J Cutan Pathol 2015: 42: 554–558 doi: 10.1111/cup.12540 John Wiley & Sons. Printed in Singapore
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Eosinophil-rich syphilis: a report of four cases The differential diagnosis for eosinophil-rich skin lesions often includes a drug reaction, allergic contact dermatitis and rarely, response to a helminth infection. However, many unrelated entities, such as infections, neoplasms and inflammatory dermatoses, can have a prominent eosinophilic infiltrate. Syphilis is classically associated with plasma cells, but other patterns of inflammation have been reported, including ulcerative, granulomatous and eosinophil-rich. Classic teaching might indicate that the presence of eosinophils argues against a diagnosis of syphilis. We present four cases of secondary syphilis with increased eosinophils, ranging from 8 to >200 eosinophils per 10 high-power fields (×400 magnification). Patient 1 had lesions on the penis and scrotum, with greater than 200 eosinophils per 10 high-power fields. Patient 2 had lesions on the back, with 150 eosinophils per 10 high-power fields. Patient 3 had lesions on the bilateral arms, with 8 eosinophils per 10 high-power fields. Patient 4 had lesions involving the anus, with 17 eosinophils per 10 high-power fields. These cases highlight that the presence of an eosinophil-rich infiltrate on skin biopsy should not exclude syphilis from the differential diagnosis. Keywords: dermatopathology, histopathology, pathology, skin Rosa G, Bennett D, Piliang MP. Eosinophil-rich syphilis: a report of four cases. J Cutan Pathol 2015; 42: 554–558. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Syphilis has been called ‘the great imitator’ of skin diseases because of its varied presentation that often mimics other diseases, making a clinical diagnosis challenging.1 The term ‘great imitator’ also applies to microscopic findings. In a review of the histopathologic patterns of secondary syphilis, Bernie Ackerman wrote, ‘the histopathologic variations of secondary syphilis proved to be as protean as the clinical presentation’.2 Classically, secondary syphilis has a superficial and deep perivascular plasma cell infiltrate with endothelial cell swelling.3 Granulomatous, eosinophil-rich, lichen planus-like and psoriasiform patterns have also been reported.2 – 5 Nodular lesions in
554
Gabriela Rosa1 , Dan Bennett2 and Melissa P. Piliang3 1
Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA, 2 Department of Dermatology, University of Wisconsin, Madison, WI, USA, and 3 Sections of the Departments of Dermatology and Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
Dr. Melissa P. Piliang, Sections of the Departments of Dermatology and Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA Tel: +216 444 5722 Fax: +216 231 5448 e-mail: [email protected] Accepted for publication January 11, 2015
secondary syphilis, rather than the typical maculopapular lesions seen clinically, are reported as well.5,6 Drug reactions and allergic contact dermatitis are often the primary consideration in eosinophil-rich skin lesions biopsied in the United States. A recent editorial highlighted the potential diagnostic pitfall of limiting our diagnoses in eosinophil-rich lesions, as a wide spectrum of diseases, including lichen planus and melanocytic tumors, can have increased eosinophils.7 In one study on the pathologic features of alopecia areata, nearly half of the cases had eosinophils within fibrous tracts.8 Although syphilis is rare, affecting 5.3 per 100,000 in 2013, the incidence of syphilis in the United
Eosinophil-rich syphilis States nearly doubled from 2005 to 2013, with high rates of human immunodeficiency virus (HIV) co-infection.9 Awareness of the varied histopathologic presentation, which includes eosinophil-rich infiltrates, can be important in recognizing secondary syphilis. Materials and methods In routine sign out, we encountered three cases of syphilis with increased eosinophils, ranging from 17 to >200 eosinophils per 10 high-power fields (×400 magnification per field). Two cases were seen at the Cleveland Clinic and one case was seen at the University of Wisconsin. The patients in all cases had a positive rapid plasma reagin (RPR) and treponemes were seen on syphilis immunohistochemistry. The institutional files at the Cleveland Clinic were then searched for 20 years, from January 1, 1992 to October 29, 2013, yielding 14 biopsy specimens from 13 patients (two biopsies from one patient). All patients had serologic evidence of syphilis or positive syphilis immunohistochemistry at the time of their skin biopsies. Eosinophils were counted per 10 high-power fields. Of these 14 in-house cases, only 1 case had noticeable eosinophils, with 8 per 10 high-power fields. We collaborated to submit these four cases with increased eosinophils, three seen incidentally in sign out and one seen upon review of the institutional files, as examples of secondary syphilis with increased eosinophils. Results Patient 1 was a 30-year-old man with a 6 month history of a burning rash involving the scrotum and penis. The lesions were thin pink annular plaques, clinically suspected to be lichen planus, granuloma annulare or sarcoidosis. He was applying only petroleum jelly to the lesions. A shave biopsy of the lesion showed an epidermis with ice-pick hyperplasia and a large subcorneal pustule. A dense infiltrate, predominantly composed of eosinophils, with admixed neutrophils, lymphocytes and rare plasma cells was present at the dermal–epidermal junction and superficial vascular spaces. There was prominent eosinophilic exocytosis, extending through all layers of the epidermis and eosinophilic spongiosis (Figs. 1 and 2). The eosinophil count in the dermis and epidermis was greater than 200 per 10 high-power fields. Syphilis immunohistochemistry was positive for treponemes. Subsequent RPR was positive while testing for HIV was negative.
Fig. 1. Case 1 with a dense eosinophil infiltrate in the epidermis, extending into a subcorneal pustule (hematoxylin and eosin, ×100).
Patient 2 was a 50-year-old man who presented for evaluation of annular lesions of the back and legs. The clinical differential included annular psoriasis, subacute cutaneous lupus erythematosus and granuloma annulare. Histopathologic evaluation revealed a neutrophilic crust and psoriasiform hyperplasia, in association with a lichenoid infiltrate in the superficial dermis, and a superficial and deep perivascular and periadnexal mixed infiltrate composed of lymphocytes, histiocytes, plasma cells and numerous eosinophils (Fig. 3). The eosinophil count was 150 per 10 high-power fields. Given the presence of plasma cells and the pattern of inflammation, immunohistochemical staining for Treponema pallidum was performed, which showed spirochetes within the epidermis. Additional clinical information was not available, as this case was reviewed in consultation. Patient 3 was a 35-year-old man with a known history of HIV, who presented with a 2 month history of a rash that started on his face and spread to his trunk. Clinical exam showed erythematous, crusted plaques involving the face, scalp, neck and upper chest. There were multiple papules and small plaques 0.5–1.5 cm in diameter on the chest, upper abdomen, back and bilateral arms (Fig. 4). The clinical differential included guttate psoriasis, pityriasis lichenoides et varioliformis acuta (PLEVA), viral reaction and cutaneous lymphoma. A skin biopsy from his chest showed a minimally hyperplastic epidermis with interface change and lymphocytic exocytosis. The dermis had a brisk perivascular and periadnexal mixed infiltrate of histiocytes, lymphocytes, plasma cells and eosinophils. Eight eosinophils were seen in 10 high-power fields. There was no eosinophilic exocytosis (Fig. 5). The RPR was positive at a 1 : 1024 dilution. The patient had no change in
555
Rosa et al.
Fig. 2. Case 1 with eosinophils at the dermal–epidermal junction (hematoxylin and eosin, ×200).
Fig. 4. Multiple erythematous papules involved the arm in patient 3.
Fig. 3. Case 2 with eosinophils in a mixed inflammatory infiltrate at the dermal–epidermal junction (hematoxylin and eosin, ×200 magnification).
mental status, but venereal disease research laboratory test (VDRL) of the cerebrospinal fluid was reactive at a 1 : 1 dilution, diagnostic of asymptomatic neurosphilis. Syphilis immunohistochemistry was not performed at the time, but was retrospectively performed and showed numerous treponemes (Fig. 6). The patient refused treatment with intramuscular benzathine penicillin and instead received intravenous penicillin G for 2 weeks, followed by oral doxycycline for 21 days. Within 1 month, his skin lesions were nearly completely healed. Repeat RPR titers were not performed as the patient was lost to clinical follow-up. Patient 4 was a 26-year-old man who was known to be HIV positive and was on anti-retroviral therapy. He presented to the emergency room with anal pain and bleeding. Examination revealed
556
Fig. 5. Case 3 with eosinophils adjacent to blood vessels in the superficial dermis (hematoxylin and eosin, ×400).
the patient’s anus was ulcerated with purulent drainage. The anal biopsy showed focal superficial ulceration and erosion of the epidermis with associated neutrophilic crust. The dermis had a mixed inflammatory infiltrate with numerous plasma cells, lymphocyte, neutrophils and eosinophils (Fig. 7). Seventeen eosinophils were
Eosinophil-rich syphilis
Fig. 6. Case 3 shows numerous spirochetes at the dermal–epidermal junction (Treponema pallidum immunohistochemical stain, ×400 magnification).
Fig. 7. Case 4 with eosinophils and hyperplastic vessels in the superficial dermis (hematoxylin and eosin, ×400).
seen in 10 high-power fields. Syphilis immunohistochemistry showed numerous treponemes. The RPR was positive at a 1 : 256 dilution and syphilis IgG was also positive. The patient was treated with oral doxycycline, because of a penicillin allergy. Repeat RPR titers were not yet available, given the recent onset of this patient’s presentation. In all cases, there was no known history of allergic contact dermatitis or drug hypersensitivity reaction. Discussion The recruitment of eosinophils in hypersensitivity phenomena (such as an insect bite reaction, drug reaction or allergic contact dermatitis) is thought to be related to cytokines, in particular interleukin (IL)-5, released by helper T cells.10 Other cytokines, including macrophage migration inhibitory factor (MIF), IL-3, IL-4 and IL-13 also recruit eosinophils.11,12 Several entities, including secondary syphilis, which are not related to hypersensitivity phenomena, have been associated with increased eosinophils.4,7,13
Some studies suggest that eosinophil attractant cytokines play a role in these non-hypersensitivity phenomena.12,14 Eosinophilic dermatosis of hematologic malignancy is a rare skin disease associated with chronic lymphocytic leukemia, which shows perivascular inflammation with increased eosinophils and mimics an insect bite.13 Davis et al. showed enhanced eosinophil survival in culture in the presence of tissue extracted from eosinophilic dermatosis of hematologic malignancy, indirectly revealing the presence of eosinophil attractant cytokines within lesions.15 Tissue eosinophilia has also been reported in secondary syphilis, but it is felt to be rare.4,7 Elevated levels of eosinophil chemoattractants have been documented in patients with syphilis. Podwinska et al. showed that blood cultures from syphilis patients in various stages of their disease had elevated IL-2, interferon (IFN), tumor necrosis factor (TNF) and MIF levels.14 Patients with secondary syphilis had the greatest amount of MIF production, which is an eosinophil chemoattractant.14 The findings were not correlated with the patients’ skin biopsies, but one could hypothesize increased eosinophils might then be seen on histopathology. This does not explain the apparent rarity of eosinophil-rich secondary syphilis, cited in case reports only. A dysregulation of cell-mediated immunity, with increased production of eosinophil chemoattractants, may play a role in our cases and other eosinophil-rich entities not typically associated with hypersensitivity reactions. Increased eosinophils probably represent one of the many histopathologic patterns seen in secondary syphilis. Even among our four cases, there were different microscopic patterns; one case had minimal hyperplastic changes and no acute inflammation, while the other cases had either psoriasiform or ice-pick hyperplasia with an associated mixed infiltrate, including neutrophils. These findings support the great variability in clinical and histopathologic presentation of secondary syphilis. The incidence of syphilis in the United States has been steadily rising since 2005. Men, particularly men who have sex with men (MSM), are at the highest risk.9 Thus, syphilis is an important diagnostic consideration in skin biopsies. It can be a challenging diagnosis because both the clinical and histopathologic appearance can vary and patients can be poor historians. Sharon et al. showed that eosinophils are rare to absent in pityriasis lichenoides, dermatomyositis, most forms of lupus erythematusus and
557
Rosa et al. graft-versus-host disease.16 In those entities, the increased eosinophils on skin biopsy might dissuade one from entertaining those diagnoses. Our cases illustrate that presence of eosinophils
should not dissuade one from including syphilis in the histopathologic differential diagnosis and obtaining supportive immunohistochemical or serologic studies.
References 1. Kent ME, Romanelli F. Re-examining syphilis: an update on epidemiological clinical manifestations and management. Ann Pharmacother 2008; 42: 226. 2. Jeerapaet P, Ackerman B. Histologic patterns of secondary syphilis. Arch Dermatol 1973; 107: 343. 3. Grayson W. Infectious diseases of the skin. In Calonje E, Brenn T, Lazar A, eds. Mckee’s pathology of the skin, 4th ed. Elsevier, China, 2012; 760. 4. Park J, Kim Y. Secondary syphilis with numerous eosinophils. J Cutan Pathol 2013; 40: 1064. 5. Rysgaard C, Alezander E, Swick B. Nodular secondary syphilis with associated granulomatous inflammations: case report and literature review. J Cutan Pathol 2014; 41: 370. 6. Papini M, Bettacchi A, Guiducci A. Nodular secondary syphilis. Br J Dermatol 1998; 138: 704. 7. McCalmont TH. Red alert or red herring. J Cutan Pathol 2014; 41: 337.
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8. Peckham SJ, Sloan SB, Elston DM. Histologic features of alopecia areata other than peribulbar lymphocytic infiltrates. J Am Acad Dermatol 2011; 65: 615. 9. CDC. Morbidity and mortality weekly report. Primary and secondary syphilis– United States, 2005–2013. URL www.cdc. gov/mmwr/preview/mmwrhtml/mm6318 a4.htm. [accessed on 24 Nov 2014]. 10. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol 2008; 20: 288. 11. Yoshihisa Y, Makino T, Matsunga K, et al. Macrophage migration inhibitory factor is essential for eosinophil recruitment in allergen-induced skin inflammation. J Invest Dermatol 2011; 131: 925. 12. Magalhães ES, Paiva CN, Souza HS, et al. Macrophage migration inhibitory factor is critical tointerleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection. FASEB J 2009; 23: 1262.
13. Farber MJ, Forgia SL, Sahu J, Lee JB. Eosinophilic dermatosis of hematologic malignancy. J Cutan Pathol 2012; 39: 690. 14. Podwiska J, Lusiak M, Zaba R, Bowszyc J. The pattern and level of cytokines secreted by Th1 and Th2 lymphocytes of syphilitic patients correlate to the progression of the disease. FEMS Immunol Med Microbiol 2000; 28: 1. 15. Davis MD, Perniciaro C, Dahl PR, Randle HW, McEvoy MT, Leiferman KM. Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: a clinical, histopathologic, and immunopathologic study of eight patients. J Am Acad Dermatol 1998; 39: 27. 16. Sharon VR, Konia TH, Barr KL, Fung MA. Assessment of the “no eosinophils” rule: are eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft versus host disease? J Cutan Pathol 2012; 39: 413.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Journal of Cutaneous Pathology
Eosinophil-rich syphilis: a report of four cases The differential diagnosis for eosinophil-rich skin lesions often includes a drug reaction, allergic contact dermatitis and rarely, response to a helminth infection. However, many unrelated entities, such as infections, neoplasms and inflammatory dermatoses, can have a prominent eosinophilic infiltrate. Syphilis is classically associated with plasma cells, but other patterns of inflammation have been reported, including ulcerative, granulomatous and eosinophil-rich. Classic teaching might indicate that the presence of eosinophils argues against a diagnosis of syphilis. We present four cases of secondary syphilis with increased eosinophils, ranging from 8 to >200 eosinophils per 10 high-power fields (×400 magnification). Patient 1 had lesions on the penis and scrotum, with greater than 200 eosinophils per 10 high-power fields. Patient 2 had lesions on the back, with 150 eosinophils per 10 high-power fields. Patient 3 had lesions on the bilateral arms, with 8 eosinophils per 10 high-power fields. Patient 4 had lesions involving the anus, with 17 eosinophils per 10 high-power fields. These cases highlight that the presence of an eosinophil-rich infiltrate on skin biopsy should not exclude syphilis from the differential diagnosis. Keywords: dermatopathology, histopathology, pathology, skin Rosa G, Bennett D, Piliang MP. Eosinophil-rich syphilis: a report of four cases. J Cutan Pathol 2015; 42: 554–558. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Syphilis has been called ‘the great imitator’ of skin diseases because of its varied presentation that often mimics other diseases, making a clinical diagnosis challenging.1 The term ‘great imitator’ also applies to microscopic findings. In a review of the histopathologic patterns of secondary syphilis, Bernie Ackerman wrote, ‘the histopathologic variations of secondary syphilis proved to be as protean as the clinical presentation’.2 Classically, secondary syphilis has a superficial and deep perivascular plasma cell infiltrate with endothelial cell swelling.3 Granulomatous, eosinophil-rich, lichen planus-like and psoriasiform patterns have also been reported.2 – 5 Nodular lesions in
554
Gabriela Rosa1 , Dan Bennett2 and Melissa P. Piliang3 1
Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA, 2 Department of Dermatology, University of Wisconsin, Madison, WI, USA, and 3 Sections of the Departments of Dermatology and Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA
Dr. Melissa P. Piliang, Sections of the Departments of Dermatology and Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA Tel: +216 444 5722 Fax: +216 231 5448 e-mail: [email protected] Accepted for publication January 11, 2015
secondary syphilis, rather than the typical maculopapular lesions seen clinically, are reported as well.5,6 Drug reactions and allergic contact dermatitis are often the primary consideration in eosinophil-rich skin lesions biopsied in the United States. A recent editorial highlighted the potential diagnostic pitfall of limiting our diagnoses in eosinophil-rich lesions, as a wide spectrum of diseases, including lichen planus and melanocytic tumors, can have increased eosinophils.7 In one study on the pathologic features of alopecia areata, nearly half of the cases had eosinophils within fibrous tracts.8 Although syphilis is rare, affecting 5.3 per 100,000 in 2013, the incidence of syphilis in the United
Eosinophil-rich syphilis States nearly doubled from 2005 to 2013, with high rates of human immunodeficiency virus (HIV) co-infection.9 Awareness of the varied histopathologic presentation, which includes eosinophil-rich infiltrates, can be important in recognizing secondary syphilis. Materials and methods In routine sign out, we encountered three cases of syphilis with increased eosinophils, ranging from 17 to >200 eosinophils per 10 high-power fields (×400 magnification per field). Two cases were seen at the Cleveland Clinic and one case was seen at the University of Wisconsin. The patients in all cases had a positive rapid plasma reagin (RPR) and treponemes were seen on syphilis immunohistochemistry. The institutional files at the Cleveland Clinic were then searched for 20 years, from January 1, 1992 to October 29, 2013, yielding 14 biopsy specimens from 13 patients (two biopsies from one patient). All patients had serologic evidence of syphilis or positive syphilis immunohistochemistry at the time of their skin biopsies. Eosinophils were counted per 10 high-power fields. Of these 14 in-house cases, only 1 case had noticeable eosinophils, with 8 per 10 high-power fields. We collaborated to submit these four cases with increased eosinophils, three seen incidentally in sign out and one seen upon review of the institutional files, as examples of secondary syphilis with increased eosinophils. Results Patient 1 was a 30-year-old man with a 6 month history of a burning rash involving the scrotum and penis. The lesions were thin pink annular plaques, clinically suspected to be lichen planus, granuloma annulare or sarcoidosis. He was applying only petroleum jelly to the lesions. A shave biopsy of the lesion showed an epidermis with ice-pick hyperplasia and a large subcorneal pustule. A dense infiltrate, predominantly composed of eosinophils, with admixed neutrophils, lymphocytes and rare plasma cells was present at the dermal–epidermal junction and superficial vascular spaces. There was prominent eosinophilic exocytosis, extending through all layers of the epidermis and eosinophilic spongiosis (Figs. 1 and 2). The eosinophil count in the dermis and epidermis was greater than 200 per 10 high-power fields. Syphilis immunohistochemistry was positive for treponemes. Subsequent RPR was positive while testing for HIV was negative.
Fig. 1. Case 1 with a dense eosinophil infiltrate in the epidermis, extending into a subcorneal pustule (hematoxylin and eosin, ×100).
Patient 2 was a 50-year-old man who presented for evaluation of annular lesions of the back and legs. The clinical differential included annular psoriasis, subacute cutaneous lupus erythematosus and granuloma annulare. Histopathologic evaluation revealed a neutrophilic crust and psoriasiform hyperplasia, in association with a lichenoid infiltrate in the superficial dermis, and a superficial and deep perivascular and periadnexal mixed infiltrate composed of lymphocytes, histiocytes, plasma cells and numerous eosinophils (Fig. 3). The eosinophil count was 150 per 10 high-power fields. Given the presence of plasma cells and the pattern of inflammation, immunohistochemical staining for Treponema pallidum was performed, which showed spirochetes within the epidermis. Additional clinical information was not available, as this case was reviewed in consultation. Patient 3 was a 35-year-old man with a known history of HIV, who presented with a 2 month history of a rash that started on his face and spread to his trunk. Clinical exam showed erythematous, crusted plaques involving the face, scalp, neck and upper chest. There were multiple papules and small plaques 0.5–1.5 cm in diameter on the chest, upper abdomen, back and bilateral arms (Fig. 4). The clinical differential included guttate psoriasis, pityriasis lichenoides et varioliformis acuta (PLEVA), viral reaction and cutaneous lymphoma. A skin biopsy from his chest showed a minimally hyperplastic epidermis with interface change and lymphocytic exocytosis. The dermis had a brisk perivascular and periadnexal mixed infiltrate of histiocytes, lymphocytes, plasma cells and eosinophils. Eight eosinophils were seen in 10 high-power fields. There was no eosinophilic exocytosis (Fig. 5). The RPR was positive at a 1 : 1024 dilution. The patient had no change in
555
Rosa et al.
Fig. 2. Case 1 with eosinophils at the dermal–epidermal junction (hematoxylin and eosin, ×200).
Fig. 4. Multiple erythematous papules involved the arm in patient 3.
Fig. 3. Case 2 with eosinophils in a mixed inflammatory infiltrate at the dermal–epidermal junction (hematoxylin and eosin, ×200 magnification).
mental status, but venereal disease research laboratory test (VDRL) of the cerebrospinal fluid was reactive at a 1 : 1 dilution, diagnostic of asymptomatic neurosphilis. Syphilis immunohistochemistry was not performed at the time, but was retrospectively performed and showed numerous treponemes (Fig. 6). The patient refused treatment with intramuscular benzathine penicillin and instead received intravenous penicillin G for 2 weeks, followed by oral doxycycline for 21 days. Within 1 month, his skin lesions were nearly completely healed. Repeat RPR titers were not performed as the patient was lost to clinical follow-up. Patient 4 was a 26-year-old man who was known to be HIV positive and was on anti-retroviral therapy. He presented to the emergency room with anal pain and bleeding. Examination revealed
556
Fig. 5. Case 3 with eosinophils adjacent to blood vessels in the superficial dermis (hematoxylin and eosin, ×400).
the patient’s anus was ulcerated with purulent drainage. The anal biopsy showed focal superficial ulceration and erosion of the epidermis with associated neutrophilic crust. The dermis had a mixed inflammatory infiltrate with numerous plasma cells, lymphocyte, neutrophils and eosinophils (Fig. 7). Seventeen eosinophils were
Eosinophil-rich syphilis
Fig. 6. Case 3 shows numerous spirochetes at the dermal–epidermal junction (Treponema pallidum immunohistochemical stain, ×400 magnification).
Fig. 7. Case 4 with eosinophils and hyperplastic vessels in the superficial dermis (hematoxylin and eosin, ×400).
seen in 10 high-power fields. Syphilis immunohistochemistry showed numerous treponemes. The RPR was positive at a 1 : 256 dilution and syphilis IgG was also positive. The patient was treated with oral doxycycline, because of a penicillin allergy. Repeat RPR titers were not yet available, given the recent onset of this patient’s presentation. In all cases, there was no known history of allergic contact dermatitis or drug hypersensitivity reaction. Discussion The recruitment of eosinophils in hypersensitivity phenomena (such as an insect bite reaction, drug reaction or allergic contact dermatitis) is thought to be related to cytokines, in particular interleukin (IL)-5, released by helper T cells.10 Other cytokines, including macrophage migration inhibitory factor (MIF), IL-3, IL-4 and IL-13 also recruit eosinophils.11,12 Several entities, including secondary syphilis, which are not related to hypersensitivity phenomena, have been associated with increased eosinophils.4,7,13
Some studies suggest that eosinophil attractant cytokines play a role in these non-hypersensitivity phenomena.12,14 Eosinophilic dermatosis of hematologic malignancy is a rare skin disease associated with chronic lymphocytic leukemia, which shows perivascular inflammation with increased eosinophils and mimics an insect bite.13 Davis et al. showed enhanced eosinophil survival in culture in the presence of tissue extracted from eosinophilic dermatosis of hematologic malignancy, indirectly revealing the presence of eosinophil attractant cytokines within lesions.15 Tissue eosinophilia has also been reported in secondary syphilis, but it is felt to be rare.4,7 Elevated levels of eosinophil chemoattractants have been documented in patients with syphilis. Podwinska et al. showed that blood cultures from syphilis patients in various stages of their disease had elevated IL-2, interferon (IFN), tumor necrosis factor (TNF) and MIF levels.14 Patients with secondary syphilis had the greatest amount of MIF production, which is an eosinophil chemoattractant.14 The findings were not correlated with the patients’ skin biopsies, but one could hypothesize increased eosinophils might then be seen on histopathology. This does not explain the apparent rarity of eosinophil-rich secondary syphilis, cited in case reports only. A dysregulation of cell-mediated immunity, with increased production of eosinophil chemoattractants, may play a role in our cases and other eosinophil-rich entities not typically associated with hypersensitivity reactions. Increased eosinophils probably represent one of the many histopathologic patterns seen in secondary syphilis. Even among our four cases, there were different microscopic patterns; one case had minimal hyperplastic changes and no acute inflammation, while the other cases had either psoriasiform or ice-pick hyperplasia with an associated mixed infiltrate, including neutrophils. These findings support the great variability in clinical and histopathologic presentation of secondary syphilis. The incidence of syphilis in the United States has been steadily rising since 2005. Men, particularly men who have sex with men (MSM), are at the highest risk.9 Thus, syphilis is an important diagnostic consideration in skin biopsies. It can be a challenging diagnosis because both the clinical and histopathologic appearance can vary and patients can be poor historians. Sharon et al. showed that eosinophils are rare to absent in pityriasis lichenoides, dermatomyositis, most forms of lupus erythematusus and
557
Rosa et al. graft-versus-host disease.16 In those entities, the increased eosinophils on skin biopsy might dissuade one from entertaining those diagnoses. Our cases illustrate that presence of eosinophils
should not dissuade one from including syphilis in the histopathologic differential diagnosis and obtaining supportive immunohistochemical or serologic studies.
References 1. Kent ME, Romanelli F. Re-examining syphilis: an update on epidemiological clinical manifestations and management. Ann Pharmacother 2008; 42: 226. 2. Jeerapaet P, Ackerman B. Histologic patterns of secondary syphilis. Arch Dermatol 1973; 107: 343. 3. Grayson W. Infectious diseases of the skin. In Calonje E, Brenn T, Lazar A, eds. Mckee’s pathology of the skin, 4th ed. Elsevier, China, 2012; 760. 4. Park J, Kim Y. Secondary syphilis with numerous eosinophils. J Cutan Pathol 2013; 40: 1064. 5. Rysgaard C, Alezander E, Swick B. Nodular secondary syphilis with associated granulomatous inflammations: case report and literature review. J Cutan Pathol 2014; 41: 370. 6. Papini M, Bettacchi A, Guiducci A. Nodular secondary syphilis. Br J Dermatol 1998; 138: 704. 7. McCalmont TH. Red alert or red herring. J Cutan Pathol 2014; 41: 337.
558
8. Peckham SJ, Sloan SB, Elston DM. Histologic features of alopecia areata other than peribulbar lymphocytic infiltrates. J Am Acad Dermatol 2011; 65: 615. 9. CDC. Morbidity and mortality weekly report. Primary and secondary syphilis– United States, 2005–2013. URL www.cdc. gov/mmwr/preview/mmwrhtml/mm6318 a4.htm. [accessed on 24 Nov 2014]. 10. Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol 2008; 20: 288. 11. Yoshihisa Y, Makino T, Matsunga K, et al. Macrophage migration inhibitory factor is essential for eosinophil recruitment in allergen-induced skin inflammation. J Invest Dermatol 2011; 131: 925. 12. Magalhães ES, Paiva CN, Souza HS, et al. Macrophage migration inhibitory factor is critical tointerleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection. FASEB J 2009; 23: 1262.
13. Farber MJ, Forgia SL, Sahu J, Lee JB. Eosinophilic dermatosis of hematologic malignancy. J Cutan Pathol 2012; 39: 690. 14. Podwiska J, Lusiak M, Zaba R, Bowszyc J. The pattern and level of cytokines secreted by Th1 and Th2 lymphocytes of syphilitic patients correlate to the progression of the disease. FEMS Immunol Med Microbiol 2000; 28: 1. 15. Davis MD, Perniciaro C, Dahl PR, Randle HW, McEvoy MT, Leiferman KM. Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: a clinical, histopathologic, and immunopathologic study of eight patients. J Am Acad Dermatol 1998; 39: 27. 16. Sharon VR, Konia TH, Barr KL, Fung MA. Assessment of the “no eosinophils” rule: are eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft versus host disease? J Cutan Pathol 2012; 39: 413.
