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Dermatopathology: Practical & Conceptual

July – September 2010 | Volume 16, No. 3

What is your diagnosis?

Jeunon, Thiago; Lopes, Raquel; Sousa, Maria Auxiliadora Jeunon

Introduction

Infective and parasitic diseases are mostly found in developing countries in tropical and subtropical areas of South and Central America, Africa, and Asia. [1] Favorable climate and environment for vectors, natural reserves of infective agents, paucity of sanitary resources, insufficient governmental policies for endemic disease control, and difficult access to health care lead to the high incidence and prevalence of these kinds of diseases, which very often manifest themselves with skin lesions. [2,3] However, factors such the increasing migratory flux, the practice of adventure tourism in exotic areas, and the transfer of troops in military missions have contributed to an increasing number of cases reported in USA and Europe. In these circumstances, the low index of suspicion and the unfamiliarity with clinical and histopathologic aspects of some diseases may account for delay in the diagnosis. [4]

As a general rule, the gold standard for the diagnosis of infectious diseases is the demonstration of the etiologic agents through microscopic analyses of squames, fluids, smears or sections of tissue (direct examination) or by isolation of them in appropriate medium (cultures). [1] Nevertheless, some infections are characterized in their paucity of infectious structures in tissue, but rapid growth of the agent in culture mediums (i.e., sporotrichosis / Sporothrix schenckii), others abound in tissue, but are not isolated in cultures (i.e., Jorge Lobo’s mycosis / Lacazia loboi), and still others are almost never found in tissue and do not dispose of an appropriate isolation technique (i.e., tuberculoid form of leprosy/ Mycobacterium leprae). In this context, the identification of a specific histopathologic pattern and clinicopathologic correlation are the cornerstones for the diagnosis. [1] In addition, ancillary techniques such as serologic and molecular tests are increasingly available and have been remarkably helpful tools to reach the diagnosis in difficult cases. [1]

Here we present infectious/parasitic diseases in a quiz format in order to highlight the histopathologic pattern, criteria for diagnosis, laboratorial confirmation, and the main biological, epidemiological and clinical aspects.

Quiz

A 0.4 cm punch biopsy of an infiltrated reddish-brown plaque was taken from the abdomen of a 28-year-old white male and received for histopathologic examination at a private practice dermatopathology laboratory in the city of Rio de Janeiro, Brazil (Figs. 1-7). There was no additional clinical information in the paperwork apart from the diagnostic hypotheses of Miescher’s elastolytic giant cell granuloma, parapsoriasis, and sarcoidosis. Can you identify the organism?

Figs. 1-7

What is your diagnosis?

Answer

Chronic ectopic cutaneous schistosomiasis (caused by Schistosoma mansoni).

Histopathology

A nodular dermatitis is seen to be made up of epitheliod histiocytes arranged in palisade around a focus of fibrinoid necrosis, associated with plasma cells, lymphocytes and eosinophils. [5] Lesions biopsied earlier in the course might have numerous neutrophils. [1] Some lesions may ulcerate. [6]

Identification of ova of the genus Schistosoma in the dermis is the sine qua non for the specific diagnosis of ectopic cutaneous schistosomiasis. Ova of Schistosoma mansoni range from 114-175 microns in length by 45-68 microns in thickness and have a thick lateral spine in its chitinous outer shell. Ova of Schistosoma haematobium measure 112-170 by 40-70 microns and have a delicate and thin spine, which is apically located. Ova of Schistosoma japonicum are 70-100 by 50-65 microns and do not have a spine (Fig. 8). [7]

Fig. 8A-C

A. Egg of Schistosoma mansoni B. Egg of Schistosoma haematobium C. Egg of Schistosoma japonicum

Laboratory confirmation

Viable eggs may be detected in the stool (S. japonicum and S. mansoni) through Kato-Katz method and in the urine (S. hematobium). Rectal biopsy is also an option for egg identification. [7,8] Serological tests (ELISA) may be used for diagnosis, especially in the acute phase when egg production has not started yet. They become positive 6 weeks after the exposure and may continue to be positive after successful treatment. [4,8]

Comment

Schistosomiasis is caused by trematodes (blood flukes) belonging to the genus Schistosoma. The most important Schistosoma species in humans are S. mansoni, S. haematobium and S. japonicum.[2,8] An estimated 200 million people are infected by Schistossoma spp. and more than half a billion live in at-risk areas, especially sub-Saharan Africa, Egypt, Brazil and some Caribbean islands. [5,9] Infection is acquired after exposure to fresh water of rivers and lakes inhabited by the intermediate host, the snail.[10] The snail is infected when schistosome eggs are excreted by human beings or animals, hatching in the water and releasing free-swimming miracidia. The latter searchs for a specie-specific genus of snail which serves as an intermediate host – Biomphalaria sp. for S. mansoni, Bilinus sp. for S. haematobium, and Oncomelania sp. for S. japonicum. [4,10]

After 4 to 6 weeks of development inside the snail, microscopic infective larvae (cercariae) are produced and released in the water. Cercariae penetrate the skin of a human host after 30 seconds to 10 minutes of exposure (Fig. 9). [4,8]

Fig. 9

The biological cycle of Schistosoma mansoni: a) human being in contact with contaminated water; b) infested human being; c) detail of the mesenteric plexus; d) detail of a couple of adult worms; e) egg; f) free-swimming miracidia; g) snail; h) cercariae.

The infection has a wide range of clinical features, varying from unapparent to fatal. It may manifest itself as acute or chronic sickness. The acute symptoms are caused by the immune response against the trematode and the chronic phase is caused by the deposition of parasite eggs (and eventually of adult worms) in host tissue. [8,10]

Once the cercariae penetrate the skin, they become schistosomulae and may elicit an inflammatory response, known as cercarial dermatitis. [10] It presents as an acute, pruritic, papular rash at the site of penetration within minutes after bathing and reflects a hypersensitivity response. Previously sensitized people may develop a widespread urticarial or erythematous papular rash which usually resolves within a week. [6,8,10] Thereafter, schistosomulae enter venules, reach the pulmonary capillaries, migrate to the liver, achieve their sexual maturity and mate in the hepatic sinusoids, finally migrating to the final habitat: mesenteric venules (S. mansoni and S. japonicum,) or retovesical plexus (S. haematobium). [2,10]

The migration of the schistosomulae in the body leads to an acute parasitic toxemia with hypersensitivity reaction and circulating immune complexes – the acute phase. These symptoms are prominent in persons who have never been infected and include fever, myalgia, headache and diarrhea and may persist for 2 to 10 weeks. Hepatomegaly and splenomegaly are often present. [10,11,12]

Once the schistosomulae reach their final habitat, the egg excretion begins. Approximately half of the eggs become trapped in adjacent tissues or are transported via the blood stream and lodge in tissue elsewhere in the body, causing ectopic disease. Worms may also take these aberrant routes. [9,10]

Deposition of eggs may be seen months or even years after infection and results in granulomatous inflammatory reaction – the chronic phase. In S. hematobium infection, the key symptom is hematuria. Painful and frequent urination is also reported. [4,9] After some years, obstructive uropathy and hydronephrosis may occur. [10] The chronic phase of the infection by S. mansoni and S. japonicum manifests clinically as abdominal discomfort, episodes of diarrhea with blood and mucus in the stool, and other non-specific symptoms. The presence of the eggs in the liver leads to fibrosis over the years, resulting in esophageal varices and ascites (pre-sinusoidal portal hypertension). [4,11,13]

Chronic cutaneous schistosomiasis (Bilharziasis) is caused by the inflammatory response to the eggs deposited in the dermis and subcutaneous tissues. The initial lesions are 2-3 mm firm, flesh-colored papules which are often pruritic and may form clusters. [10,11] Later, they may coalesce into lichenified plaques or nodular lesions that sometimes become pigmented and without treatment remain unchanged. The lesions are typically located in the periumbilical area, the chest, upper dorsal regions and the anogenital area. Later in the course, the buttocks, vulva, scrotum and penis may present lesions that include painless, skin-colored, pink or brown eroded papules and warty, vegetative lesions that may become ulcerated, necrotic and give rise to fistulous tracts. These lesions may be complicated by secondary bacterial infection and squamous cell carcinoma. [8,10] Table 1 summarizes clinical data of several cases of chronic cutaneous schistosomiasis reported previously.

Treatment for cercarial dermatitis and acute schistosomiasis include a symptom-guided approach. Application of 1% hydrocortisone cream combined with oral antihistamines is useful for releaving symptoms of cercarial dermatitis. Antibiotics may be used in case secondary bacterial infection develops. [10] Acute schistosomiasis requires oral glucocorticoids. [4,10]

Praziquantel 40mg/kg is the most widely used specific anti-schistosomal drug, being effective against all species of human-infecting schistosomes. Artemisine has also been shown to be effective for the treatment of schistosomiasis [4,8] and Oxamniquine is an alternative treatment for S. mansoni. Excision of skin lesions may be required for chronic cutaneous schistosomiasis when there is a poor response to pharmacological treatment. [2]

Schistosomiasis infection can only be prevented by avoiding contact with cercariae-infested water. In case it is impossible, clothes to cover the skin in contact with the water may provide some protection. Mass chemotherapy may be useful but its cost-benefit should be carefully evaluated. [14] Snail control in endemic areas is also important, but appropriate disposal of feces and urine is essential in controlling schistosomiasis endemics. [3,4]

Two international research teams have determined the complete genetic sequences of Schistosoma mansoni and Schistosoma japonicum. The genomic information obtained through these sequencing projects suggests ways to design drugs or other compounds targeted specifically at proteins or other gene products required by the parasite to find or survive in its human or snail host. This information could lead to new treatments and ways of preventing schistosomiasis. [15]

Table I. Data of some cases of chronic cutaneous schistosomiasis reported previously. NA: Information not available.

Case Number Age (years) Sex Procedence Anatomical site Elementary Lesions Organism Estimated time since infection Reference
1 14 M Brazil periumbilical papules S. mansoni 2 months 16
2 32 M Brazil Left abdomen papules S. mansoni 3 months 16
3 13 M Nigeria Face Hypopigmented plaque S. mansoni 1 year 17
4 26 F Brazil Lombar region Erythematous papules S. mansoni 2 month 18
5 28 F Brazil Post. thorax Confluent erythematous papules S. mansoni 15 years 18
6 12 M Nigeria Neck papules S. haematobium and S. mansoni NA 19
7 10 M Nigeria Chest Lichenoid papules S. haematobium NA 19
8 24 M Zambia Genital, Abdomen, chest and scalp papules S. haematobium 3,5 months 20
9 11 M Egypt Periumbilical Nodular mass S. haematobium NA 21
10 12 M Egypt Suprapubic area and abdomen Papules, nodules and plaques S. haematobium NA 21
11 28 M Brazil Face Papules S. mansoni 3 months 22
12 NA F NA Foot Papules S. mansoni NA 23
13 NA F NA Chest Papules S. mansoni NA 23
14 NA F NA Chest Papules S. mansoni NA 23
15 20 M Brazil Lombar region and left abdomen Papules S. mansoni NA 24
16 32 F Brazil Left abdomen Papules S. mansoni NA 24
17 18 M Brazil Right adbomen Erythematous papules S. mansoni NA 24
18 41 F Brazil Left hypochondrium Purplish papules S. mansoni NA 24
19 29 F Brazil Left hypochondrium Confluent papules S. mansoni 3 meses 25
20 32 F Brazil Right hypochondrium Isolated and confluent papules S. mansoni NA 25
21 23 F Brazil Right hypochondrium Grouped papules S. mansoni 1 month 25
22 NA NA Philipines Leg Chronic ulcer S. japonicum NA 26
23 21 M Nigeria Lower chest, upper abdomen, right flank, the lower part of the back and the buttock. Pinky and violet papules and violet indurated nodules S. hematobium 4 months 26
24 28 M Nigeria Lower left chest, lumbar, sacral and gluteal region Pink papules S. hematobium 4 months 26
25 10 M Nigeria Perineum Firm papules S. hematobium NA 27
26 17 F Brazil Scapula Papules and vesicules S. mansoni NA 28
27 28 M Brazil Left hemithorax Papules and vesicules S. mansoni NA 28
28 11 M Brazil Left inguinal region Papules S. mansoni NA 28
29 36 M Brazil Perineum Expansive lesion S. mansoni NA 28
30 31 F Brazil Vulva (labium major) Nodule S. mansoni NA 29
31 34 F NA Perineum NA S. hematobium NA 30
32 31 M Senegal Foot Macule S. hematobium NA 31
33 15 F Senegal Vulva Papillomatous, vegetating lesions S. hematobium NA 31
34 13 NA Senegal Armpit Papillomatous, vegetating lesions S. hematobium NA 31
35 7 F NA Vulvar region Papillomatous, vegetating lesions S. hematobium NA 31
36 11 F Senegal Vulvar region Vegetating, ulcerative lesions S. hematobium NA 31
37 46 F NA Disseminated on the body Hypochromic spots S. hematobium NA 31
38 22 F Brazil Neck and left clavicular region Erithematous papules with linear arrangement S. mansoni 8 months 32
39 33 F Brazil Abdomen Erithematous brownish papules S. mansoni NA 32
40 23 M Brazil Penis, scrotum, left area of the abdomen Erithematous papules and plaques S. mansoni 8 months to 2 years 32
41 30 F Brazil Left mammary and abdominal regions Erithematous papules with linear arrangement S. mansoni 20 years 32
42 33 M Central and Northeastern Africa Both lower thoracic paraspinal areas Prurituc papules S. mansoni 6 years 33
43 24 M Puerto Rico Periumbilical Brownish-red irregularly circular plaque of confluent papules. S. mansoni NA 34
44 60 M NA Anal orifice Polypoid mass S. mansoni NA 34
45 55 M Puerto Rico Anal orifice Polypoid mass S. mansoni NA 34
46 23 M South Africa Lefto of the upper abdominal midline Colourless papules S. hematobium NA 35
47 18 F Rhodesia Left side of the trunk Papules in zosteriform distribution S. hematobium NA 35
48 57 M NA Right buttock, trunk, right shoulder and axila Papules and patches S. hematobium NA 35
49 41 M NA Upper chest Papular erythematous rash S. hematobium 3 months 35
50 41 M NA Upper chest Papular erythematous rash S. hematobium 3 months 35
51 14 M NA Periumbilical and left chest Papules S. hematobium NA 35
52 24 F Brazil Left pectoral area and left arm Firm papules with erythematous and lichenoid aspect S. mansoni NA 36
53 27 F Brazil Left flank Papules S. mansoni NA 36
54 22 F Brazil Left pectoral region Erythematous papules S. mansoni 2 months 36
55 26 F Brazil Right dorsal region Papules and plaques S. mansoni NA 36
56 36 F Brazil Left chest and back Isolated or grouped erythematous papules S. mansoni NA 36
57 45 F Brazil Central dorsal region Erythematous papules and plaques S. mansoni 1 year 36
58 25 F Brazil Left scapula Infiltrated erythematous papules S. mansoni 1 year 36
59 12 M Brazil Right posterior thigh Papules S. mansoni 3 months 36

Acknowledgement

The authors feel indebted to Carlos Eduardo Sampaio, who gently produced the drawings of figures 8 and 9.

Summary

Background: Schistosomiasis is caused by trematodes belonging to the genus Schistosoma. High risk areas for infection are sub-Saharan Africa, Egypt, Brazil and some Caribbean islands. Three species cause most human infections: S. mansoni, S. japonicum, and S. haematobium. Adult worms of the former species live at mesenteric venules and deposit its eggs at rectal and colonic mucosa, while the latter prefers the retovesical plexus and deposits the eggs in the urinary tract. Eventually, eggs are transported via blood stream and lodge in the dermis, causing chronic cutaneous ectopic schistosomiasis. Objectives: To demonstrate a case of chronic cutaneous ectopic schistosomiasis. Patient/methods: A 0.4 cm punch biopsy of an infiltrated reddish-brown plaque was taken from the abdomen of a 28-year-old white male at a private practice dermatopathology laboratory in the city of Rio de Janeiro, Brazil. The clinical diagnostic hypotheses were Miescher’s granuloma, parapsoriasis and sarcoidosis. The diagnosis was based on presence of S. mansoni eggs in the dermis, in company of granulomatous palissading nodular dermatitis. Conclusion: The authors highlight the histopathologic pattern, criteria for diagnosis, laboratorial confirmation methods and the main biological, epidemiological and clinical aspects of Schistosoma spp. infection.

Dr. Raquel Lopes is a second-year resident of dermatology at the Department of Dermatology of Hospital Federal de Bonsucesso, Rio de Janeiro, Brazil. Dr. Maria Auxiliadora Jeunon Sousa is the director of ID – Investigação em Dermatologia S/C Ltda, a private dermatopathology laboratory in Rio de Janeiro, Brazil. Dr. Thiago Jeunon is the head of dermatopathology at the Department of Dermatology of Hospital Federal de Bonsucesso and an associate dermatopathologist at ID – Investigação em Dermatologia S/C Ltda. This article was reviewed by Johannes Dayrit, M.D., and Betina Werner, M.D. Contact corresponding author via email: thiago.jeunon@gmail.com .

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