Pathological agent
Lesion
Site
Morphology
Bacteria
Staphylococcus aureus
Abscess
Any, bone
Cocci Gram +
Streptococcus spp.
Abscess
Skin, any
Cocci Gram +
Mycobacteria tub.
Tuberculoma
Any
any
Granul. Patterns, Zielh+
NonTub. Mycobact. bovis, avium, kansasii, chelonei, fortuitum
Tuberculoma-like
Granul. Patterns, Zielh+
Klebsiella rhinoscleromatis
Rhinoscleroma
Nose, eye
Mikulicz cells, plasma cells
Klebsiella scleromatis
Donovanosis
Genital areas
Donovan bodies, plasma cells
Treponema pallidum
Syphilis
Genital
Plasma cells around vessels
Borrelia
Lyme disease
Skin
Pseudolymphoma B cells
Bartonella
Cat scratch disease
Bacillary angiomatosis
Lymph node
Skin
Chronic adenitis
Infectious angiomatosis
Actinomycetes
Pseudotumors
Lung, Digestive
Genital
Grains with abscesses
Viruses
Herpes virus EBV
Mononucleosis
Lymph node
Pleomorphic inf. Hodgkin-like
Herpes VIII
Kaposi diseases
Skin, Any
Spindle cells, LANA positive
Human Papillomaviruses
Warts, verruga
Oropharynx
Skin
Papillomatosis
Protozoa
Entamoeba histolytica
Amoeboma
Liver, ileo-caecal
Abscess with ameba
Leishmania
Diffuses Leishmaniasis
Skin
Granuloma Leishmania +
Leishmania
Kala- Azar
Liver, spleen
Histiocytes 2–3 μm
Nematodes
Onchocerca volvulus
Onchocercosis
Skin
Granuloma, adult worm with cuticular annulations
Strongyloides stercoralis
Stronguloidosis
Small intestine
Worms (Striated cuticle, long esophagus)
Ascaris
Ascaridosis
Intestines
Worms
Wuchereria bancrofti
Lymphatic filariosis
Lymph nodes and lymp
Eosinophils, adult worms, microfilariae
Dirofilaria immitis
Dirofilariosis
Lung
Granuloma with worms
Dirofilaria repens
Any
Granuloma with worms (thin cuticle, striated ridges)
Trematodes
Schistosoma haematobium
Schistosomiasis
Mostly genito-urinary
Polyps, Granul eggs
S. haematobium—terminal spine
S. mansoni—lateral spine
Schistosoma mansoni
Mostly digestive
Schistosoma intercalatum
Paragonimus
Fasciola hepatica
Paragonimosis
Distomatosis
Lung
Liver
Biliary tract
Abscess with eosinophils and eggs with polar opercula
Cestodes
Taenia solium
Cysticercosis
Any
Brain
Granuloma and larva
Echinococcus granul.
Hydatid cyst
Protoscolices- hooklets, laminated wall
Arthopod s
Lingatula
Pentastomosis
Any
Granuloma and larva
Fungi/yeasts
Histoplasma capsulatum caps
Histoplasmosis
Lung, any organ
3–5 yeasts
Histoplasma capsulatum dub
Af Histoplasmosis
Lung, any organ
8–12 μm
Blastomyces derm.
Blastomycosis
Lung, skin
8–12 μm
Pneumocystis jiroveci
Pneumocystosis
Lung in HIV
8–10 μm
Paracoccidioides brasiliensis
Paracoccidioidomycosis
Lung, skin, lymph nodes
15–20 μm peripheral budding
Coccidioidiomyces immitis
Coccidioidomycosis
Lung, any org
15–30 μm intern endospores
Rhinosporidium seeberi
Rhinosporidiosis
Nose
150 μm
Hyphae not pigmented
Aspergillus fumigatus
Aspergilloma and invasive Aspergillosis, neutropenia
Lung, brain, skin
Hyphae 6–8 μm septated
Mucor, Absidia, Rhizopus
Zygomycosis
Any
Hyphae 8–20 μm irregular
Fusarium
Fusariosis
Hyphae 6–8 μm
Pigmented hyphae
Phaeohyphomycetes
Phaeohyphom cyst
Skin
Braun pigmented hyphae
Fonseca cladosporium
Chromomycosis
Braun Fumagoid cell
We will focus only on those inflammatory conditions which simulate neoplasms clinically, radiologically, or even morphologically. For further information readers should consult textbooks on infectious diseases [1–5].
Diagnosis can be performed by using cytology or small-volume biopsy if the patterns observed reveal characteristic and specific features of the infection. If not, an excisional biopsy is necessary.
2.1.1 Bacteria
2.1.1.1 Pyogenic Bacteria: Gram Positive and Gram Negative
Streptococcus and Staphylococcus are the most frequently isolated bacteria which induce abscess formation, superficial or deep-seated, localized, or disseminated in any organ: skin, lymph nodes, lung, kidney, bone, and brain. Less common agents are Pseudomonas, Acinobacter, Peptostreptococcus spp, Fusobacterium, Propionibacterium acnes and Prevotella (Fig. 2.1). These infectious lesions are not frequently biopsied because the diagnosis of infection is usually obvious and the diagnosis easily performed. Small-volume biopsy specimens contain numerous granulocytes, histiocytes, necrotic debris, and aggregated Gram-positive cocci or Gram-negative bacteria.
Fig. 2.1
Skin abscess . Numerous leukocytes surrounding granule. Inset, Staphylococcus aureus, hematoxylin-eosin safran (HES) and Gram stains
Enterobacteriaceae are able to induce deep-seated abscesses in lung, brain, and kidney. E. coli, Proteus, Salmonella are most commonly encountered.
Yersinia pestis is seen in endemic areas (e.g., Madagascar) and induces severe septicemia with large lymphadenopathy: the “bubon.” Cytology and histological biopsy reveal clusters of polymorphonuclear cells and histiocytes surrounding Gram negative bacteria (Fig. 2.2). These bacteria can be difficult to observe in HE and in Papanicolaou staining. They are also Warthin Starry negative but can be observed in Giemsa staining and using immunohistochemistry (Fig. 2.2).
Fig. 2.2
Plague . Lymph node abscess. Numerous leukocytes. Inset, Yersinia pestis evidenced by immunohistochemistry (Courtesy of F. Guinet, Yersinia Unit, Institut Pasteur, Paris)
2.1.1.2 Bartonella Henselae: Cat Scratch Disease
Since the demonstration of Bartonella henselae, a Gram-negative bacteria in lymph node tissues, by Douglas Wear in 1983, numerous cases have been reported in cytology and histology [6]. The disease most commonly affects cervical, axillary or inguinal lymph nodes in children following inoculation of bacteria by cats. Other sites have also been reported [7] and exposure to cats is not always proven. The morphological picture can be divided into three stages. The first stage reveals a hyperplastic lymphadenopathy. In the second stage, suppurative changes and abscess formation occur. The third stage is characterized by pseudo caseous necrosis and granuloma formation with epithelioid histiocytes (Fig. 2.3). The lesion heals by fibrosis. FNA taken from various disease stages therefore produces different cytological pictures. Donnelly et al. reported that neither granulomas nor suppurative inflammation were seen in all cases [6]. Bartonella may be demonstrated by Warthin Starry silver stain in aggregates, chains, or singly in the areas of necrosis (Fig. 2.3). The staining, however, is difficult to perform and is negative in early stages of disease. The presence of bacilli can also be demonstrated by polymerase chain reaction (PCR) . The differential clinical diagnoses are tuberculosis, toxoplasmosis, mononucleosis, and lymphoma. The Ziehl-Neelsen staining is always negative.
Fig. 2.3
Cat scratch disease . Combination of abscess and epithelioid granuloma with caseous necrosis. Inset, Whartin Starry: cluster of aggregated bacilli (Bartonella)
Bacillary angiomatosis is also induced by Bartonella henselae. Pseudoangiomatous tumor in HIV-infected patients with numerous Bartonella are detected at the Warthin-Starry staining.
2.1.1.3 Chlamydia Species: Lymphogranuloma Venereum (LGV)
This sexually transmitted disease is caused by Chlamydia sp of serotypes L1, L2, L3, and is rarely observed in children. The clinical manifestation is a small, herpetiform, painless genital ulceration of 2–4 mm combined with inguinal lymphadenopathy that may be prominent. Undiagnosed ulcerative lesions may evolve into chronic perirectal abscesses, rectal strictures, and atypical fistulae that can simulate a neoplasm. The cytology and surgical biopsy show unspecific inflammatory changes that go through various stages: lymphocytic hyperplasia with plasma cell infiltration, suppurative abscess formation, non-necrotizing granuloma with multinucleated giant cells and epithelioid cells, fibrosis. Chlamydia can be demonstrated by immunohistochemistry or detected by PCR.
2.1.1.4 Mycobacteria
Mycobacterium Tuberculosis
Tuberculosis (Tb) is the main disease afflicting children in the world. Lungs and lymph nodes are most commonly affected. Tuberculous cavities in the lungs are more common than tuberculomas, but less suspicious of a neoplasm. Tuberculous lymphadenopathy is especially common in countries where HIV is endemic. Mediastinal, cervical, and axillary lymph nodes are most commonly affected and may simulate lymphoma. Microscopically, the key lesion contains caseous necrosis combined with epithelioid and Langhans cells, surrounded by lymphocytes, plasma cells, calcifications, and fibrosis in the late stages (Fig. 2.4). Langhans cells may not always be present. The diagnosis is confirmed by the demonstration of acid-fast bacilli by Ziehl-Neelsen in areas of necrosis; however, they can be demonstrated in only one-half to two-thirds of cases (Fig. 2.4).
Fig. 2.4
Lymph node tuberculosis : Granuloma with caseous necrosis, epithelioid cells and lymphocytes. Inset, Ziehl positive bacterias
In HIV-positive patients, severe and extensive lesions of hemorrhagic necrosis can be observed combined with no granuloma and a high density of acid bacilli (Fig. 2.5).
Fig. 2.5
Tuberculosis in HIV-positive patient. Extensive necrotic lymphadenitis without granuloma. Inset, Ziehl staing showing numerous Mycobacterium tuberculosis
Atypical Mycobacteria
Atypical mycobacteria , defined as non-Tb mycobacteria, are frequently observed in patients with impaired immunity. Numerous mycobacteria such as Mycobacterium avium, Mycobacterium bovis, kansasii, fortuitum, chelonae, and other species are involved in lung pathology, lymph nodes, and other organs (Fig. 2.6). In lung, lymph nodes, digestive system and in other target sites, the histologic patterns are quite different from Tb because these lesions are less granulomatous, contain numerous histiocytes with a clear cytoplasm (Fig. 2.7), many neutrophils, and the necrosis is more hemorrhagic than caseous. In addition, in immunocompromised patients there is a high number of Mycobacteria both within histiocytes and extracellularly (Fig. 2.7). There is no morphologic difference between Mycobacterium tuberculosis and other mycobacteria except the size of M. kansasii, and a morphologic diagnosis usually cannot be performed.
Fig. 2.6
Non-tuberculosis infection . Autopsy specimen of pseudolymphomateous colon lymph node enlargement in HIV-positive patient. (Courtesy of Prof. P.P. de Saint Maur, St. Antoine Hospital, Paris.)
Fig. 2.7
Same specimen as that in Fig. 2.6. Diffuse histiocytic infiltrate with a clear cytoplasm. Inset: Numerous Mycobacterium avium intracellulare (MAC) using Ziehl staining
The predictive value of Ziehl-Neelsen staining is better for demonstrating atypical mycobacteria than for M. tuberculosis, reaching 90%. The PCR has been used but sometimes difficult to evaluate because it is more sensitive, leading to false positive results. In HIV-positive patients morphological patterns correlate with the defect of CD4 T cells and are characterized by severe and extensive lesions with hemorrhagic necrosis, combined with a few granulomas and a high density of bacilli in areas of necrosis.
Mycobacterium Leprae
Leprosy or Hansen disease is a neuroectodermal infection, endemic around the world, targeting the skin, mucosae, and the nerves. The incidence has dropped significantly during the last 20 years. There are two clinical presentations: multibacillary and paucibacillary. The multibacillary form causes multiple small nodules, and clinical presentation is well known in endemic areas, rarely suspected of neoplasm. Various morphological pictures exist. In lepromatous leprosy, biopsies show histiocytic infiltrations surrounding nerves and skin adnexa. Histiocytes contain numerous clusters of Mycobacteria which stain with a modified Ziehl-Neelsen stain (Fite Faraco). The tuberculoid form has a sarcoidal granulomatous reaction, sometimes with Langhans cells but without necrosis [8].
2.1.1.5 Spirochetes
Treponema Pallidum
Treponema pallidum causes syphilis, which has four distinct stages: primary, secondary, latent, and tertiary. The primary stage is ulceration; the secondary stage is characterized by spread of bacteria with maculopapular rash, condyloma latum in the anogenital area, lymphadenopathies and ulcerated nodules. Tertiary syphilis is characterized by gummas that can be present in many organs including the skin, soft tissues, bones, heart. This disease is re-emerging.
Condylomatous form on the skin suggests a benign human papilloma virus (HPV)-induced neoplasm despite HIV-induced condyloma are usually exophytic. Histology reveals a lympho-plasmocytic infiltrate surrounding vessels (Fig. 2.8). Argentic impregnation and immunohistochemistry allows the demonstration of spirochetes (Fig. 2.8). Serology is always positive. Gumma are granulomatous lesions with fibrosis in which the load of spirochetes is usually low.
Fig. 2.8
Syphilis . Condylomatous tumor in perianal area. Tahiti hospital. Polynesian. Dense infiltrate with numerous lymphocytes and plasma cells surrounding vessels. Inset, Immunohistochemistry with a polyclonal anti Treponema pallidum antibody. (Courtesy of A. Carlotti, Cochin Hospital, Paris.)
Histology of lymph node reveals a diffuse cortical follicular hyperplasia, a capsular inflammation with considerable plasma cells infiltration, and proliferation of blood vessels with swelling of endothelium. Non-caseataing granuloma can rarely be seen.
Treponema Pallidum Pertenue-Yaws
Yaws is a disease of children mainly between 2 and 10 years of age, common in warm and humid regions including equatorial Africa, Southeast Asia, and South and Central America. The characteristic lesion is a cutaneous papillomatous tumor, frambesioma, reaching several centimeters. Lesions are located on the hand, trunk, axilla, and mouth, and are accompanied by lymphadenopathy and extension to cartilage and bone at the late stages. The histological patterns include lymphocyte and plasma cell infiltration. Serology is always positive.
Borrelia
Borrelia burgdorferi induces a large exanthema in the skin at the point of inoculation, combined with regional lymphadenopathy suspicious of cutaneous lymphoma. Histology is not specific and is unable to render an accurate diagnosis. There is a pleomorphic infiltrate (Fig. 2.9) with lymphocytes and plasma cells. In most cases, Borrelia is never observed despite the use of immunohistochemistry. The diagnosis is made by PCR and serology.
Fig. 2.9
Boreliosis . Extensive exanthema in a patient coming back from Eastern Europe. Pleomorphic infiltrate with follicular pattern, HES
Other Spirochetes
Vibrio vulnificus induces deep muscular abscesses in immunocompromised patients. Numerous spirochetes, seen in Warthin-Starry staining, are present among numerous polymorphonuclear cells.
2.1.1.6 Klebsiella Rhinoscleromatis
Rhinoscleroma is observed in Africa, central and eastern Europe, Asia, and Central America. This is a true neoplasm-like lesion affecting the nose (Fig. 2.10), pharynx, and larynx, caused by a capsulated bacteria, Klebsiella rhinoscleromatis . Microscopic picture shows large, foamy macrophages containing bacilli with capsulae called Mickulicz cells (Fig. 2.10) They are surrounded by lymphocytes and plasma cells containing Russell bodies. Fibrosis is seen in late stages. The bacteria stain with periodic acid-Schiff (PAS), Warthin-Starry, or Grocott and with more sensitive immunohistochemistry.
Fig. 2.10
Klebsiella rhinoscleromatis intranasal tumor in an African patient. Inset, Mikulicz cells resembling macrophages, May-Grünwald-Giemsa (MGG)
Donovanosis is induced by Klebsiella granulomatis. This pseudotumor is observed in the genital area of people from Oceania, central America, India, and Africa. The patterns are very similar to Rhinoscleroma including the classical Donovan bodies measuring 1.6 × 0.7 μm, usually observed in a mononuclear cells, measuring 25–80 μm, similar to Mikulicz cells. These mononuclear cells are combined with Russell bodies and fibrosis.
2.1.1.7 Actinomyces and Nocardia
Actinomycosis is a chronic infection producing pseudotumors in the lung, the digestive system (mouth, ileo-caecal junction), and the genital areas (Fallopian tubes and ovary). The key lesion is an abscess containing numerous neutrophils and grains or sulfur granule with frequent elongated, eosinophilic, club-like structures around the grain (Splendore Hoeppli phenomenon). The grain is composed of Gram and Warthin-Starry positive, Ziehl-Neelsen negative filamentous bacteria (Fig. 2.11).
Fig. 2.11
Left, Lung mass of the upper lobe showing Actinomycosis sulfur granule with Splendore Hoeppli phenomenon. Middle, Lung abscess in immunocompromised patient. Nocardia Ziehl-positive hyphae. Right, Bladder tumor. Aggregates of PAS positive histiocytes in malacoplakia. Hanseman bodies (arrow)
Nocardia also produce chronic infections affecting immunocompromised patients. Deep abscess may be observed in any organ with filamentous, Ziehl-Neelsen positive bacteria (Fig. 2.11).
2.1.1.8 Malacoplakia
Escherichia coli, Pseudomonas aeriginosa, Rhodococcus have been isolated in malakoplakia, a rare granulomatous disease characterized by numerous histiocytes PAS-positive cells (von Hauseman cells), containing Michaelis Gutman calcified bodies (Fig. 2.11). In fact this entity is correlated to a defect of phagocytosis by histiocytes.
2.1.2 Viruses
2.1.2.1 Papillomavirus and Related Disease
Numerous Human papilloma virus (HPV) are able to induce benign tumors in children and are not pseudo-tumoral lesions in the strict sense of the word. Juvenile laryngeal papillomata and warts are extremely frequent in children and adolescents, induced by HPV Type 6 and 11 and without neoplastic potential. Histologically, papillomata and condylomatous lesions exhibit focal epithelial hyperplasia and koilocytosis.
2.1.2.2 Epstein-Barr Virus: Infectious Mononucleosis
Infectious mononucleosis (IM) is commonly reported in children and young adolescents. It is characterized by pharyngitis, lymphadenopathy, and splenomegaly in a context of acute fever. Epstein-Barr virus (EBV ) is observed in approximately 85% of cases, and Cytomegalovirus is observed in 8–10% of cases. Lymphadenopathy is present in almost all cases, mostly in posterior cervical and axillary regions. Diagnosis is often made by serology. However, IM is often present in lymphoma patients and therefore any enlarged lymph node in such patients has to be investigated for a possible recurrence. Morphology of FNA smears is not conclusive, but flow cytometry shows a reactive immunophenotype. Histology reveals a pleomorphic immunoblastic hyperplasia of paracortical area with plasma cells (Fig. 2.12). The diagnosis may be extremely difficult in cytology and histology because large immunoblastic cells may mimic Sternberg and Hodgkin cell. Immunohistochemistry and in situ hybridization using Epstein-Barr Virus–encoded RNA (EBER ) probe allow detection of EBV (Fig. 2.12) within immunoblastic cells.
Fig. 2.12
Infectious mononucleosis in lymph node in a 14-year-old child. Immunoblastic hyperplasia and foci of hemorrhagic necrosis. Inset, In situ EBER Hybridization
Mononucleosis-like syndromes and immunoblastic proliferations may be caused by several other microorganisms such as Toxoplasma gondii (1%), Adenovirus, Hepatitis A virus, and Herpes virus 6.
2.1.2.3 Herpesvirus 8: Kaposi Disease
Kaposi disease is induced by Herpesvirus 8 and it has long been debated whether the lesion is a sarcoma. Herpesvirus 8 induces a proliferation of spindle cells which is polyclonal at the beginning and becomes oligoclonal as disease progresses. Monoclonality develops in a few cases with chronic and advanced stages of the disease, suggesting these lesions are chronic reactive proliferations rather than true malignancies.
Clinically, macula, plaques, and nodules are observed in areas in which Kaposi disease is endemic, with involvement of lymph nodes in a few cases. Histologically, Kaposi lesions are characterized by sheet of spindle cells (Fig. 2.13) containing vessels with red blood cells. Deposits of Perls positive material are a common feature, but are not specific because they are observed also in hemangioma. Spindle cells are labeled with CD31 and CD34. Immunohistochemistry is available since 2000: the nuclei of spindle cells are specifically labeled with anti-LANA antibody, a Herpesvirus 8 protein (Fig. 2.13). This is particularly interesting in early lesions where only a few spindle cells are labeled.
Fig. 2.13
Kaposi disease . Sheets of spindle cells with angiomatous cavities. Inset, LANA-positive cells (HHV8)
2.1.3 Parasites
2.1.3.1 Protozoa
Entamoeba Histolytica
Entamoeba histolytica is the most common human pathogenic protozoon affecting the colon and terminal ileum. Usually the common form is an ulceration, single or multiple, lasting several days or weeks. This lesion may sometimes develop into a pseudotumor, the amoeboma which occurs in the context of chronic colitis with abdominal pain, fever, and loss of weight. Endoscopy demonstrates a tumor-like lesion within in the ileo-caecal junction combined with ulceration, hemorrhages, and induration of the wall. Biopsies reveal large inflammatory areas, with several foci of necrosis and a dense infiltrate of polymorphonuclear cells, histiocytes, lymphocytes, and plasma cells. The trophozoite Entamoeba histolytica can be observed, measuring 25 μm and resembling histiocytes. However, the nucleus is much smaller and eccentric, containing a single central karyosome (Fig. 2.14). The cytoplasm of Entamoeba histolytica is clear and granular, bluish grey with rare ingested red blood cells, and PAS positive. Specific antibodies may be used in immunohistochemistry, demonstrating the presence of amoeba in the areas of necrosis. Serology can be helpful. Complications of amoebiasis include migration to other organs, especially to the liver, the first extra intestinal localization, then to lung, brain, and peritoneum.
Fig. 2.14
Large protozoa (Entamoeba histolyticica) resembling macrophages in ileo-caecal tumor. Inset, Higher magnification. Compare small nucleus of E.H compared to large nucleus of macrophage, HES
2.1.3.2 Leishmania
Leishmaniasis are human and zoonotic infections caused by more than 15 species of the parasite with two clinical forms: cutaneous and visceral.
Cutaneous leishmaniasis presents as reddish, ulcerated nodules which can reach the size of 4–8 cm. FNA is probably the best method to demonstrate the presence of Leishmania amastigotes within macrophages. This parasite measures 4 μm at Giemsa stain (Fig. 2.15).
Fig. 2.15
Leishmania , Protozoa of 3 μm Cytological smear, MGG
Visceral leishmaniasis, or Kala-azar, is produced by several species of Leishmania donovani. It is observed in endemic countries with three major geographical areas in South America (Leishmania chagasi), in the Mediterranean basin including France, Spain, Italy, Greece, Turkey, and Morocco (Leishmania infantum), and in eastern Africa, Ethiopia, Somalia, Kenya, Sudan (L. donovani). Clinically, the majority of infections are unapparent and only a minority of cases are symptomatic with fever, weight loss, and hepato-splenomegaly mimicking myeloproliferative disease like acute leukemia and lymphoma. The diagnosis is performed by identification of the parasite in the bone marrow, the liver, or the spleen. Biopsy of spleen may be associated with hemorrhages and therefore potentially dangerous even in the hands of experienced operators. The morphology of parasites, which are strictly intra-histiocytic, is characteristic and similar in both disease forms. The amastigotes measure up to 4 μm, contain a nucleus filling one-third to one-half of the cytoplasm and a small kinetoplast which is considered an ancestor of the flagellum. The parasite can be demonstrated by immunohistochemistry using a polyclonal antibody (Fig. 2.16). The main differential diagnosis are infections caused by Histoplasma capsulatum (Grocott positive), Toxoplasma, and Trypanosoma cruzi.
Fig. 2.16
Leishmania. Liver biopsy. Numerous protozoa of 3 μm with a polar nucleus. Inset, immunohistochemistry with a polyclonal antibody anti Leishmania: Visceral Leishmaniasis (Kala-azar). (Courtesy of Dr. J.C. Antoine, Institut Pasteur, Paris.)
2.1.3.3 Toxoplasma
Toxoplasma gondii is a worldwide parasite that is transmitted to humans from cat feces and undercooked meat. Most infections are undetected, while 20% of patients complain of fever, headache, and myalgia. Children and young women are commonly affected. Main clinical manifestation is discrete and non-tender lymphadenopathy in suboccipital, cervical, or axillary regions. Other reported localizations include the brain, especially in HIV-positive and immunocompromised patients, and the lung, heart, and bladder.
FNA smears show a polymorphous population of reactive lymphoid cells and epithelioid cell granulomas, while necrosis, giant cells, and neutrophils are not present. Choudhury et al. [9] reported tissue cysts containing PAS-positive bradyzoites, which are oval with polar nucleus and measure 3–4 μm. Malović demonstrated Toxoplasma gondi tachyzoites in lymphatic cells on cytologic material using specific monoclonal antibodies [10].
Histologically, this is a difficult diagnosis. It is exceptional to detect Toxoplasma gondii in lymph node even in using immunohistochemistry or PCR. The differential diagnosis includes mononucleosis, Hodgkin disease, and viral lymphadenitis. Diagnosis is generally performed by using serology with specific antibodies IgG and IgM.
In other localizations, especially the brain in HIV-positive patients, cysts and pseudocysts containing tachyzoides are observed (Fig. 2.17). Differential diagnoses include Trypanosoma cruzi and Histoplasma cephalatum. Immunohistochemistry using specific polyclonal antibody allows a specific diagnosis (Fig. 2.17).
Fig. 2.17
Cerebral Toxoplasmosis. Toxoplasmosis Cysts containing tachyzoids. Inset, Immunohistochemistry with a polyclonal Toxoplasma gondii antibody
2.1.3.4 Helminthes
Nematodes
Nematodes are the most common of the parasites that infect humans. Clinical presentation correlates with the load of infestation in the digestive system or with migration of parasites to deep organs such as the lung, subcutaneous tissues, and peritoneum. Infestation with Nematodes in children may simulate presence of a tumor and can be divided into three clinical settings:
- 1.
Accumulation of parasites in the digestive system
- 2.
Migration of nematodes to the lung (Löeffler syndrome and lung nodule)
- 3.
Cutaneous and subcutaneous nodules
Strongyloides stercoralis, Ancylostoma, and Ascaris are frequent in endemic areas causing intestinal obstruction, usually without change in the intestinal wall. However, mucosal ulceration and hemorrhage may be observed. Eosinophilia is observed in more than 60% of cases. Adult parasitic female worms of Strongyloides stercoralis are filiform, measure 2–3 mm by 30–60 μm, covered by a thin striated cuticle and containing a long cylindrical esophagus in the anterior part of the worm. The reproductive organs are observed in the posterior three-fourths of the worm, with two ovaries. Rhabditoid larvae are smaller, 200–350 μm long and 10–20 μm large, with a short buccal capsule and esophagus (Fig. 2.18). Eggs can be very rarely observed, mostly within the crypts. Conversely, in Ancylostoma infection, eggs are numerous in stools.
Fig. 2.18
Strongyloidosis . Parasites in the small intestine. Numerous strongyloides stercoralis within the crypts, HES
Migration of Ascaris lumbricoides, Ancylostoma, and Strongyloides stercoralis to the lungs causes benign pneumonitis or Löeffler syndrome with local infiltrates that do not simulate a tumor. Dirofilaria immitis , on the other hand, is considered as a great imitator of lung neoplasm. Histologically, the nodule is characterized by fibrosis, granulomatous infiltrates, and calcifications surrounding a nematode measuring 220–340 μm, whose thick cuticle (6–12 μm) does not contain external cuticular ridges. New lesions contain well-preserved worms with a good morphology, whereas in older lesions worms are necrotic and surrounded by calcifications, eosinophils, and fibrosis.
Onchocerca volvulus causes onchocerciasis, a tropical disease affecting the skin and eyes. Subcutaneous nodules (1–5 cm in diameter) develop on the trunk and extremities, 9 months to 2 years after inoculation. There is a papular rash over the affected area with lymphedema and hyperpigmentation, leading to lichenification and skin atrophy. Histology reveals the presence of a nematode, sometimes calcified, with cuticular ridges, larger than those of Dirofilaria repens and internal microfilariae in the uterus of females (Fig. 2.19).
Fig. 2.19
Nematodes. Left, Cutaneous nodule on the trunk. Partially calcified Onchocerca volvulus with regularly spaced cuticular annulations. Right, Nodule on the arm. Dirofilaria repens with thin, regular and striated ridges on the cuticle
Dirofilaria repens and larval stages of Strongyloides, Ancylostoma, Nekator, and Gnathostoma (Larva migrans) also produce cutaneous nodules in which parasites are present.
Trematodes
Distomatosis is the common name for all infections caused by trematodes.
Biliary and Pancreatic Trematodes
Fasciola hepatica, a parasite causing fasciolosis, is described in Africa, Central Europe, and South America. People are infected by ingestion of contaminated plants and water. The clinical presentation may simulate hepatic or cholangic tumor due to hepatomegaly. Computer tomography of the liver shows several low-density nodules or irregular structures in the biliary tract in the liver suggesting abscesses or tumors. The diagnosis of fasciolosis may be suggested by marked eosinophilia and serology. Biopsies contain eggs measuring 130 × 70 μm with polar opercula, surrounded by eosinophils and Charcot-Leyden crystals (Fig. 2.20).
Fig. 2.20
Fasciola Hepatica . Liver abscess and parasites Inset, Large eggs of Fasciola hepatica measuring 130 × 65 μm with polar opercula
Clonorchis sinensis is described in Taiwan, Japan, Korea, Vietnam, Russia, and Turkey, while Opistorchis Viverrini is endemic in Laos, Thailand, and generally around the Mekong River. These parasites are hosted by the biliary tract and induce asymptomatic infections and chronic cholangitis, sometimes mimicking cholangiocarcinoma. Biopsies show inflammatory changes with dilated bile ducts, adenomatous proliferation of bile ducts, parasite eggs (15 x 30 μm) combined with Charcot-Leyden crystals and eosinophils in areas of necrosis. Chronic infection leads to cholangiocarcinoma.
Pulmonary Trematodes
Several trematodes in the genus Paragonimus induce human infection in Eastern Asia and Western Africa. These parasites are transmitted by contaminated water from crabs and crayfish, containing larval stages that cross the intestinal wall and the diaphragm to reach the lung. The main clinical symptoms include productive chronic cough, and hemoptysis. Chest radiograph shows a cavitating lesion or an irregular mass in the upper lung frequently accompanied by pleural effusion that may easily be confused with tuberculosis or a neoplasm. These infiltrates are transient, migratory, and combined with eosinophils. The diagnosis is made by the detection of characteristic ova in the sputum or stools measuring 120 μm with a polar opercules. The wall of these ova are able to deviate the polarized light as all the ova of parasites causing distomatosis. Other localizations have also been reported, such as the brain and gastrointestinal tract.
Trematodes of Gastrointestinal and Urinary Tract
Schistosoma mansoni, S. japonicum, and S. mekonji cause pathologic changes in the colon and rectum. S. hematobium colonizes the colon in about 60% of cases, while the main infection is seen in the urinary system. In the digestive system, only 20% of patients infected with Schistosoma have gross abnormalities in the form of plaques and polyps in the colon and rectum. Polyps are covered with thin mucosa and contain several granulomas with epithelioid cells, eosinophils, and a variable amount of eggs with characteristic morphology. Eggs of S. mansoni measure 140 × 70 μm with a lateral spine which is Ziehl-Neelsen positive (Fig. 2.21). S. japonicum (120 μm) and S. mekongi (80–100 μm) are smaller and without a spine. Old lesions are characterized by extensive fibrosis of the colon/rectum wall, peritoneum, and the liver with portal hypertension. The morphology of eggs in fibrosis may be variable with deformation and numerous atypias. Diagnosis is made by the demonstration of eggs in biopsies, but serology is helpful.
Fig. 2.21
Schistosomiasis . Right, Colic eggs of Schistosoma mansoni with a lateral spine. Upper left, Eggs in Lugol staining. Lower left, Ziehl staining
Clinical manifestations of urinary schistosomiasis are related to the load of parasites and eggs in the infected tissues. Children in endemic areas have signs of urinary infection with hematuria and dysuria. Proteinuria is present in 50–75% of patients. Endoscopy reveals polypoid mass in the bladder and/or thickening of the bladder wall. The diagnosis can be made by demonstrating the eggs and S. haematobium in urine. They measure 150 × 70 μm, have a polar terminal spine, and are Ziehl-Neelsen negative. Biopsies show epithelioid granulomas and eosinophils centered on eggs, most often with a typical morphology or calcified. In old lesions, eggs are surrounded by eosinophilic material described as Splendore Hoeppli phenomenon.
Schistosoma may target also the skin, lung, central nervous system (frequent with S. Japonicum), spinal cord (S. haematobium and mansoni), genital system, and peritoneum.
Cestodes
Hydatosis
Hydatidosis is a parasitic infection caused by larval tapeworms of Echinococcus. Two main species are endemic: The most common, Echinococcus granulosus, is transmitted by dogs, while the less common Echinococcus multilocularis is transmitted also by foxes and rodents. The former is endemic in Southern Europe, the Mediterranean basin, most countries of Africa, Madagascar, and South America (Chile and Peru). The latter is observed in the eastern part of France, Germany, Italy, Austria, and Western Europe. Both types are endemic in Canada, Australia, New Zealand, and in the western parts of the United States.
Parasites form cystic lesions that are found mainly in the liver, less commonly in the lungs, and rarely in other organs. Hydatid cysts grow slowly and are therefore seldom observed in small children. Symptoms are related to localization of the cyst. In the liver, they may produce abdominal pain, acute or chronic jaundice, portal hypertension, and episodes of cholangitis. Patients with hydatid cysts in the lung may complain of chest pain, coughing, and hemoptysis. However, most patients are asymptomatic and cysts are an accidental finding. Hydatoid cysts are usually diagnosed by a combination of characteristic ultrasound image and positive serology for anti-Echinococcus IgG antibodies. Small-volume biopsy is not a method of choice for obtaining a diagnosis because there is a risk of inoculation, and some anaphylactic reactions have been reported following the procedures. However, ultrasound images may not be characteristic when cysts are complicated by hemorrhage or infection [11]. Furthermore, 10% of patients do not produce detectable antibodies, especially children between 3 and 15 years of age. In such cases FNA is indicated because lesions simulate tumors. The material obtained by FNA macroscopically resembles abscess. Background of smears contains granular necrotic precipitate with various amounts of parasite remnants depending on the duration of the lesion. Almost intact scolices, complete with the rostrum of hooklets, may be found, surrounded by many free hooklets (Fig. 2.22). Alternately, degenerated, unrecognizable scolices may be present, or only a few hooklets. Klopčič et al. described scolices and hooklets in 24 of 38 FNA samples from hydatid cysts; the remaining 14 specimens contained only free hooklets [12]. In tru-cut specimens of Echinococcus multilocularis a conglomerate of cysts and vesicles were described by Ciftçioğlu et al., containing PAS-positive mucoid material [13]. They also observed coagulative necrosis and occasionally foreign body giant cells. In the FNA specimens the same authors describe necrotic background, PAS-positive cuticular structures, and mucoid globules, as well as foreign body giant cell in some cases [13].
Fig. 2.22
Hepatic hydatidosis (Echinococcus granulosus). Left, laminated layers. Right, Protoscolices with hooklets
Taenia
Taenia solium cysticercosis is the development of the larval stage of the tapeworm occurring in many organs. Most of the infections are asymptomatic. The main target is the brain mimicking brain tumor. Histologically there is a cyst with pseudoglandular pattern (Fig. 2.23).
Fig. 2.23
Cysticercosis . Pseudoglandular pattern, HES
2.1.4 Fungi
2.1.4.1 Yeasts
Histoplasma Capsulatum
Histoplasma capsulatum exists in two human forms: Histoplasma capsulatum var.capsulatum found in America, Asia, Oceania, and Africa, and Histoplasma capsulatum var.duboisii, described only in Africa. There is no autochthonous case in Europe. All patients with histoplasmosis come from endemic areas. Histoplasmosis is similar to tuberculosis and is asymptomatic and benign in 85% of cases. Acute pulmonary and disseminated infection is seen in immunocompromised children, mostly HIV-positive.
In severe forms, the dissemination may target any organ. The lymph nodes are enlarged, simulating tuberculous lymphadenopathies. In the lung, the classical form includes Histoplasmoma or localized/diffuse infiltrates. The cytology or small biopsy of lymph nodes and any organ show necrosis, epithelioid cells and histiocytes containing Giemsa and Grocott positive yeasts measuring 3 μm (Fig. 2.24). Morphology is indistinguishable from tuberculosis but the Ziehl-Neelsen staining is always negative. The presence of small yeasts (2–4 μm) leads to diagnosis of classical histoplasmosis (Fig. 2.24) and the presence of large yeasts, 8–14 μm long, with polar budding, is a sufficient criterion to affirm a diagnosis of African Histoplasmosis (Figs. 2.25 and 2.26). Some pitfalls may occur. Red cells could be intensively Gomory-Grocott positive, while in Histoplasma only the wall is stained. Calcifications and nuclear debris in lymph nodes can be stained by Grocott. Candida is rarely observed in lymph nodes and characterized by pseudo hyphae and yeasts. Some cases need the use of immunohistochemistry in specialized laboratories, but cross-reactions may occur (Blastomycosis, Sporothrix).