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Sarcoidosis is a rare multisystem inflammatory disease of largely unknown etiology. While pulmonary sarcoidosis is the most abundant organ manifestation, involvement of the skin that occurs in up to 30% of patients is the most common extrapulmonary presentation of the disease. Dermatologists therefore play an important role not only for establishing the diagnosis and delineating it from potential differential diagnoses but also for the interdisciplinary care of the patient. The clinical presentation of skin sarcoidosis is manifold, which occasionally aggravates making the final diagnosis. Specific skin lesions (with granulomas) and nonspecific skin manifestations (without granulomas) can be differentiated. Since a variety of organ systems can be affected, multidisciplinary cooperation is mandatory. Therapy of sarcoidosis is difficult; evidence-based studies and therapy guidelines are widely lacking. Our review intends to outline the characteristic clinical presentations of cutaneous sarcoidosis, describe the diagnostic approach and how to assure or exclude extracutaneous manifestations of sarcoidosis, and suggest a therapy algorithm for the treatment of skin sarcoidosis.

The histogenesis of granulomata is dependent on various cell types. The typical composition is a center of macrophages/histiocytes with lymphocytes at the border. The sequence of events leading to granuloma formation is regulated by various cell types and cytokines: While Th1-associated mechanisms promote granuloma development, it appears that regulatory T cells as well as M2 macrophages together with interleukin (IL)-10 and IL-13 lead to their dissociation and tissue healing. There is a strong correlation between structure and function of granulomas. Chronic inflammatory granulomatous skin diseases are primarily based on dysfunctional downmodulation of inflammatory processes that lead to and maintain granuloma formation.

Inflammation of the adrenal glands is caused by autoimmunopathies or infections and can induce adrenal insufficiency. Autoimmune lymphocytic adrenalitis is often combined with other autoimmune diseases and the most frequent cause of Addison's disease; however, it only becomes clinically apparent when more than 90 % of the adrenal cortex has been destroyed. Histological features are characterized by lymphoplasmacytic inflammation leading to an increased destruction of adrenocortical tissue but less severe courses can also occur. The second most frequent form of adrenalitis is adrenal tuberculosis, showing typical granulomatous findings that are nearly always caused by spreading from a tuberculous pulmonary focus. Other bacterial as well as viral infections, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and others, generally affect the adrenal glands only in patients with immunodeficiency disorders. In these infections, the adrenal cortex and medulla are frequently involved to roughly the same extent. Although surgical specimens from inflammatory adrenal lesions are extremely rare, the various forms of adrenalitis play an important role in the post-mortem examination of the adrenal glands for clarification of unclear causes of death (e.g. death during an Addisonian crisis).

Insulitis is considered to be the key morphological lesion of type 1 diabetes mellitus (T1DM) for which the diagnostic criteria were recently defined. From the immunophenotype of the lymphocytic infiltration, its frequency and extent during the course of T1DM and the presence of autoantibodies against beta cell proteins, it has been deduced that T1DM is a chronic autoimmune disease leading to gradual destruction of the insulin-producing cells of the islets of Langerhans in the pancreas, profound insulin deficiency and chronic hyperglycemia. This review article presents the morphological findings that support this hypothesis and addresses questions that need to be answered in order to further clarify the pathogenesis and to develop specific treatment options.

Despite being a frequent cause of arthritis and bone erosions, the underlying cellular and subcellular reaction in gout is insufficiently understood. The inflammasome as intracellular sensor for crystals plays an important role, notably resulting in interleukin (IL)-1 production. Morphologically, hyperplasia of the synovial membrane with joint effusion, along with fibrinogen deposition and influx of neutrophils and lymphocytes are observed. Extracellular NET formation by neutrophils is involved in the regulation of inflammatory tissue reaction. Furthermore, the release of IL-10 and tumor necrosis factor (TNF)-receptors along with lymphocyte proliferation induce the natural resolution of acute gouty arthritis which typically occurs after several days. In contrast to acute gout, tophi consisting of urate crystals are surrounded by histiocytes and multinucleated cells, resembling a foreign body reaction. The deposition of extracellular matrix by fibrocytes is usually observed around tophi. This fibrotic reaction is likely enhanced by Th2-lymphocytes. Bone erosions in gout occur around tophi and are triggered by osteoclast activation through RANK-ligand expression by lymphocytes. In conclusion, understanding the orchestration of inflammation in gout might help to identify new therapeutic targets.

Numerous theories on the pathomechanism of SIDS favor a multifactorial genesis whereby infections of the upper respiratory tract and the pulmonary tissue have a trigger function. The aim of the presented study was to prove the presence of inflammatory responses in pulmonary tissue in SIDS cases because various studies revealed contradictory results about the evidence of inflammatory pulmonary responses in SIDS cases. For this purpose, 10 cases with defined causes of death were examined in comparison to 75 cases of sudden infant death syndrome (SIDS) with regard to CD45RO, CD68 and LCA positive cells in pulmonary tissue. Furthermore, the cell adhesion molecules E-selectin, P-selectin and VCAM were investigated. In the study group, the immunohistochemical imaging of CD45RO and LCA positive cells showed mostly negative results. There were no significant differences between study and control group as to the number of cells expressing CD45R0, CD68 and LCA. The same was true for the adhesion molecules E-selectin, P-selectin and VCAM.

Cytology in uropathological diagnostics is mainly performed for oncological purposes. The assessment of malignancy by urothelial cell morphology is therefore decisive; however, cytology is only sensitive enough to detect high-grade tumor cells and the different low-grade tumors cannot be reliably diagnosed. Thus, the four-tier classification system of cytological findings (i.e. negative, atypical cells but significance uncertain, suspicious and positive) refers to high-grade tumor cells only. Furthermore, for valid cytological diagnostics not only the cytological specimen but also clinical information on cystoscopy findings and, if applicable, a biopsy should be evaluated together. In difficult differential diagnostic settings, e.g. differentiation between reactive versus neoplastic atypia or difficult to access lesions in the upper urinary tract, additional fluorescence in situ hybridization of cytological preparations might be helpful. At the moment there are no indications for further immunocytology or additional biomarker tests.

Although advances in targeted therapies have recently been achieved, lung cancer remains a major health burden worldwide. It is therefore pivotal to investigate the biology of lung cancers in order to design new therapeutic strategies. To address this a multi-antibody assay has been developed for the classification of non-small cell lung cancer (NSCLC). Using this assay the pathologist is able to reliably subtype NSCLC into adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma (LCNEC) and NSCLC not otherwise specified (NOS) large cell carcinoma, as required by the new World Health Organization (WHO) classification of 2015, on a single glass slide. In our cohort this classification algorithm showed significant differences in overall survival of the therapeutically important subgroups, which reflects the accuracy of the assay. To investigate the biology of NSCLC subtypes further, several proteins involved in carbohydrate metabolism were analyzed. In a hierarchical cluster analysis it could be shown that adenocarcinoma and squamous cell carcinoma harbor different metabolic shifts and, furthermore, that two distinct groups of squamous cell carcinoma seem to exist, a hypoxia and a transporter type. These results could be verified by analysis of mRNA data obtained from the TCGA database. As a close association between tumor metabolism and anti-tumor immune response has been reported, the lymphocytic infiltrates were characterized with respect to T-cells and their location within the tumor. Besides a negative correlation of lymphocyte density and expression of lactate dehydrogenase, it could be shown that depending on the location and type a high lymphocyte density indicates a significantly better overall survival of NSCLC patients. Investigating the expression of PD-L1 in NSCLC cells, a significant correlation with lymphocyte density was detected. In conclusion, the multi-antibody assay is a new and economically attractive tool for a reliable subclassification of NSCLC. This subtyping results in a better biological stratification of NSCLC and is the basis not only for palliative treatment options but also for further investigations on NSCLC biology. It was discovered that metabolic changes during malignant transformation are different in adenocarcinoma and squamous cell carcinoma. The latter group can be further divided into a hypoxia and a transporter type. Anti-tumor immune responses are influenced by the metabolic shift in NSCLC and lymphocyte density with respect to the location within the tumor is of prognostic significance in NSCLC. Therefore, the results contribute to a better biological understanding of NSCLC and may lead to new treatment options by targeting metabolic enzymes or triggering anti-tumor responses.

A relative or absolute increase of lymphocytes in peripheral blood is a frequent incidental finding. The differential diagnosis of such a finding includes a broad spectrum ranging from normal variations to neoplastic diseases. As for other laboratory parameters lymphocytosis must be interpreted within a given clinical situation. Further diagnostics aim to reliably differentiate between reactive and neoplastic conditions. If a lymphoma or leukemia is suspected this should lead to a rapid hemato-oncological investigation.

Nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin's lymphoma. The histological patterns of NLPHL variants are characterized by different localizations of the tumor cells, intranodular and perinodular and by the varying composition of the microenvironment. T-cell/histiocyte-rich B-cell lymphoma may be the result of an aggressive transformation of NLPHL. Classical lymphocyte-rich Hodgkin's lymphoma can usually be clearly distinguished from NLPHL by the immunophenotype of the tumor cells. Further differential diagnoses include follicular lymphoma and the follicular variant of peripheral T-cell lymphoma. Angioimmunoblastic T-cell lymphoma with CD20-positive blasts represents a differential diagnosis to the diffuse variants of NLPHL.

Microscopic colitis (MC) is recognized to be a common cause of chronic, non-bloody diarrhea with rising incidence in the last decade. The diagnosis can only be made by histology and the specific histological findings define two subtypes of MC: lymphocytic (LC) or collagenous colitis (CC). The key histological feature of LC is an increased number of surface intraepithelial lymphocytes (IEL). In the literature, >20 IELs/100 epithelial cells are required to warrant the diagnosis of LC. IELs are mostly cytotoxic CD8+ T-lymphocytes. The key histological criterion for CC is a continuous subepithelial fibrous band underneath the surface epithelium (>10 µm). Other hallmarks of CC are chronic mucosal inflammation, and the collagen band can contain entrapped capillaries, red blood cells, and inflammatory cells. Damaged epithelial cells appear flattened, mucin depleted, and irregularly oriented. Focally, small strips of surface epithelium may lift off from their basement membrane. In both subtypes of MC, the lamina propria shows increased numbers of plasma cells and lymphocytes with loss of the normal gradient, even eosinophilic and neutrophilic granulocytes may be present. But these histological features alone do not warrant the diagnosis of MC even though they may be responsible for the clinical symptoms. The term MCi (MC incomplete) is suggested for the subgroup of patients with diarrhea and an increase in cellular infiltrate in the colonic lamina propria and either an abnormal collagenous layer and/or intraepithelial lymphocytes coming but not fulfilling the criteria for CC or LC.

Background: The influence of silicone implants on the formation of a periprosthetic capsule can be well examined in animal studies. New implant materials have been developed to reduce capsular contracture. In order to evaluate the capsule formation, Wilflingseder et al. developed a histological score system. Because of new knowledge in the development of capsular contracture, the Wilflingseder classification is no longer appropriate. Current references are not considered so that a modification is required., Material and Method: In a randomised, experimental animal study 31 mini-implants were implanted into the dorsum of female Wistar rats [17 smooth, 10 mL saline-filled silicone implants (Group A) and 14 titanium coated silicone implants (Group B)]. After 12 (group A/B12) or 36 (group A/B36) weeks, surgical removal of the implants with subsequent histomorphological and immunohistochemical examination of periprosthetic capsule formation was performed by 2 independent investigators in a double-blind manner., Results: An analysis of the studies showed that the inner synovia metaplasia and the infiltration by inflammatory cells such as lymphocytes, histiocytes, plasma cells and granulocytes are of crucial importance in the development of a fibrotic capsule. The occurrence of these factors correlated significantly with each other and influenced also significantly the capsule architecture depending on implant surface. An adjustment of the existing Wilflingseder classification system was evaluated. The current rating system contains the following parameters: capsule thickness and cell layers of the capsule, the thickness of the inner synovial metaplasia, collagen structure, presence of histiocytes and the incidence of inflammatory cells. According to this classification, titanium-coated implants show an advantage in terms of the formation of capsular contracture., Conclusion: In 1974 Wilflingseder et al. developed a classification system for capsular contracture which is no longer appropriate, since current histological and immunohistochemical findings are not mentioned. Our study presents a new system which includes the latest insights into the development of capsular contracture and provides an objective classification of histological changes. Furthermore, we were able to show that titanium-coated implants are a promising approach in the reduction of capsular contracture., (© Georg Thieme Verlag KG Stuttgart · New York.)

Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by a dramatic onset of high fever, neutrophilia and typical skin lesions. About 20 % of patients have an associated malignancy, most commonly hematologic diseases. Chronic and paucisymptomatic manifestations of Sweet syndrome may be misdiagnosed or misinterpreted as harmless, resulting in delayed diagnosis. "Atypical" manifestations are especially suspicious for associated malignancies. This is demonstrated by a 39-year old patient with chronic and afebrile disease who was referred to our clinic only after symptoms had persisted for several months. By that point, an underlying nodular lymphocyte predominant Hodgkin's lymphoma had already reached an advanced stage. Skin biopsies revealed dermal infiltrates of histiocytoid cells of myelogenous origin, supporting a diagnosis of histiocytoid Sweet syndrome. Specific cutaneous infiltrates associated with myelogenous leukemia were ruled out., (© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 µm. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea.

Graft-versus-host disease (GvHD) occurs as a major complication in 35%-50% of all patients undergoing allogeneic stem cell transplantation. A distinction is made between acute and chronic GvHD depending on the time of onset, type of clinical symptoms and histology. Both forms preferably show manifestations in the skin, mucosal membranes, gastrointestinal tract, liver and (less often) lung. As the clinical presentation is rather unspecific, particularly for the diagnosis of acute GvHD, histology is important to exclude infectious diseases or drug reactions. This review covers the diagnostic morphological criteria and differential diagnoses of GvHD in the skin, gastrointestinal tract and the liver.

Since the first heart transplantation in 1967, the procedure has become an established therapy in the treatment of terminal heart failure. Constant advances in the development of potent immunosuppressive drugs, as well as greater clinical experience and pathological diagnostics have improved patient survival dramatically. The first grading system for rejection was published in 1990 by the International Society for Heart and Lung Transplantation (ISHLT) and revised in 2004. The 2004 grading system comprises three grades of severity (1R, 2R, 3R), whereby the former grade 2 in the 1990 system has been incorporated in the new grade 1R. Recommendations are made for the histological diagnosis of acute antibody-mediated rejection using immunohistochemical staining against C4d and macrophages. To the present day, the pathological examination of endomyocardial biopsies remains the gold standard for post-transplant diagnostic procedures. Whether or not non-invasive diagnostic approaches (e.g. gene array profile analysis on leukocytes) can replace morphological investigations needs to be clarified in randomised, prospective clinical studies.

The 2005 EORTC/WHO classification includes three CD30+ lymphoproliferative disorders: 1) primary cutaneous anaplastic large cell lymphoma, 2) lymphomatoid papulosis and 3) borderline cases. These entities may present with many different clinical appearances. Therefore, a precise differentiation among them often is impossible. We present a 40-year-old female who initially presented with a neutrophil-rich, anaplastic CD30+ T cell lymphoma followed by lymphomatoid papulosis.

To optimize the reliability of histopathological criteria for periprosthetic infection, 110 tissue specimens from joint prostheses were analyzed with quantification of the inflammatory cells and immunohistochemical typing of lymphocytes and plasma cells. As reported in the literature the density of granulocytic infiltration was the most sensitive marker of periprosthetic infection with an accuracy of 84%, a sensitivity of 91%, a specificity of 81%, a positive predictive value of 67%, and a negative predictive value of 95%, using the mostly favored limit value of 5 granulocytes per HPF. T lymphocytes were also found to a high degree in cases of aseptic loosening. In contrast, B lymphocytes were predominantly seen in cases with periprosthetic infection. For B lymphocytes an accuracy of 80% and a sensitivity of 79% were calculated and for plasma cells an accuracy of 75% and a sensitivity of 79%. Our data suggest that the quantification of granulocyte, B-cell, and plasma cell infiltrates is an important parameter for verifying the diagnosis of periprosthetic infection.

To clarify a suspected implant allergy, a patch test with implant metals and bone cement components can be used. The (immuno)histology of periimplant tissue may also indicate T-lymphocyte-dominant inflammation. Identification of histological allergy characteristics and evaluation of the lymphocyte transformation test beyond indications of sensitization will be possible only when larger studies are available.

Lymphomatoid papulosis is a rare disease with a worldwide incidence of 1.2 to 1.9 per 1 million. It affects all age groups with a peak incidence between 30 and 40 years and an apparent male predominance. Occurrence in childhood has also been described. Both the etiology and pathogenesis of the disease are unknown. The clinical presentation is extremely variable and frequently uncharacteristic. A papulonodular eruption, characterized by self-healing skin lesions appearing in crops can often be seen, particularly on extremities. We report on 17 patients, including 2 children. By detailing 6 cases we point out the variable morphologic manifestations, the different courses of disease and therapeutic options.

Diagnosis of polyarteritis nodosa is often delayed due to the vast heterogeneity of initial clinical symptoms. The case presented shows the clinical image of the disease, leading from the first symptoms up to verification of the diagnosis by sural-nerve biopsy. We discuss the classification of the disease among other types of vasculitis, the classification criteria proposed by the American College of Rheumatology (ACR) as well as current therapeutic options. This case underlines the interdisciplinary character of the disease, challenging neurologists, dermatologists, rheumatologists and orthopedics alike.

Epstein-Barr virus (EBV) infection has a prevalence of 90 % and is - depending on the immune status of the host - associated with a broad spectrum of clinical manifestations. By presenting a case report we would like to demonstrate an unusual clinical course of a primary infection with EBV in an elderly patient. A 77-year-old patient was admitted to hospital in reduced health condition because of a persisting bronchopulmonary infection with B symptoms. The patient had already been treated with antibiotics. Because of elevated liver enzymes, a liver biopsy was performed. Histopathology revealed moderate acute hepatitis with cholangitis und endothelialitis, pointing to an EBV-induced hepatitis. Serological examinations confirmed the diagnosis, revealing a primary infection with positive EBV VCA IgM and IgG. EBV PCR of the liver tissue was positive, viral genome could be demonstrated within lymphocytes. A short period later the patient was discharged to reconvalescence. This case report demonstrates an unusual primary infection with EBV at the age of 77 with atypical clinical symptoms and hepatitis. The relevance of EBV in the differential diagnosis of atypical infectious diseases with hepatitis of unknown aetiology is strengthened on taking data reports from the literature into consideration.

History and Admission Findings: A 37-year-old woman was admitted with total loss of vision of the left eye within 24 hours. Additionally, she complained about fatigue, headache, chills, fever, muscle pain and neck stiffness since 4 days. At admission, the body temperature was 38.7 degrees C. Neurological examination revealed papilledema and meningism., Investigations: Ophthalmologic findings were consistent with a papillitis. The vision was lost, the pattern-shift checkerboard visual evoked potentials were not measurable. MRI of the brain and the optical nerve was without pathological findings, meningeal or cerebral Gadolinium enhancement was not present. The CSF analysis yielded a lymphocytic meningitis with 249 cells/mm (3), the glucose ratio of cerebrospinal fluid and serum was normal., Diagnosis, Treatment and Course: The papillitis was treated unsuccessfully with high-dose methylprednisolone, the left eye remained blind. Persistence of the pleocytosis under initial treatment with aciclovir and ceftriaxone, reduction of the glucose ratio of cerebrospinal fluid and serum and intrathecal immunoglobuline A -- synthesis required a change of the diagnostic and therapeutic regimen. Various common and rare differential diagnoses were considered and ruled out, a chronic meningitis of unclear aetiology with the complication of amaurosis was diagnosed. In consideration of the most probable diagnosis, a tuberculostatic therapy was initiated. A prolonged reduction of the pleocytosis and normalization of cerebrospinal fluid parameters could be observed., Conclusions: A large number of aetiologies can cause chronic meningitis; this case report reviews the most important differential diagnoses and highlights the limitations of the diagnostic work-up although various methods are available. Clinical course and symptoms of chronic meningitis are mild to moderate and may even be absent, but it can cause severe complications.

Case Report: A 25-year-old patient with fever, dysphagia, and reduced general condition was referred to our department by his dentist after 1 week of antibiotic therapy. He presented with a painful palpable mass in the right lower jaw that had developed 2 weeks before. The orthopantomogram showed a caries and periapical lesion at the right lower wisdom tooth. During extraction of the tooth and putative intra- and extraoral abscess incision, no pus could be drained and the mass persisted. CT scans then revealed lobulated soft tissue masses on both sides of the neck with the main focus on the right side. In an additional operation with excision of the mass, Castleman's disease of the hyaline vascular type was diagnosed., Histopathologic Findings: Staging could not detect further pathological findings and the patient's postoperative general condition improved continuously. The histological features of the hayline vascular type of Castleman's disease were characterized by multiple germinal centers surrounded by circumferentially arranged layers of small lymphocytes interconnected by a prominent vascular stroma with occasional plasma cells ("onion skin")., Conclusion: Castleman's disease is a rare and yet poorly understood disease, characterized by inhomogeneous growth of lymphoid tissue. Mostly benign it remains a diagnostic challenge before histological investigation. In unclear submandibular swellings and neck lumps assumed to be an abscess, this rare differential diagnosis must be considered. Facing recurrence and potential for malignancy, follow-up of the patients over several years is necessary.

Several tumour entities have been described to develop in chronic inflammatory disease mainly hepatocellular carcinoma in chronic hepatitis. Compared to HCC bile duct carcinomas or other tumour entities are rare. The risk for HCC increases if liver cirrhosis occurred. Despite a huge progress in detecting many genes involved and altered in hepatocarcinogenesis the exact mechanisms of HCC development is not understood. Various causes initiate a multistep process of several steps: chronic liver injury, chronic inflammation, cell death, regeneration, cirrhosis, DNA damage, dysplasia and HCC. Molecular changes cannot be used for risk assessment of patients with liver cirrhosis or liver cell dysplasia. They are not helpful for problems in differential diagnosis between dysplasia and HCC.

Carl-Adolph von Basedow described the typical clinical features of immune-mediated hyperthyroidism (tachycardia, proptosis, goiter) in 1840 and termed it the "Merseburg trias". Graves' disease is an autoimmune disease with thyroidal and extra-thyroidal manifestations such as endocrine orbitopathy, which is caused by a dense lymphocytic infiltrate. A genetic predisposition combined with so far unidentified environmental factors and a complex immunological process seem to be important for its pathophysiology. The pathognomonic histopathophysiological picture is characterised by the typical lymphocytic infiltration of the ocular muscles and retrobulbar connective and adipose tissues leading to the classical exophthalmus. No specific therapy is available. The goal of therapy is therefore the correction of the hyperthyroidism and inhibition of the immune-mediated orbital inflammation which can be achieved by early interdisciplinary team work of endocrinologists, ophthalmologists and radiation therapy.

Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disease and leukaemia in western countries. CLL occurs more frequently in men than women, the median age at diagnosis is 65 years. CLL is defined as a persisting chronic lymphocytosis > 5 G/l with classical morphological features (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however, deviations from classical morphology are frequent. In cases with classical diagnostic features in the peripheral blood, a bone marrow biopsy is not necessary for diagnosis. Prognostic features comprise the stage of the disease according to the Rai or Binet systems, laboratory markers such as LDH, beta-2-microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry (and ZAP-70 expression if available) as well as the status on IgV(H) hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need treatment at the time of diagnosis and can initially be followed using a watch and wait strategy. If therapy becomes necessary, initial standard treatment still is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options for refractory or relapsing disease. Therapies with antibodies such as Alemtuzumab and Rituximab in combination with purine analogues are currently under clinical investigation. With recurrent or atypical infections, hypogammaglobulinemia should be searched for and immunoglobulins should be substituted if necessary. However, their prophylactic use is not recommended.

The differential diagnosis of absolute lymphocytosis is variegated. In general, reactive (secondary) lymphocytosis can be well differentiated from a lymphoproliferative disease (primary lymphocytosis). Together with correspondent clinical characteristics, an absolute lymphocytosis often suggests a potential diagnosis and the further diagnostic process. Reactive lymphocytosis is usually self limiting and normalizes after cessation of the inflammatory stimulus. If a lymphoproliferative disorder is suspected further diagnostic procedures (i.e. cytometry, bone marrow examinations, biopsies of other organs if needed and molecular analyses) should be performed. If the distinction between malignant lymphoproliferation and reactive lymphocytosis cannot be done immediately, a watch and wait strategy may be implemented. In case of persistent lymphocytosis for longer than six months or occurrence of additional symptoms earlier on, diagnosis should be forced.

An open lung biopsy was performed in a 28-year-old woman with tuberous sclerosis and with spontaneous pneumothorax and interstitial changes in the chest X-ray. Microscopically a micronodular pneumocyte hyperplasia in addition to a lymphangioleiomyomatosis was found. The micronodular pneumocyte hyperplasia is considered to be a very rare lesion. Only 27 well documented such cases have been recorded so far, 24 in women and 3 in men. The age of the patients ranged between 20 and 57 years, with an average of 36 years. The micronodular pneumocyte hyperplasia occurs mainly in patients with tuberous sclerosis (20 of 27 cases) and it is often combined with a lymphangioleiomyomatosis (19 cases). In the differential diagnosis the atypical adenomatous hyperplasia is to be considered in the first place. In contrast to it, the proliferating cells of the micronodular pneumocyte hyperplasia show no atypia. The differentiation from a papillary adenoma can be difficult in small biopsies.

Although stem cell transplantation is a life-saving measure and the treatment of choice for many patients with various hematologic malignancies, a high incidence of complications and a transplantation associated mortality of about 30% are to be expected.Graft-versus-Host Disease (GvHD) is the major cause of morbidity and mortality after stem cell transplantation. GvHD can arise at various time points. Acute GvHD occurs during the first 100 days after transplantation in up to 50% of graft recipients, while chronic GvHD develops in about 30-50% usually within 100-500 days following allogeneic stem cell transplantation. It can involve the skin, liver, gastrointestinal tract, and less frequently the lungs, eyes and neuromuscular system. Early diagnosis of GvHD can be difficult, as drug reactions, viral infections and cutaneous reactions to radiation therapy may have clinical and histological similarities. In this review, the various cutaneous manifestations of GvHD, the histopathologic features, prophylaxis and therapy of acute and chronic GvHD are discussed in light of the recent literature.

Background: In middle Europe the prevalence of allergic rhinitis is up to 15 % to 25 %. Allergic rhinitis is characterised by an inflammation of the nasal mucosa induced by different allergens. The patients suffer from symptoms like sneezing, rhinorrhea and nasal airway obstruction caused by morphological changes of the nasal mucosa. This symptomatology is considered to be a result of accumulation and activation of inflammatory cells. Further some neuropeptides like Calcitonin Gene Related Peptide (CGRP) and Substance P (SP) play an additional role in pathophysiology of allergic rhinitis., Patients and Methods: Tissue samples from 28 human turbinates of patients with perennial rhinitis were taken during nasal surgery and preserved in phosphate-buffered glutaraldehyde or paraformaldehyde. Ultrathin sections were cut. The samples were dehydrated and embedded in Araldit. After polymerization an immunocytochemical staining-technique using a gold-labeled antibody was carried out. Immunostained structures were photodocumented by using a transmission electron microscope., Results: In the lamina propria mucosae an extensive edema and several inflammatory cells like lymphocytes, plasma cells, eosinophiles and macrophages was found. The capillaries showed an activated endothelium. Immunoreactive nerve fibers were found in the periglandular tissue around the acini, ducts and in the glandular connective tissue. Neuroglandular synapses with dense core vesicles and positive immunoreactions to CGRP and SP could be detected. Neuropeptidergic axons were often observed near to plasma cells., Conclusions: In the edematous nasal mucosa an infiltration with different inflammatory cells was found. Using electron microscopical techniques nerve structures near the submucosal glands could be demonstrated. Immunoreactions to the neuropeptides CGRP and SP were detected in the periglandular nerves and in neuroglandular synapses. These findings demonstrate the direct nerve control of glandular functions in allergic rhinitis. CGRP is generally known to have a vasodilatatory effect and to stimulate the secretion of nasal seromucous glands. In addition, SP as a short-acting vasodilatator may induce vascular permeability and glandular secretion. These immunoelectron microscopical findings further elucidate pathomorphological mechanisms in allergic rhinitis.

Introduction: The zeta-chain as an important component of the T cell receptor (TCR) is involved in the transduction of intracellular signals and is therefore critical for T cell activation and subsequent induction of an anti-tumor response. In patients with squamous cell carcinoma of the head and neck (SCCHN) several mechanisms of immune suppression have been described. The expression of the TCR zeta-chain of both peripheral blood lymphocytes (PBLs) and tumor infiltrating lymphocytes (TILs) has been analysed in patients with SCCHN and correlated to clinical data., Methods: TIL and PBL from 47 patients with SCCHN were obtained. To determine expression of the zeta-chain in both PBLs and TILs, double immunostaining with mAbs and flow cytometric analysis was performed. The technique combined an intracellular staining with a surface staining., Results: As compared to healthy controls (n = 23), zeta-chain expression was significantly reduced (p < 0.002) in patients with SCCHN (n = 23) with lowest expression in those with UICC VI disease. Our results show a tight correlation between the loss of zeta-chain expression and the clinical aggressiveness of the tumor. Higher tumor stages frequently show a higher loss of the zeta-chain. In 11 patients zeta-chain expression of the PBL could be compared with TIL. Independent of the tumor stage the loss of the zeta-chain expression is much higher in TIL than in PBL. The loss of the zeta-chain expression also correlates with the progression of the disease. Patients with a high loss of the zeta-chain expression develop a recurrence more frequently., Conclusion: The loss of the zeta-chain documents a systemic immune defect, which even occurs in early tumor stages. Additionally to locoregional approaches future therapeutic strategies should also focus on systemic immunomodulation.

Ulcerated primary cutaneous lymphomas are not rare, but the clinical manifestation as a pyoderma gangrenosum look-alike is extraordinary. CD8-positive lymphomas are rare, unclassifiable tumours with variable prognosis. We report on a 49-year-old patient with a large ulcerated primary cutaneous lymphoma on the left chest wall presenting as pyoderma gangrenosum. With immunohistochemical staining, most lymphocytes were shown to be CD8-positive. The CD30 antigen was not expressed. After radiotherapy with complete skin irradiation, the lymphoma regressed completely. The patient has been free of relapse for 28 months so far.

Background: A tapetoretinal dystrophy with crystalline deposits of the retina and limbal cornea was described by Bietti in 1937. To date, only a few cases with long-term follow up have been reported., Patients and Methods: Two patients are presented including the clinical findings, fluorescein angiography, electrophysiology [electroretinography (ERG); electrooculography (EOG), multifocal electroretinography (MERG)], adaptometry, and transmission electron microscopy (TEM) of peripheral blood lymphocytes. The clinical findings were at least in part documented over a period of 30 years., Results: The most striking features were deposits in the retina and cornea associated with crystalloid lysosomal inclusions in peripheral lymphocytes, and choroidal atrophy especially in advanced stages of the disease. The light rise (EOG), rod- and cone-driven responses (ERG), the responses of the MERG and visual fields were affected progressively during the course. These advanced changes of the retinal pigment epithelium and choriocapillaris were observed in the 2(nd) decade already., Conclusions: The findings of deposits in the cornea, retina and lymphocytes may help to differentiate BCD from other chorioretinal dystrophies. The results confirm a variable course in clinical expression of BCD between individuals.

Lymphocytic gastritis, first described by Haot et al. in 1986, is a very rare form of gastritis (0.8-1.6% of cases) with unclear pathogenesis. On endoscopy, lymphocytic gastritis may present either a normal appearance, such as gastritis varioliformis with multiple elevated chronic erosions in the corpus and fundus, or as a giant fold gastritis in the corpus and fundus. This type of gastritis is diagnosed histologically based on an accumulation of intraepithelial lymphocytes (more than 25/100 epithelial cells) in the surface cells of the gastric mucosa. Its etiopathogenesis is currently thought to be a sprue-associated reaction or an atypical reaction to Helicobacter pylori infection. Some studies report the lymphocytic gastritis in almost 45% of cases of sprue, with the gastritis regressing in response to a gluten-free diet, while others report a correlation of lymphocytic gastritis with serologically and/or histologically confirmed H. pylori infection, with the lymphocytic gastritis being cured by H. pylori eradication treatment in a high percentage of the cases. It is possible that a similar abnormal immune reaction to an inflammatory agent underlies both pathological entities, sprue and lymphocytic gastritis--in the one case gluten and in the other H. pylori--which would mean that sprue-induced and H. pylori-induced forms of lymphocytic gastritis exist side by side.

The diagnosis of celiac disease (CD) is based upon histological findings in duodenal or jejunal biopsy specimens. In recent years it has been seen that the development of CD lesion in the small bowel is a dynamic process which may present in various histological forms. At one end of the spectrum is a mucosa with normal architecture and an increase in intraepithelial lymphocytes; at the other end is the classical flat mucosa. Histological features supporting the diagnosis of CD are architectural changes of the villi and/or crypts, an increase in lamina propria cell density, and an increase in intraepithelial lymphocytes counts. Exact histological classification of the histological findings is required for diagnostic purposes and for monitoring of CD patients. This has become possible by using a modified Marsh classification. We present both the histological presentation of CD and the modified Marsh classification, and the most important differential diagnoses.

Background: Titanium as a biomaterial in ossicular replacement has widely spread within the last couple of years., Methods: 23 prostheses (12 PORPs, partial ossicular replacement prostheses and 11 TORPs total ossicular replacement prostheses) removed during revision surgery were studied using scanning electron microscopy. The average implantation time was 8 (range 3-15) months. The specimens were investigated regarding tissue growth, epithelialization, inflammation and cellular signs of rejection., Results: Only few prostheses were totally covered by connective tissue or epithelium due to technical problems in removing the implant and the covering tissue as one specimen. But this offered the possibility to study the interface at the edges where the tissue was torn off. The connective tissue looked unremarkable. Polygonal squamous epithelium was detected on several implants. Respiratory epithelium with ciliated cells and mucus producing goblet cells was seen in two specimens. In cases of cholesteatoma or protrusion the explanted prostheses showed typical rosette-like formation of hornifying squamous epithelium. According to underlying disease a lymphocytic infiltration could be seen. There were no cellular signs of incompatibility noticed neither macrophages nor foreign body giant cells., Conclusions: From these investigations titanium seems to be a favorable biomaterial for ossicular replacement with good acceptance also in an implantation site showing chronic inflammation.

Differentiation of focal or extended lymphoid bone marrow infiltrates presents a diagnostic challenge and therefore warrants systematic evaluation of those features which affect this. One of the basic requirements is an appropriate technique of processing the bone marrow specimens. This includes the possibility of enzyme evaluation (naphthol-AS-D-chloroacetate esterase) and immunohistochemistry (set of monoclonal antibodies) and comparison with the corresponding lymph node histology. A number of histological parameters have emerged with a distinctive property for distinguishing between reactive focal lymphoid aggregates and malignant lymphomas. Amongst these the pattern of infiltrates, i.e., histotopography (subcortical infiltrates, paratrabcular-endosteal localization, margination, tandem-like extension between adipocytes and cribriform appearance), content of reticulin fibers, cytology (small lymphocytes versus large blast cells) and, finally, immunohistochemistry (monoclonal versus polyclonal expression of cytoplasmic immunoglobulins, uniform versus mixed population of B or T lymphocytes) are most important. In conclusion, synoptic consideration of several parameters, in particular histotopography and immunohistochemistry provides a most promising approach to differentiate neoplastic from reactive lymphoid lesions in the bone marrow.

Unlabelled: Chronic sialectatic parotitis (CSP) causes problems in differential diagnosis and therapy. CSP shows the typical clinical features of chronic recurrent parotitis and will be investigated histopathologically only after ultimative parotidectomy. The etiology and pathogenesis of these unspecific inflammations is still unknown. Therefore no causal therapy is available and a lot of different trials (sialogoga, gland massage, infrared light, antibiotics, antiphlogistics, Trasylol, duct occlusion, duct ligation, gland denervation, radiotherapy) are not successful in the long run., Material and Method: The salivary gland registry of the University of Hamburg (1965-1996) contains 22 infants and juvenile patients showing very severe courses of CSP. These cases have been investigated clinical (ultrasound, sialography), histopathological (paraffin embedded sections, histomorphometry of the ectatic duct lumina) and immunohistochemical (CK-MNF, AKTIN, KiM4) in a retrospective study to research the pathogenesis of CSP., Results: Recurrent and always very dolent parotid swelling occurs between the age of 3 and 14 years for the first time. The courses vary from 3 months until 25 years. Local findings as well as ultrasound and sialographic features allow no certain differentiation of chronic recurrent parotitis. Conservative therapy fails in each case and leads to the necessity of surgical treatment. Histopathological three different stages of development can be observed: Initial stages show regular lobular architectonic structure of the parotid gland parenchyme with duct ectasies surrounded by slight inflammation of lymphocytes and plasmacells. Advanced stages are characterized by an increase of periductal inflammation and the appearance of lymphfollicels. Nearly complete lymphatic transformation of the parenchyme with destruction of the lobular formation dominates the terminal "immunologic" stage. Some cases show multiple myoepithelial islands within this lymphatic stroma typically observed in benign lymphoepithelial lesions. Whether bacteria nor primary obstructive changes can be observed. The histomorphometric analyses of the average and maximal luminal duct diameters show marked increase of 39% respectively 46% from and- vanced to terminal stages of CSP. Therefore the pathognomonic duct ectasies seem to depend on the progredient inflammation and are not due to a hereditary malformation of the duct system. Immunohistochemical terminal stages show follicular lymphatic hyperplasia (KiM4) expressing overshooting humoral immune reaction of MALT., Conclusion: Concerning the pathogenesis CSP corresponds to a immunopathological disorder of MALT and seems to be a prestage of benign lymphoepithelial lesion. Consequently important changes in the diagnosis and therapy of CSP lead to early histopathological investigation to differentiate the stage of inflammation. In stage III conservative parotidectomy should be carried out because spontaneous healing can not be expected. In contrast initial cases should be treated at first by glucocorticoids and immunosuppressives.

Palpable arciform migratory erythema of Clark (PAME) has been described as a rare member in the group of T-cell pseudolymphoma. The clinical picture of infiltrated annular erythema developing into large migrating lesions with the trunk as predilection site is distinctive from other pseudolymphomas. Because of the very similar histology and immunohistochemistry in comparison to the more frequent lymphocytic infiltration of the skin of Jessner and Kanof (LIS) doubts have been raised about the existence of PAME as an unique entity. A 46-year old patient presented with the typical picture of PAME on his trunk while showing typical lesions of LIS on his neck and face. Both diseases showed synchronous intermittent remissions in response to different therapeutic modalities. Multiple biopsies were subsequently performed and histological, immunohistochemical and molecular biological examinations did not reveal relevant differences between PAME and LIS in this patient. We conclude that the findings in this key case suggest that the T-cell pseudolymphoma PAME is not an unique entity, but a special clinical presentation of LIS.

We describe granulomatosis disciformis Miescher in a 57-year old female patient with typical clinical manifestation: disc-shaped plaques with slight central sclerosis and lesions resembling necrobiosis lipoidica and granuloma anulare. Histology revealed an infiltrate mainly composed of macrophages and lymphocytes and small foci of necrobiotic collagen and of new collagen formation. We review the literature on granulomatosis disciformis and nosology, concluding--as do most authors--that granulomatosis disciformis is a characteristic variant within the spectrum of cutaneous noninfectious granulomatous disease lying in between generalized granuloma anulare and necrobiosis lipoidica.

Lichen aureus is a special localized variant of purpura pigmentosa chronica. A patient presented with an unusual striate and segmental or zosteriform distribution of lichen aureus involving the left leg and lower abdominal area. Histology showed the characteristic dense band-like infiltrate consisting mainly of small lymphocytes and numerous hemosiderin-containing macrophages. No underlying infection or medication could be identified as a trigger. The lesions did not respond well to topical corticosteroid therapy.