermal superficial, perivascular, lymphohistiocytic
Dermal superficial, perivascular, lymphocytes and eosinophils
Dermal Lymphocytes & monocytes
Dermal superficial, sparse, perivascular, lymphohistiocytic
Dermal superficial, sparse, perivascular, lymphohistiocytic
Associated inflammatory infiltrate
Follicular necrotic keratinocytes
635
636
2014
2014
Hay6
Our case
1998
Orenstein18
Hyperplastic lymph node, tonsil, adenoid, and gastrointestinal Follicular dentritic cells HIV+ patients without measles infection
Appendix germinal centers & focal epithelium Focal epithelium Lung Epithelial lining alveoli
Focal Strictly follicle and sebaceous gland
Epidermis Follicle
Area involved
Not mentioned
Not mentioned
Few necrotic epithelial cells
Yes Multifocal Satellite cell necrosis Yes Single and clusters
Necrotic cells
WFGC
Yes
WFGC
Yes # nuclei 6 Serial sections necessary to discover
Not mentioned
Syncytial multinucleated giant cells
Not mentioned
Yes Intranuclear Eosinophilic Multinucleated cells
No
No
Not mentioned
Intracellular inclusions
EM, electron microscopy; HIV, human immunodeficiency virus; IHC, immunohistochemistry; WFGC, Warthin-Finkeldey-type giant cells.
1996
Rahman17
Noncutaneous 1991 Gaulier16
Year
Author
Table 1. continued
Edema, congestion, fibrosis and hyaline membranes IHC: + measles virus antigen EM: inclusions containing tubuloannular structures IHC: + CD21, CD35 & vimentin in WFGC
Diffuse hyperplasia of lymphoid tissue
Hyperkeratosis Parakeratosis Dermal-epidermal circumscribed vacuolar change
Not mentioned
Additional findings
Lymphocytes
Interstitial parenchymal lymphocytic
Polymorphonuclear infiltrate Immunoblastic cells
Dermal mild superficial & deep perivascular lymphohistiocytic
Dermal Superficial, perivascular lymphocytic with atypia
Associated inflammatory infiltrate
Tirado et al.
Follicular necrotic keratinocytes Table 2. Differential diagnosis of cutaneous measles infection histopathologically Differential diagnosis In the absence of giant cells Measles infection
Hypersensitivity and drug reactions
Papular stage of coxsackie infection Pityriasis rosea Subacute contact dermatitis In the presence of giant cells Herpes virus infection Squamous cell carcinoma
Distinguishing feature
Common feature
Changes can involve strictly adnexae14,15 Giant cells can be found in serial sections with normal chromatin pattern9 and nuclear or cytoplasmic inclusions2,8 – 12,15 Scattered necrotic keratinocytes along the dermo-epidermal junction9 Mostly superficial perivascular infiltrate9 Scattered necrotic keratinocytes throughout all levels of the epidermis19 Usually devoid of necrotic keratinocytes9 Usually devoid of necrotic keratinocytes9
Parakeratosis Necrotic keratinocytes Spongiosis
Larger cells, with molding of ground glass nuclei and marginated chromatin9 Atypia9 Lack inclusion bodies9
Giant cells 2,6,8 – 18 Necrotic keratinocytes 2,6,8 – 13,15
cells of measles appears to be normal.8 These syncytial-type multinucleate epithelial cells may or may not show both intranuclear and intracytoplasmic eosinophilic inclusion bodies.2,8,12,13 The inflammatory infiltrate was described in most reports as being predominated by lymphocytes with occasional neutrophils7 – 9,11 – 14 and eosinophils.2,10 Syncytial-type multinucleated giant cells (typically in measles infection called Warthin–Finkeldey cells) have been described in inflammatory reactions of other tissues (such as lymphoid and lung tissue) in patients with measles infection.16 – 18 They have also been reported in other viral infections, such as HSV I and II, HIV, parainfluenza type 2 and type 3 and respiratory syncytial viruses.17,18 Consideration has been given to the possibility that these giant cells actually represent a heterogeneous population of similar-appearing cells of various etiologies.18 Serial sections are often necessary to reveal multinucleated cells in lesions of measles.
Several differential diagnoses must be taken into consideration in the presence or absence of multinucleated cells in skin biopsies of initial stages of non-specific cutaneous rashes.2,9,19 A summary of differential diagnoses can be found in Table 2. In conclusion, small regional outbreaks of measles, although rare, can occur because of suboptimal vaccination coverage over periods of time. Therefore, it is important to be familiar with the characteristic cutaneous histopathologic findings of measles infection. These findings include foci of parakeratosis, necrotic keratinocytes, spongiosis and multinucleated syncytial giant cells, mild vacuolar change and a dermal superficial and deep perivascular infiltrate of lymphocytes and histiocytes predominantly with some neutrophils and eosinophils. Restriction of cytopathic changes to follicular and sebaceous epithelium is a rather typical feature of the measles exanthem. However, serial sections are often necessary to reveal unequivocally diagnostic features.
References 1. de Vries RD, Mesman AW, Geijtenbeek TBH, Duprex WP, de Swart RL. The pathogenesis of measles. Curr Opin Virol 2012; 2: 248. 2. Sheikine Y, Hawryluck EB, Burgin S, Zimarowski MJ. Histopathology of measles exanthem: a case with characteristic features and eosinophils. J Cutan Pathol 2012; 39: 667.
3. Carrillo-Santisteve P, Lopalco PL. Measles still spreads in Europe: who is responsible for the failure to vaccinate? Clin Microbiol Infect 2012; 18(Suppl. 5): 50. 4. Seitz C, Rose C, Kerstan A, Trautmann A. Drug-induced exanthems: correlation of allergy testing with histologic diagnosis. J Am Acad Dermatol 2013; 69: 721. 5. Muscat M. Who gets measles in Europe? J Infect Dis 2011; 204(Suppl 1): S353.
6. Hay CM, Shepard JO, Hyle EP, Duncan LM. Case 23–2014: a 41-year-old man with fevers, rash, pancytopenia, and abnormal liver function. N Engl J Med 2014; 371: 358. 7. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS, Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations
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8.
9.
10.
11.
12.
of the Advisory Committee on Immunization Practices (ACIP). MMWR. Recomm Rep 2013; 62(RR-04): 1. Suringa DW, Bank LJ, Ackerman AB. Role of measles virus in skin lesions and Koplik’s spots. N Engl J Med 1970; 283: 1139. Ackerman AB, Suringa D. Multinucleate epidermal cells in measles: a histologic study. Arch Dermatol 1971; 103: 180. Kimura A, Tosaka K, Nakao T. Measles rash. I. Light and electron microscopic study of skin eruptions. Arch Virol 1975; 47: 295. McNutt NS, Kindel S, Lugo J. Cutaneous manifestations of measles in AIDS. J Cutan Pathol 1992; 19: 315. Makino S, Yamaguchi F, Sata T, Urushibata Kurata T, Nishiwaki M. The rash of measles
638
13.
14.
15.
16.
is caused by a viral infection in the cells of the skin: a case report. J Dermatol 1994; 21: 741. Yanagihara M, Fujii T, Mochizuki T, Ishizaki H, Sata T. Measles virus was present in the inner cell of the acrosyringium in the skin rash. Pediatr Dermatol 1998; 15: 456. Yoshida M, Yamada Y, Kawahara K, Itoh M. Development of follicular rash in measles. Br J Dermatol 2005; 153: 1226. Scrivener Y, Marcil T, Lipsker D, Cribier B. Measles: a follicular disease. Ann Dermatol Venereol 2011; 138: 111. Gaulier A, Sabatier P, Prevot S, Fournier JG. Do measles early giant cells result from fusion of non-infected cells? An immunohistochemical and in situ hybridization
study in a case of morbillous appendicitis. Virchows Arch A Pathol Anat Histopathol 1991; 419: 245. 17. Rahman SM, Eto H, Morshed SA, Itakura H. Giant cell pneumonia: light microscopy, immunohistochemical, and ultrastructural study of an autopsy case. Ultrastruct Pathol 1996; 20: 585. 18. Orenstein JM. The Warthin-Finkeldey-type giant cell in HIV infection, what is it? Ultrastruct Pathol 1998; 22: 293. 19. Haneke E. Electron microscopic demonstration of virus particles in hand, foot and mouth disease. Dermatologica 1985; 171: 321.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Follicular necrotic keratinocytes – a helpful clue to the diagnosis of measles A skin specimen taken from the exanthem of a 22-year-old man with measles infection was examined by light microscopy. The most characteristic changes were foci of multiple necrotic keratinocytes, partially confluent and partially isolated, strictly within follicles and sebaceous glands. Serial sections revealed occasional necrotic and none-necrotic syncytial-type multinucleated epithelial cells in some infundibula. Neither nuclear nor cytoplasmic viral inclusions were present.
Mariantonieta Tirado1 , Karoline Adamzik2 and Almut Böer-Auer3
Keywords: dermatopathology, exanthema, follicular necrotic keratinocytes, measles, syncytial-type multinucleated epithelial cell
Mariantonieta Tirado, MD, Dermatology Diagnostics, Histologie Labor 1. Stock, Drehbahn 1–3, 20354, Hamburg, Germany Tel: +049 152 0433 1088 Fax: +049 40 350 17714 e-mail: [email protected]
Tirado M, Adamzik K, Böer-Auer A. Follicular necrotic keratinocytes – a helpful clue to the diagnosis of measles. J Cutan Pathol 2015; 42: 632–638. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Measles is a highly contagious viral disease caused by a virus belonging to the Paramyxoviridae family, genus Morbillivirus. The maculopapular rash of measles occurs three or four days after the onset of fever, malaise and headache in conjunction with cough, coryza and conjunctivitis. Measles virus is transmitted by aerosols entering the respiratory tract or by direct contact with respiratory secretions.1 The disease is largely self-limiting in immunocompetent and immunized individuals, but may be severe and even deadly in immunocompromised patients.2 Those who survive the virus can suffer respiratory and neurological complications.3 The exanthem of measles infection is clinically distinctive but clinicians may confuse it with other infectious or allergic exanthems because of a lack of experience with the disease or an unusual presentation.4 In such cases, biopsies may be submitted to a dermatopathology service to rule out an infectious cause. Often, exanthems of infectious diseases are not
632
1
Department of Pathology, Marienkrankenhaus Hamburg/Dermatology Diagnostics, Hamburg, Germany, 2 Department of Dermatology, University of Kiel, Kiel, Germany , and 3 Department of Dermatology, Dermatologikum Hamburg, Hamburg, Germany
Accepted for publication May 7, 2015
distinctive on histopathology and difficult to tell from allergic reactions. Case report A 22-year-old complaining of hallucinations under alcohol influence was presented by a social worker to the psychiatric department. The patient was admitted to the psychiatric ward and treatment with clorazepate dipotassium and vitamin B was initiated. After 12 days of hospitalization, he developed a skin rash. Cutaneous examination revealed an exanthem on the face and chest with mild pruritus. Palms and soles were uninvolved. There was no documentation of mucosal involvement. The patient also had 39 ∘ C fever, dry cough, odynophagia, back pain and diarrhea. Laboratory studies were significant for a white blood cell count of 7.2 nl with 74.9% of neutrophils, 13.3% of lymphocytes and 11.2% of monocytes. Toxicology screen was positive
Follicular necrotic keratinocytes
Fig. 1. Right shoulder. A) Orthokeratosis, focal parakeratosis, focal dyskeratotic cells and mild vacuolar change of the epidermal-dermal junction, HE 100× (B) 400× (C) Fourth serial section showing focal dyskeratotic cells strictly within the follicle, HE 100× and (D) 400×.
for Cannabis, Diclofenac and Paracetamol. Two skin biopsies were obtained from the exanthem, one from the right shoulder, the other from the right temple. Histopathology revealed basket-woven orthokeratosis with superimposed parakeratosis. Circumscribed-basal vacuolar change was seen with associated lymphocytes (Fig. 1A,B). Multiple dyskeratotic keratinocytes, partially confluent and partially isolated, were present within follicles and sebaceous glands (Figs. 1C,D and 2A,B,D,E,F,G). Serial sections revealed occasional multinucleated keratinocytes, necrotic and none-necrotic, in some infundibula. The multinucleated keratinocytes showed moderately eosinophilic cytoplasm and three to six irregularly shaped nuclei with indistinct nucleoli packed together (Fig. 2C,H). No cytoplasmic or nuclear inclusions, no abnormal chromatin distribution nor atypia was seen within epithelial cells or lymphocytes. No ballooning or acantholysis were encountered. The dermis showed a mild superficial and deep perivascular lymphohistiocytic infiltrate and some extravasated erythrocytes. Polymerase chain reaction assessment of the biopsy for Herpes simplex (HSV-1/2), Varicella zoster and Treponema pallidum was negative. With the combined clinical presentation and histologic findings, a viral infection including measles and coxsackie infections were
considered as differential diagnoses. Shortly thereafter, the results of serology testing arrived reavealing measles IgM-antibodies of 504 U/ml and IgG-antibodies of 230mlU/ml. Additional laboratory studies included negative testing for syphilis (rapid plasma regain test), human immunodeficiency virus (HIV), hepatitis B and hepatitis C. Antibody profiles of ParvoB19, Varicella and Rubella were negative. Additional history taking revealed that patient had had contact with a measles infected neighbor at his home. Immunization history, however, remained unknown. The patient was discharged on day 21 and was lost for follow-up. Discussion In 2011, 30 567 cases of measles were reported by the countries in the European Region of the World Health Organization (WHO). Suboptimal vaccination coverage over a period of time leads to the accumulation of susceptible individuals.3 In the United States of America and Europe, measles recent cases have been linked to families who opted out of having their children vaccinated highly influenced by anti-vaccination movements. Anti-vaccination attitudes are often supported by religious or philosophical beliefs. These religious minorities represent pockets of under-immunized populations.3 Suboptimal
633
Tirado et al.
Fig. 2. Right temple. A) Multiple dyskeratotic keratinocytes, partially confluent and partially isolated, restricted within follicles and sebaceous glands (circles), HE 40×. B) Dyskeratotic keratinocytes and necrosis within a sebaceous gland, HE 400×. C) None necrotic syncytial-type multinucleated epithelial cell showed moderately eosinophilic cytoplasm and three to five irregularly shaped nuclei with indistinct nucleoli packed together (circle), HE 400×. D) Second follicle showing multiple dyskeratotic keratinocytes, partially confluent and partially isolated, HE 100× and (E) 400×. (F) Third and fourth follicle showing multiple dyskeratotic keratinocytes, partially confluent and partially isolated, HE 100×. G) Third follicle, 400×. H) Fourth follicle showing a necrotic syncytial-type multinucleated epithelial cell.
vaccination coverage over a period of time and reduction in herd immunity leads to the accumulation of susceptible individuals that increases the risk of developing measles.5 Also, immunity is often incomplete after a single dose. This is particularly true if the vaccine was administered during the first year of life. In the early 1990s, it was recommended that patients receive a booster dose of the combined measles-mump-rubella vaccine.6 Even in the context of vaccination, it is possible to contract measles after having had the appropriate vaccinations as reported for 15% of cases in the European outbreaks.5 Pregnant women might be at high risk for severe measles and complications. The disease may also be associated with increased rates of spontaneous abortion, premature labor and preterm delivery and low birthweight.7
634
Few descriptions of histopathologic findings in lesions of the measles exanthem have been published. A summary of cutaneous and noncutaneous histopathologic features described in various reports can be found in Table 1. Ackerman et al. emphasized the syncytial-type multinucleate epithelial cell as the most specific finding of skin lesions in measles infection.9 The multinucleate cells, have been found associated to areas of spongiosis with or without necrotic keratinocytes and parakeratosis within the epidermis9,12 or strictly within follicular epithelium.14,15 The number of nuclei within syncytial-type multinucleate ranges from 3 to 26, it usually being about 5,9 irregular in shape, tightly packed-like pieces of a jigsaw puzzle and with indistinct nuclei.18 The chromatin pattern of nuclei in epidermal multinucleate
Year
1970
1971
1975
1992
1994
1998
2005
2011
2012
Author
Cutaneous Suringa8
Ackerman9
Kimura10
McNutt11
Makino12
Yanagihara13
Yoshida14
Scrivener15
Sheikine2
Focal Follicle Focal Strictly follicle (outer root sheath and sebaceous gland) Epidermis Follicle Acrosyringium
Focal Acrosyringium and follicle
Epidermal upper and basal layers HIV+ patient Focal Epidermal Follicular
Epidermal
Focal Upper epidermis Primarily around adnexae
Focal Epidermis
Area involved
Yes Single and clusters
Yes
No
Yes Associated to other epidermal changes
Yes Associated to other epidermal changes
Yes Single
Yes Single
Yes Associated to other epidermal changes
Yes
Necrotic cells
Yes Serial sections necessary to discover
Yes
Yes
Yes Associated to necrotic cells
Yes Associated to other epidermal changes
Yes
Yes Always among spongiosis No. of nuclei 3–26 Serial sections necessary to discover Normal chromatin pattern Yes
Yes No. of nuclei 3–26
Syncytial multinucleated giant cells
Table 1. Summary of reported histologic findings in patients diagnosed with measles infection
Possible epithelial inclusions
Yes Epithelial
No
Yes Epithelial Cytoplasmic and nuclear Pink-staining No
Yes Nuclear
Epidermal inclusion-like eosinophilic bodies
Yes Epithelial Cytoplasmic and nuclear Pink-staining
Yes Epithelial Cytoplasmic and nuclear Pink-staining
Intracellular inclusions
Focal spongiosis associated to eosinophils Vacuolar change
Spongiosis with eosinophilic bodies IHC: + measles virus antigen in necrotic cells, cells of acrosyringium and infundibular cells EM: nuclear microtubule aggregates in acrosyringial cells IHC: + measles virus antigen in giant cells of the follicles Spongiosis of the follicle
Hyperkeratosis Parakeratosis Spongiosis
Spongiosis, hyperkeratosis, focal parakeratosis, dermal edema EM: cytoplasmic microtubule aggregates in endothelial cells and rarely lymphocytes Psoriasiform hyperplasia Focal parakeratosis
Focal parakeratosis, spongiosis associated with a few lymphocytes. Electron microscopy EM: nuclear and cytoplasmic microtubule aggregates in epidermal cells Focal parakeratosis, spongiosis associated with lymphocytes
Additional findings
Dermal perifollicular Lymphocytes, eosinophils and some neutrophils
Dermal perifollicular lymphocytic and some neutrophils
Dermal perifollicular lymphocytic
Dermal superficial, perivascular, lymphocytes and neutrophils
Dermal superficial, perivascular, lymphohistiocytic
Dermal superficial, perivascular, lymphocytes and eosinophils
Dermal Lymphocytes & monocytes
Dermal superficial, sparse, perivascular, lymphohistiocytic
Dermal superficial, sparse, perivascular, lymphohistiocytic
Associated inflammatory infiltrate
Follicular necrotic keratinocytes
635
636
2014
2014
Hay6
Our case
1998
Orenstein18
Hyperplastic lymph node, tonsil, adenoid, and gastrointestinal Follicular dentritic cells HIV+ patients without measles infection
Appendix germinal centers & focal epithelium Focal epithelium Lung Epithelial lining alveoli
Focal Strictly follicle and sebaceous gland
Epidermis Follicle
Area involved
Not mentioned
Not mentioned
Few necrotic epithelial cells
Yes Multifocal Satellite cell necrosis Yes Single and clusters
Necrotic cells
WFGC
Yes
WFGC
Yes # nuclei 6 Serial sections necessary to discover
Not mentioned
Syncytial multinucleated giant cells
Not mentioned
Yes Intranuclear Eosinophilic Multinucleated cells
No
No
Not mentioned
Intracellular inclusions
EM, electron microscopy; HIV, human immunodeficiency virus; IHC, immunohistochemistry; WFGC, Warthin-Finkeldey-type giant cells.
1996
Rahman17
Noncutaneous 1991 Gaulier16
Year
Author
Table 1. continued
Edema, congestion, fibrosis and hyaline membranes IHC: + measles virus antigen EM: inclusions containing tubuloannular structures IHC: + CD21, CD35 & vimentin in WFGC
Diffuse hyperplasia of lymphoid tissue
Hyperkeratosis Parakeratosis Dermal-epidermal circumscribed vacuolar change
Not mentioned
Additional findings
Lymphocytes
Interstitial parenchymal lymphocytic
Polymorphonuclear infiltrate Immunoblastic cells
Dermal mild superficial & deep perivascular lymphohistiocytic
Dermal Superficial, perivascular lymphocytic with atypia
Associated inflammatory infiltrate
Tirado et al.
Follicular necrotic keratinocytes Table 2. Differential diagnosis of cutaneous measles infection histopathologically Differential diagnosis In the absence of giant cells Measles infection
Hypersensitivity and drug reactions
Papular stage of coxsackie infection Pityriasis rosea Subacute contact dermatitis In the presence of giant cells Herpes virus infection Squamous cell carcinoma
Distinguishing feature
Common feature
Changes can involve strictly adnexae14,15 Giant cells can be found in serial sections with normal chromatin pattern9 and nuclear or cytoplasmic inclusions2,8 – 12,15 Scattered necrotic keratinocytes along the dermo-epidermal junction9 Mostly superficial perivascular infiltrate9 Scattered necrotic keratinocytes throughout all levels of the epidermis19 Usually devoid of necrotic keratinocytes9 Usually devoid of necrotic keratinocytes9
Parakeratosis Necrotic keratinocytes Spongiosis
Larger cells, with molding of ground glass nuclei and marginated chromatin9 Atypia9 Lack inclusion bodies9
Giant cells 2,6,8 – 18 Necrotic keratinocytes 2,6,8 – 13,15
cells of measles appears to be normal.8 These syncytial-type multinucleate epithelial cells may or may not show both intranuclear and intracytoplasmic eosinophilic inclusion bodies.2,8,12,13 The inflammatory infiltrate was described in most reports as being predominated by lymphocytes with occasional neutrophils7 – 9,11 – 14 and eosinophils.2,10 Syncytial-type multinucleated giant cells (typically in measles infection called Warthin–Finkeldey cells) have been described in inflammatory reactions of other tissues (such as lymphoid and lung tissue) in patients with measles infection.16 – 18 They have also been reported in other viral infections, such as HSV I and II, HIV, parainfluenza type 2 and type 3 and respiratory syncytial viruses.17,18 Consideration has been given to the possibility that these giant cells actually represent a heterogeneous population of similar-appearing cells of various etiologies.18 Serial sections are often necessary to reveal multinucleated cells in lesions of measles.
Several differential diagnoses must be taken into consideration in the presence or absence of multinucleated cells in skin biopsies of initial stages of non-specific cutaneous rashes.2,9,19 A summary of differential diagnoses can be found in Table 2. In conclusion, small regional outbreaks of measles, although rare, can occur because of suboptimal vaccination coverage over periods of time. Therefore, it is important to be familiar with the characteristic cutaneous histopathologic findings of measles infection. These findings include foci of parakeratosis, necrotic keratinocytes, spongiosis and multinucleated syncytial giant cells, mild vacuolar change and a dermal superficial and deep perivascular infiltrate of lymphocytes and histiocytes predominantly with some neutrophils and eosinophils. Restriction of cytopathic changes to follicular and sebaceous epithelium is a rather typical feature of the measles exanthem. However, serial sections are often necessary to reveal unequivocally diagnostic features.
References 1. de Vries RD, Mesman AW, Geijtenbeek TBH, Duprex WP, de Swart RL. The pathogenesis of measles. Curr Opin Virol 2012; 2: 248. 2. Sheikine Y, Hawryluck EB, Burgin S, Zimarowski MJ. Histopathology of measles exanthem: a case with characteristic features and eosinophils. J Cutan Pathol 2012; 39: 667.
3. Carrillo-Santisteve P, Lopalco PL. Measles still spreads in Europe: who is responsible for the failure to vaccinate? Clin Microbiol Infect 2012; 18(Suppl. 5): 50. 4. Seitz C, Rose C, Kerstan A, Trautmann A. Drug-induced exanthems: correlation of allergy testing with histologic diagnosis. J Am Acad Dermatol 2013; 69: 721. 5. Muscat M. Who gets measles in Europe? J Infect Dis 2011; 204(Suppl 1): S353.
6. Hay CM, Shepard JO, Hyle EP, Duncan LM. Case 23–2014: a 41-year-old man with fevers, rash, pancytopenia, and abnormal liver function. N Engl J Med 2014; 371: 358. 7. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS, Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations
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study in a case of morbillous appendicitis. Virchows Arch A Pathol Anat Histopathol 1991; 419: 245. 17. Rahman SM, Eto H, Morshed SA, Itakura H. Giant cell pneumonia: light microscopy, immunohistochemical, and ultrastructural study of an autopsy case. Ultrastruct Pathol 1996; 20: 585. 18. Orenstein JM. The Warthin-Finkeldey-type giant cell in HIV infection, what is it? Ultrastruct Pathol 1998; 22: 293. 19. Haneke E. Electron microscopic demonstration of virus particles in hand, foot and mouth disease. Dermatologica 1985; 171: 321.
