IMMUNOLOGIC DEFICIENCY SYNDROMES V. Žampachová I. PAÚ LF MU IMMUNODEFICIENCY nPresentation as infections nSerious nPersistent nUnusual nRecurrent PRIMARY IMMUNODEFICIENCY ngenetically determined nhumoral and/or cellular arms of adaptive immunity (mediated by B and T lymphocytes) – defects in maturation and/or activation ndefense mechanisms of innate immunity (NK cells, phagocytes, complement) PRIMARY IMMUNODEFICIENCY nmanifestation mostly in infancy, (6-24 months) nsusceptibility to: nrecurrent infections by opportunistic pathogenes nsystemic inf. by microorg. normally superficial, nunusually extensive inf. by common pathogenes nautoimmune diseases (disorder of regulation) n n T-cell defect nBacterial sepsis nCytomegalovirus, Epstein-Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses nCandida, Aspergillus, Pneumocystis jirovecii nAggressive disease with opportunistic pathogens, failure to clear infections B-cell defect nStreptococci, staphylococci, Haemophilus –skin, respiratory tract nEnteroviral enteritis, encephalitis nSevere intestinal giardiasis (protozoan), other GIT infections nRecurrent sinopulmonary infections, sepsis, chronic meningitis npanhypogammaglobulinemia x selective deficiency n! immunization w. live vaccines (polio, etc.) n Granulocyte defect nStaphylococci, Pseudomonas nCandida, Nocardia, Aspergillus nLeukocyte adhesion deficiency nDefects in phagolysosome function nDefects in microbicidal activity Complement defect nNeisserial infections, other pyogenic infections nDefects in complement components nDefects in complement system regulators PRIMARY IMMUNODEFICIENCY nmainly B-cell defect: X-linked agammaglobulinemia of Bruton, transient hypogammaglobulinemia of infancy, selective IgA deficiency, common variable immunodeficiency (CVID) nmainly T-cell defect: DiGeorge syndrom (thymic hypoplasia), hyper-IgM syndrome nB- and T-cell defect: severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (immunodeficiency with thrombocytopenia and eczema – systemic disorder) ndefect in phagocyte function: chronic granulomatous disease, leukocyte adhesion deficiency, myeloperoxidase deficiency nprimary complement deficiencies n n Severe combined immunodeficiency nSCID ndefects in both humoral and cell-mediated immunity nrecurrent, severe infections, wide range of pathogens, incl. Candida albicans, P. jirovecii, Pseudomonas, cytomegalovirus, varicella, many bacteria. nmorbilliform rash shortly after birth – GVH disease due to maternal T-cells nX-linked (~ 50%), autosomal recessive n„bubble children“, bone marrow transplantation, gene therapy (! acute T-cell leukemia) n DiGeorge syndrome (thymic hypoplasia) nT-cell defect; chromosomal deletion; commonly only partial hypoplasia nfailure of embryonal development of the 3rd and 4th pharyngeal pouches (thymus, parathyroids, part of thyroid clear cells → hypocalcemic tetany; heart + great vessels defects) nT- cell zones depleted (LN – paracortical, periarteriolar sheaths of the spleen) n↑ fungal and viral infections n Immunodeficiency with thrombocytopenia and eczema nWiskott-Aldrich syndrome nX-linked recessive, defect of a gene for a specific multifunctional signal molecule nprogressive secondary depletion of T-cells in the peripheral blood and in LN paracortical areas nIgM↓, IgG ~ normal, IgA + IgE may ↑. n↑ removal of platelets by splenic macrophages – thrombocytopenia, small defects – fatal bleeding n Common variable immunodeficiency nCVID nrelatively common, heterogenous group of disorders (dg. by exclusion), both sexes, children - adolescents nhypogammaglobulinemia nsporadic and inherited forms nB cells in normal numbers, not able to differentiate into plasma cells nintrinsic B-cell defects, abnormalities in T helper cell–mediated activation of B cells nhyperplastic B-cell zones in lymphoid tissue Common variable immunodeficiency nrecurrent sinopulmonary pyogenic infections nrecurrent herpesvirus infections npersistent diarrhea due to G. lamblia nenterovirus meningoencephalitis n↑ frequency of autoimmune diseases (RA) nrisk of lymphoid malignancy X-linked agammaglobulinemia (Bruton's a.) nfailure of B-cell precursors (pro-B cells and pre-B cells) to develop into mature B cells nlight chains not produced nmales almost only nmanifestation after 6 months of life (depletion of maternal Ig) n X-linked agammaglobulinemia (Bruton's a.) nrecurrent bacterial infections of the respiratory tract nHaemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus (failed opsonisation + phagocytosis) nenteroviruses (echovirus, poliovirus, coxsackievirus), GIT infection → hematogenous spread → CNS nGiardia lamblia persistent infections n↑ autoimmune diseases (rheumatoid arthritis, dermatomyositis) - ? chronic infections + ↓ self-tolerance n↓ germinal centers, absent plasma cells Isolated IgA deficiency ncommon immunodeficiency in Caucasians (1:600), severe reaction after blood transfusion possible nfamilial or acquired after some infections (toxoplasmosis, measles, some viral inf.) nlow levels of both serum and secretory IgA nmostly asymptomatic; possible respiratory, GIT, urogenital recurrent infections n↑respiratory tract allergy, autoimmune diseases Hyper-IgM syndrome n↑ production of IgM; ↓ IgG + IgA + IgE nnormal number of T-, B-cells nX-linked or autosomal recessive nautoimmune hemolytic anemia, thrombocytopenia, neutropenia nrecurrent pyogenic infections, pneumocystis pneumonia nprophylactic drugs, bone marrow transplantation n Chronic granulomatous disease n↓ oxygen radicals production needed for bacteria killing in effective phagocytosis nX-linked; other types n↑ pyogenic bacteria (Staph., G- rods), fungi (Aspergillus) nrespiratory, GIT, skin, … infections – abscess, giant-cell granuloma nliver vascular lesions → portal hypertension Genetic deficiencies of the complement system nC2 deficiency the most common, almost no ↑ susceptibility to infections, ↑ SLE-like autoimmune disease (glomerulonephritis, rash, vasculitis, fever) nC3 deficiency → ↑ serious, recurrent pyogenic infections, sepsis nC5-C8 deficiency → neisserial infections nC1 inhibitor deficiency → hereditary angioedema, attacks incl. larynx! SECONDARY IMMUNODEFICIENCY nDue to impaired synthesis and function: nprotein, vitamin and energy deficiency in malnutrition, cachexia in disseminated cancer, anorexia, alcoholism nprevalent monoclonal Ig in some lymphoproliferative diseases nbone marrow infiltration or fibrosis (leukemia, myelofibrosis) nsuppression of cell mediated immunity due to acute viral infection (CMV, EBV, measles, etc.), bacterial and protozoal infection – macrophagic dysfunction (leprosy, leishmaniasis) SECONDARY IMMUNODEFICIENCY niatrogenic (immunosuppressive and cytostatic drugs, radiotherapy, splenectomy – pneumococcus sepsis) ndiabetes mellitus and other metabolic diseases nchronic stress nsarcoidosis (↓ Tcell function) ncertain age groups (old, newborn, immature infants) nIncreased catabolism or loss: nephrotic syndrome and renal failure, inflammatory intestinal diseases (IBD, lymphangiectasia) SECONDARY IMMUNODEFICIENCY nHumoral immunodeficiency nintestinal lymphangiectasia, IBD → ↓ all Ig classes, commonly + lymphopenia nnephrotic sy, chronic diarrhea → ↓ IgG niatrogenic immunosuppression/cytostatic therapy nB-cell malignancies nSplenectomy – spleen B-cell – Ab x polysaccharide antigens – encapsulated microorg. – vaccination x pneumococci SECONDARY IMMUNODEFICIENCY nCellular immunodeficiency ntemporary after acute viral infection (CMV, EBV, measles, etc.) niatrogenic immunosuppression/cytostatic nAIDS n SECONDARY IMMUNODEFICIENCY nCombined immunodeficiency nSevere general metabolic problems (DM, renal insufficiency), malnutrition, anorexia, chronic alcoholics – inadequate hormones, glucose, vitamins level SECONDARY IMMUNODEFICIENCY nDefect of phagocytosis nneutropenia in bone marrow insufficiency (irradiation, immunosuppressant/cytostatic th., some chemicals) nautoantibodies n↑ loss in hypersplenism nmetabolic diaseases nmyeloid leukemia SECONDARY IMMUNODEFICIENCY nComplement defficiency nimmunocomplex diseases nsepsis nsevere liver disease Brain mycotic abscess Lung mycotic abscess Fungal structures in necrotic brain Cryptococcus in skin Toxoplasmosis in myocardium Brain toxoplasmosis inflammation Brain toxoplasmosis cysts HIV - AIDS nThe goal – ending the AIDS epidemic by 2030 nStopping the new infections nEverybody infected should have access to treatment nPre-exposure prophylaxis AIDS epidemics nSince the start of the epidemics: ~ 78 millions of infected; 35,4 millions have died nGlobally the spread of HIV peaked in the 1996, when 3.5 million new HIV infections occurred. n2019 estimated 1,7 newly infected nAIDS related mortality max. in 2005 (1,9 million), 2019 0,69 million – access to HAART AIDS epidemics nEstimated 38 million people living with HIV at the end of 2019. n81 % had been diagnosed n67 % were receiving treatment n59 % had achieved suppression of the HIV virus to the point at which they were at low risk of infecting others. AIDS epidemics nAIDS related illnesses still the leading cause of death among women of reproductive age (15–49 years) globally nIncreases in AIDS infections over the past decade in the Middle East and North Africa (22%↑), Latin America (21% ↑) and eastern Europe and central Asia (72%↑). AIDS epidemics nDecrease in new infections and deaths, increase in number of people living with HIV (Highly Active Antiretroviral Therapy - HAART) n> 10 millions in need of treatment (+ preexposure prophylaxis) n n AIDS epidemics nHIV infection in Europe: National epidemics concentrated among key populations at higher risk (men who have sex with men – MSM, injecting drug users; prisoners, sex workers, sexual partners of key population). HIV in the Czech Republic ncca 3800 HIV+ cases in Czechia, 86 % males; 490 foreigners (mostly Eastern Europe, Sub-Sah. Africa) nTransmission: MSM > heterosexual > IDU > blood derivates (survivors) > vertical transmission (mother – child) nMost cases in/around Prague (1828), South Moravia 312 HIV ISSUES nBlood safety nHIV treatment: antiretroviral therapy should begin immediately after diagnosis nPrevention of mother-to-child transmission nCo-management of tuberculosis and n HIV treatment nHIV testing in the general and most-at-risk population nPreexposure prophylaxis HIV - AIDS nMore than 90% of children living with HIV acquired the virus during pregnancy, birth or breastfeeding - forms of HIV transmission that can be prevented. AIDS epidemics nEurope, Australia and Canada: mortality rates namong people living with HIV in the first five nyears after infection now ~ in the nHIV-uninfected population nMortality among HIV-infected people increases nwith the duration of infection nIncreasing complications of chronic HAART – highly active antiretroviral therapy Noninfectious HIV-related comorbidities: nThe premature aging process in HIV-infected people n2x ↑ risk of myocardial infarction n↑ risk of osteoporosis incl. fractures (even in adolescents!) n↑ risk of chronic renal failure nNon-AIDS tumors Noninfectious HIV-related comorbidities: nhyper-activated immunological profile, accelerated T-cell senescence naccelerated process of immune senescence and inflammatory aging during HIV infection → increased risk of age-related diseases nlong-term tolerability of HAART regimens HAART complications nDiarrhea, nausea , and vomiting. nLipodystrophy: fat in adipous tissue redistributed to other regions, i.e.face and limbs → thin, breasts, stomach and/or neck enlarge. nGlucose intolerance, diabetes. Lactic acidosis. nLiver toxicity – acute hepatitis incl. liver failure. Pancreatitis. nNephrotoxicity nNeuropathy nOsteonecrosis, osteoporosis, osteopenia HAART complications nCardiovascular complications: toxicity, endothelial dysfunction, atherosclerosis, dyslipidemia. Myocardial infarction nReconstitution of the immune system (major goal of HAART treatment): risk of debilitating Immune reconstitution inflammatory syndrome (IRIS) - ↑ CD4 count + function. Immune response against antigens associated with infection diseases (TB, MAC, Pneumocystis pneumonia, CMV, HZV). 10-25% of patients nDrug interactions n HAART resistance nDrug switching necessary nNew regiments/drugs nTimely start of therapy HIV-2 nEndemic in West Africa. nLimited spread outside this area, suspicion – in persons of West African origin/risk contact nPrevalence of HIV-2 disproportionately high in countries with strong socioeconomic ties to West Africa (e.g., France; Spain; Portugal; and former Portuguese colonies such as Brazil, Angola, Mozambique, and parts of India near Goa). HIV-2 nClinical course - longer asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rates compared with HIV-1 infection nResistance-associated mutations develop commonly in HIV-2 patients on therapy HIV infection of cells nT-lymphocytes (CD4+) nmacrophages/monocytes (viral reservoir, replication and transport) nmucosal and follicular dendritic cells ncells in CNS (microglia) Immune dysfunctions in AIDS nLymphopenia (selective loss of CD4+ T-cells – direct cytophatic effect, apoptosis of noninfected) nDecreased T-cell function in vivo (loss of memory T-cells, susceptibility to opportunistic infections and neoplasms, decreased delayed-type hypersensitivity) nPolyclonal B-cell activation (hypergammaglobulinemia, CIC, inability of new antibody response) nAltered monocyte or macrophage functions (decreased chemotaxis, phagocytosis, antigen presentation; increased spontaneous secretion of TNF, IL-1 etc. n Phases of HIV infection nAcute retroviral syndrome (3-6 wks after infection, in 40-90%, self-limited in 2-4 wks) nChronic phase (clinical latency, persistent generalized lymphadenopathy – PGL) nProgression to AIDS (AIDS-related complex – ARC, AIDS indicator conditions: constitutional, neurologic, opportunistic infection, neoplasm Acute HIV infection nSuspect: Signs or symptoms of acute HIV infection with recent (within 2–6 weeks) high risk of exposure nPossible signs: fever, lymphadenopathy, skin rash, myalgia/arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, transaminase elevation. Acute HIV infection nHigh-risk exposures include sexual contact with a person infected with HIV or at risk of HIV, sharing of injection drug use paraphernalia, or contact of potentially infectious blood with mucous membranes or breaks in skin. nDifferential diagnosis: Epstein-Barr virus (EBV)- and non-EBV (e.g., cytomegalovirus [CMV])-related infectious mononucleosis syndromes, influenza, viral hepatitis, streptococcal infection, syphilis HIV-PGL02 Persistent generalized lymphadenopathy Opportunistic infections and neoplasms nProtozoal and helmintic (cryptosporidiosis, toxoplasmosis, giardiosis, etc.) nFungal (Pneumocystis, candidiasis, cryptococcosis, coccidiomycosis, histoplasmosis) nBacterial (mycobacteriosis – atypical, TB; salmonellosis, nocardiosis) nViral (CMV, Herpes simpex, Varicella-zoster, progressive multifocal leukoencephalopathy – JC polyoma virus) nNeoplasms ( Kaposi sarcoma – HHV 8, B-cell non-Hodgkin lymphomas, primary brain lymphomas – EBV, aggressive cervical and anal carcinomas – HPV) HIV neurologic disease nAcute aseptic meningitis nsubacute and chronic: HIV-associated neurocognitive disorders nHIV meningoencephalitis – AIDS-dementia complex, vacuolar myelopathy, myopathy and peripheral neuropathy nbefore HAART, clinical signs of neurologic lesion in 40-60% of patients (HIV, opportunistic infection, tumor) nnow ↓– chronic encephalitis – microglial nodules + multinucleated giant cell, microfoci of necrosis n HIV-cerebral-atr-CT HIV encephalopathy – brain atrophy Copy HIV encephalopathy HIV-PML103 HIV-encephalitis-mi HIV encephalitis Copy HIV-IMH-p24 p24 immunohistochemistry CNS infections nToxoplasmosis nCryptococcosis nProgressive multifocal leukoencephalopathy (JC virus) nCytomegalovirus nHSV, VZV in disseminated infections n n n Toxoplasmosis nprotozoa with complicated life-cycle nbrain abscess, mostly in cortex and gray nuclei nacute lesion: central necrosis, mixed inflammatory reaction, macrophages („soap bubble“), toxoplasma pseudocyst nchronic lesion: cystic space with macrophages, hemosiderin HIV-cryptococ-mening-ma Toxoplasmosis Copy HIV-toxopl-encef03 Toxoplasma encephalitis HIV-toxopl-encef201 Toxoplasma encephalitis HIV-toxopl-encef302 Toxoplasma encephalitis Cryptococcus nfungus, PAS+ capsule n~ 10% of AIDS patients, now ↑ diagnosis in Africa – prophylaxis started nmeningitis mostly HIV-cryptoc-mening01 Cryptococcal meningitis HIV-cryptoc-mening202 Cryptococcal meningitis HIV-cryptococ-mening-PAS Cryptococcal meningitis PML: progressive multifocal leukoencephalopathy – demyelination Copy HIV-encephalopathy-luxol LUNG INFECTIONS nPneumocystis nCandidiasis, histoplasmosis, coccidiomycosis nCMV (+ in combination) nTBC nToxoplasmosis nNocardiosis n n LUNG INFECTIONS nCommon, diffuse infiltrates: CMV, Pneumocystis, drug reaction nCommon, focal infiltrates: Mycobacterium tbc, mycobacterium avium-intracellulare (MAC), G- rods, Staph. aureus, Aspergillus, Candida, malignant tumor nUncommon, diffuse infiltrates: bacteria, Aspergillus, Cryptococcus, malignant tumor nCommon, diffuse infiltrates: Cryptococcus, Mucor, Pneumocystis, Legionella Pneumocystis pneumonia Copy HIV-pneumocyst03 Pneumocystis pneumonia HIV-pneumocyst-silver01 Pneumocystis pneumonia TBC nearly in the course of HIV infection nreactivation/reinfection npulmonary and/or disseminated nmultiple and/or highly resistant mycobacteria nproblems in combination therapy (HIV + TBC) HIV-tbc02 TBC Invasive fungal infections nAspergillus spp (esp. A. fumigatus) nEpidemiology nWidespread, grows on rotting vegetation. Spores commonly present in air. Immunosuppression - important predisposing factor. nClinical presentations in HIV/AIDS nAspergilloma (fungal ball) - develops in cavities (lungs, sinuses, less common). nInvasive disease - tissue destruction, pneumonia. HIV-mycosis-colony01 Fungal colony HIV-fungal-pneu-mi Aspergillus pneumonia - angioinvasion Histoplasmosis nmacrophagic intracellular parasite - fungus nclinical presentation + morphology ~tbc nvariable course: localized/self limited – coin lesion in the lung nchronic progressive similar to tbc nlocalized extrapulmonary (mediasinum, liver, adrenals, meninges) ndisseminated in immunocompromised Histoplasmosis nMorphology nepithelioid cell granuloma + caseous necrosis, cavities – fibrosis – calcification nin immunodeficient – no granuloma; accumulation of macrophages with fungal yeasts ndg. – identification of fungal bodies (x tbc, coccodiomycosis), culture, Ab HIV-histoplasma03 Histoplasmosis Copy HIV-coccidiomyc03 Coccidiomycosis HIV-coccidiomyc-Grocott01 Coccidiomycosis HIV-intstic-pneu02 Interstitial pneumonia - viral GIT INFECTIONS nVery common, persistent diarrhea nCryptosporidiosis, isosporidiosis (protozoa; watery diarrhea, major fluid loss; dg.- oocysts in the stool) nAtypical mycobacteriosis (M. avium-intracellulare complex) nSalmonella, Shigella nCMV HIV-eroziv-gastr-ma02 Erosive gastritis HIV-eroziv-gastr-ma02 HIV-hemor-colitis03 Haemorrhagic colitis CRYPTOSPORIDIUM copy HIV-CMV-colitis-ma CMV colitis HIV-CMV-colitis202 CMV colitis HIV-ameb-colitis-ma02 Protozoan colitis (amoebiasis) HIV-ameb-colitis-mi03 Protozoan colitis (amoebiasis) Mycobacterium avium complex (MAC) enteritis HIV-MAC-enteritis-ma copy HIV-MAC-HE03 MAC enteritis copy HIV-MAC-Ziehl01 MAC enteritis copy HIV-bact-tromb01 Bacterial thrombus HIV + hepatitis co-infection nCommon coinfection of HIV + HBV and/or HCV n↑ acute HCV in HIV infected naccelerated progression of chronic hepatitis to cirrhosis + liver failure nproblems in HAART / HCV drug interaction and toxicity nvalue of the transplantation? n SKIN + ORAL INFECTIONS nChronic, relapsing, non-healing nCommonly ulcers nEBV + HIV – oral hairy leukoplakia nCandida nHSV, VZV n Oral lesions §Oral lesions due and acording to the rate of loss of T-helper cells. §Oral lesions - prominent features of AIDS and HIV infection. §Early studies: approximately 90% of HIV+ patients will present with at least one oral lesion in the course of their illness. nCurrent studies report the prevalence or oral lesions has significantly declined (HAART) § Oral hairy leukoplakia nAssociated with chronic shedding of EBV in the oral cavity. nPresentation: Poorly demarcated, corrugated, white plaques on lateral aspect of tongue. nUnlike thrush, cannot be removed by scraping. nOccurs with immunosuppression (esp. AIDS) and warrants HIV workup. nDiagnosis by microscopy and in situ hybridization nManagement includes establishing diagnosis and treating immunosuppression. HIV/AIDS oral-pharyngeal syndromes nInterferes with oral hygiene nMore oral pharyngeal pathology nInterferes with nutritional intake nWasting syndrome HIV treatment compliance may be impacted by oral pain, xerostomia, dysphagia nPsychosocial dimensions nAvoidance of social contact due to facial appearance nDepressive effects of persistent oral pain Oral lesions strongly assoc. with HIV nCandidiasis – erythematous, hyperplastic, pseudomembranous nHairy leukoplakia (EBV) nHIV-associated periodontal disease – necrotizing ulcerative gingivitis, HIV periodontitis, necrotizing stomatitis nKaposi‘s sarcoma (HHV-8) nNon-Hodgkin‘s malignant lymphoma (EBV) HIV/AIDS oropharyngeal syndromes – most common nCandidiasis 28%-75% nNecrotizing gingivitis nHSV, CMV, HIV, EBV ulcers nRecurrent aphthous ulcers nZalcitabine ulcers nKaposi’s sarcoma nDental abscesses n Oral hairy leukoplakia hairy%20leukoplakia HIV-oral-hairy-leuc01 Oral hairy leukoplakia HSV in immunocompromised 80FF9 Hard palate HSV in AIDS 17_024 HIV-HSV-mi HSV CMV Ulcerations MVC-014S copy Oral-pharyngeal candidiasis candi6 candi4 candi5 candi3 copy HIV-associated neoplasia nHHV-8: Kaposi sarcoma nEBV: non-Hodgkin‘s malignant lymphoma, primary brain ML nHPV: agressive anal, cervical squamous cell carcinoma nwith HAART: general increased risk of malignancy Human herpes virus 8 nHHV-8 is found to be associated with Kaposi sarcoma in virtually all cases. nIncludes AIDS, post-transplant, African and Mediterranean cases. nHHS-8 is found in KS lesions, saliva, blood and semen of infected individuals. nAssociated with body cavity based B-cell lymphoma. nLesions on mucosal membranes possible, usually starts on skin. HIV-Kaposi-ma+mi Kaposi sarcoma copy HIV-Kaposi-ma102 Kaposi sarcoma HIV-Kaposi-ma203 Kaposi sarcoma HIV-Kaposi-mi202 Kaposi sarcoma HIV-CMV-Kaposi02 Kaposi sarcoma + CMV colitis copy HIV lymphoma nSolitary lump or nodule, swelling, nonhealing ulcer nThe swelling may be ulcerated or may be covered with intact, normal-appearing mucosa. nUsually painful, rapid growth. nCommon association with EBV nSeveral histopathologic types, atypical localization HIV lymphoma. 17_021 HIV-ML-brain03 Primary brain malignant lymphoma HIV-ML-brain Primary brain malignant lymphoma Human papilloma viruses nHuman papilloma virus lesions appear most commonly in immunocompromised individuals. nDiagnosis based on history, clinical appearance, and biopsy. nCommon in early HIV infection. nSpiky warts, raised, cauliflower-like appearance. cerv-HPV-koilocyt-mi02 HPV – koilocytosis - LSIL cerv-HPV-imuno03 HPV - immunohistochemistry gbp350 Invasive squamous cell carcinoma Invasive cervical carcinom cerv-ca-ma02 Image070 Cervical squamous cell carcinoma