Postmortem investigation of fatalities following vaccination with COVID-19 vaccines.

Thorough postmortem investigations of fatalities following vaccination with coronavirus disease 2019 (COVID-19) vaccines are of great social significance. From 11.03.2021 to 09.06.2021, postmortem investigations of 18 deceased persons who recently received a vaccination against COVID-19 were performed. Vaxzevria was vaccinated in nine, Comirnaty in five, Spikevax in three, and Janssen in one person. In all cases, full autopsies, histopathological examinations, and virological analyses for the severe acute respiratory syndrome coronavirus 2 were carried out. Depending on the case, additional laboratory tests (anaphylaxis diagnostics, VITT [vaccine-induced immune thrombotic thrombocytopenia] diagnostics, glucose metabolism diagnostics) and neuropathological examinations were conducted. In 13 deceased, the cause of death was attributed to preexisting diseases while postmortem investigations did not indicate a causal relationship to the vaccination. In one case after vaccination with Comirnaty, myocarditis was found to be the cause of death. A causal relationship to vaccination was considered possible, but could not be proven beyond doubt. VITT was found in three deceased persons following vaccination with Vaxzevria and one deceased following vaccination with Janssen. Of those four cases with VITT, only one was diagnosed before death. The synopsis of the anamnestic data, the autopsy results, laboratory diagnostic examinations, and histopathological and neuropathological examinations revealed that VITT was the very likely cause of death in only two of the four cases. In the other two cases, no neuropathological correlate of VITT explaining death was found, while possible causes of death emerged that were not necessarily attributable to VITT. The results of our study demonstrate the necessity of postmortem investigations on all fatalities following vaccination with COVID-19 vaccines. In order to identify a possible causal relationship between vaccination and death, in most cases an autopsy and histopathological examinations have to be combined with additional investigations, such as laboratory tests and neuropathological examinations.

177 Lu-DOTATATE (Lutathera) Therapy in 68 Ga-DOTATATE PET/CT-Negative Liver Metastases of a Neuroendocrine Tumor.

ABSTRACT: A 73-year-old man with metastatic pancreatic neuroendocrine tumor was evaluated with 68 Ga-DOTATATE PET/CT for peptide receptor radionuclide therapy. Both PET-positive and negative lesions were seen in the liver, along with extrahepatic metastases. Histopathology was obtained from one of the PET-negative liver lesions to exclude secondary malignancy. Histology confirmed a well-differentiated (G2) metastasis of pNET with high somatostatin receptor expression. We initiated peptide receptor radionuclide therapy with close monitoring of the PET-negative liver metastases. We present a rare case, where posttherapeutic scintigraphy revealed vigorous uptake of 177 Lu-DOTATATE even in the 68 Ga-DOTATATE PET-negative liver metastases. Follow-up PET/CT showed a partial response to therapy.

Therapeutic potential of CAMPATH-1H in skeletal tumours.

AIMS: CD 52 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that is expressed abundantly on all lymphocytes, monocytes, macrophages, eosinophils and in the male genital tract. To date, the physiological role of CD52 on lymphocytes has not been elucidated. However, an antibody directed to CD52 called CAMPATH-1H has been shown to be capable of depleting lymphocytes. The aim of this study was to analyse tissue and cell lines of non-neoplastic bone, cartilage and skeletal tumours for CD52 expression. METHODS AND RESULTS: The expression of CD52 mRNA and protein both in vivo and in vitro was detected. Malignant tumours showed higher CD52 expression compared to benign tumours, suggesting a role in the development and progression of bone tumours. Interestingly, immunohistochemistry and flow cytometry revealed that CD52 was expressed not only on the surface of tumour cells, but also in the cytoplasm. The results obtained in osteosarcoma cells showed that CAMPATH-1H leads to a complement-independent reduction of viable cells. CONCLUSION: CD52 is expressed in a variety of bone tumours and the in vitro studies presented herein suggest that CAMPATH-1H treatment might have therapeutic potential for osteosarcoma patients.

Pathomorphological changes after radiofrequency ablation in the liver.

Radiofrequency ablation (RFA) has become a widespread treatment option for liver carcinoma. There is limited knowledge regarding the macroscopic and histomorphological changes of induced lesions. Twelve domestic pigs underwent RFA using a Starburst XL device with ablation diameter of 3 cm. One animal died within 24 h, two animals were killed after 2 weeks, and nine after 4 weeks. Their livers were used for macroscopic and histological investigation. Six human liver resection specimens after previous treatment with RFA were also investigated. In pig samples, acute RFA change showed a necrosis zone demarcated by resorption zone with granulocytes and hyperemia. In subchronic and chronic RFA change, the zone of thermofixation was followed by a fibrous capsule and a liver reaction zone. Small blood vessels in the lesions showed damage involving endothelial destruction and thrombosis. Larger vessels within the lesions were observed with intact vessel walls, surrounded by a rim of vital hepatocytes. In the human samples, tumor-infiltrating lymphocytes were reduced (CD3+ cells: 8.4 +/- 3.7/10 high-power fields (HPF); CD4+ cells: 4.2 +/- 1.9/10 HPF), whereas the number of histiocytes was found to be increased (CD68+ cells: 15.5 +/- 9.02/10 HPF). The recognition of thermofixation and the process of resorption of the RFA lesion is important for the interpretation of biopsies and surgical resection specimens.

Spontaneous tumour development in human papillomavirus type 8 E6 transgenic mice and rapid induction by UV-light exposure and wounding.

Cutaneous human papillomavirus type 8 (HPV8) is carcinogenic in patients with epidermodysplasia verruciformis. Transgenic mice with the complete early region (CER) of HPV8 spontaneously developed papillomas, dysplasia and squamous cell carcinomas of the skin. To characterize the role of individual early genes in carcinogenesis, the E6 and E6/E7 genes were expressed separately in transgenic mice. Nearly all HPV8-E6-positive mice spontaneously developed multifocal tumours, characterized by papillomatosis, hyperkeratosis and varying degrees of epidermal dysplasia. In 6 % of the cases, the tumours became malignant, comparable with HPV8-CER mice. Thus, in the murine epidermis, E6 is the major oncogene necessary and sufficient to induce spontaneous tumour development up to the level of squamous cell carcinoma. To evaluate the synergistic effects of UV light and wound healing, the skin of HPV8 mice was irradiated with UVA/UVB light or wounded with punch biopsies. These treatments induced papillomatosis in HPV8-CER and -E6 mice within 3 weeks. Irradiation with UVA alone did not induce papillomatosis and UVB alone had a weaker effect than UVA/UVB, indicating a synergistic role of UVA in UVB-induced papillomatosis. An HPV8 infection persisting over decades in interaction with sun burns and wound healing processes may be a relevant cause of skin cancer in humans.

First presentation of a Nora-lesion of the talus in a paraossal fasciitis.

Nora-Lesion is a proliferation that normally develops out of an intact corticalis. The entity of this fibroostotic pseudotumor, as discussed in literature, is triggered from repeating trauma or reactive periosteitis. In the literature, there are more than 200 cases defined as Nora lesion. In the daily routine of medical offices or ambulances, the Nora- Lesion should be established as a differential diagnosis for a swelling of the foot. Our case report of a 49-year-old patient is the worldwide first description of a Nora lesion of the talus, as well as secondary of the calcaneus. In the immense differential diagnosis discussion for bony pathologies of the hindfoot the Nora-lesion should be now added.

Hepatic granulomas: histological and molecular pathological approach to differential diagnosis--a study of 442 cases.

BACKGROUND/AIMS: The incidence of hepatic granulomas is reported in 2-15% of liver biopsies. This study was carried out to evaluate the incidence and aetiology of hepatic granulomas in a German Institute of Pathology with specialization in liver diseases. METHODS: A retrospective case review was performed on 12,161 liver biopsies of the Institute of Pathology (University of Cologne) between 1996 and 2004. Aetiology was determined according to histomorphological changes, clinicopathological data and liver tissue polymerase chain reaction (PCR) for detection of diverse putative pathogens in the liver tissue. RESULTS: Four hundred and forty-two liver biopsies revealed granulomatous lesions (3.63%). Two hundred and fifteen cases (1.77% of all biopsies and 48.64% of granulomatous lesions) were diagnosed as primary biliary cirrhosis. In 37 cases (0.3% of all biopsies and 8.37% of granulomatous lesions), the diagnosis of sarcoidosis was established. A positive PCR result for an infectious pathogen was obtained in 15 samples (3.39%) [Bartonella henselae (n=2), Listeria (n=3), Mycobacterium tuberculosis (n=3), Yersinia pseudotuberculosis (n=1), cytomegalovirus (n=2), Epstein-Barr virus (n=4)]. In six cases, a putative diagnosis was established according to the report of clinical conditions. In 11 cases (2.48%), drugs were the putative causative agent. In 158 cases (36%) a definite diagnosis could not be established. CONCLUSIONS: Hepatic granulomas have a broad range of underlying aetiologies. With a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 64% of the cases. Owing to the diverse prognosis and therapeutic implications, a detailed interdisciplinary workup of all liver biopsies with granulomatous lesions is mandatory.

Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8.

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo.

Giant cell tumors of the bone: molecular profiling and expression analysis of Ephrin A1 receptor, Claudin 7, CD52, FGFR3 and AMFR.

Giant cell tumors (GCTs) of the bone are osteolytic neoplasms with variable degrees of aggressiveness. The aim of this study was the molecular characterization of GCT tissue. We established gene expression profiles and discovered a number of genes that have not been described in GCTs before. RNA was prepared from 7 cryopreserved GCTs (primary tumors n = 5, relapses n = 2) and was hybridized to Affymetrix HG U133A microarrays. Paraffin-embedded samples were used for immunohistochemical validation (primary tumors n = 16, relapses n = 6). Gene ontology revealed that the majority of genes, found to be differentially expressed between primary and recurrent GCTs, were associated with receptor tyrosine kinase activity. We selected one upregulated gene (Claudin 7) and four downregulated genes (CD52, Ephrin A1 receptor, autocrine motility factor receptor [AMFR] and fibroblast growth factor receptor 3 [FGFR3] for further analysis using immunohistochemistry. Immunohistochemical analysis of CD52, AMFR, and Ephrin A1 receptor revealed expression profiles concordant with the microarray data, also with regard to differences between primary tumors and relapses.

Precision cut tissue slices of the liver as morphological tool for investigation of apoptosis.

BACKGROUND: Apoptosis, programmed cell death, is involved in a broad range of pathological processes. Dysregulation of apoptosis plays a key role in the pathogenesis of hepatitis, toxic liver disease and also liver tumor development. For the study of apoptosis in liver diseases, different in vivo models and different in vitro approaches have been developed. They include cell culture models based on hepatocellular carcinoma cell lines or isolated primary hepatocytes. MATERIALS AND METHODS: We have established precision cut tissue slices (PCTS) of the liver as a morphological tool for the study of apoptosis. From porcine livers, PCTS were prepared and incubated in a static system with different types and amounts of media. Viability, morphology, spontaneous apoptosis and proliferation were investigated. Apoptosis was induced with actinomycin D and tumor necrosis factor (TNF) alpha. RESULTS: Morphology and viability was well preserved for at least 24 h. After 48 h, deterioration with single and group cell autolysis was seen. There was a low rate of spontaneous apoptosis and proliferation. Using a combination of TNF alpha and actinomycin D, a significant amount of apoptosis occurred. CONCLUSION: PCTS can be used to directly analyse apoptosis at the tissue level in a qualitative and quantitative manner.

Florid ischemic cholangitis due to leucocytoclastic vasculitis.

Ischemia-induced biliary tract lesions, called ischemic cholangitis, often lead to strictures of biliary ducts and cholestasis. Causes of ischemic changes of the biliary tract can be found in the arterial blood supply or in the peribiliary capillary plexus. Known examples are thrombosis after transplantation, intraoperative ligation, or the application of chemotherapeutic drugs. Rarely, such changes are due to inflammation of the blood vessels, such as occurs in polyarteritis nodosa or giant cell arteritis. We present a report of a 49-year old man with leucocytoclastic vasculitis after viral infection, influenza vaccination, and antibiotic treatment, leading to florid ischemic cholangitis. We conclude that hypersensitivity vasculitis must be included in the differential diagnosis of cholestasis and cholangitis.

Dominance of CD4+ alpha/beta T-cells and inferior role of innate immune reaction in liver metastases.

BACKGROUND: Tumor infiltrating lymphocytes (TIL) are frequently present in human tumors with CD8+(-)T-cells as effector and CD4+ T-cells as helper cells. Despite the well established knowledge about primary tumors, only little is known about metastatic disease, especially for liver metastases. The role of the innate immune system in the tumor defence is still enigmatic. MATERIALS AND METHODS: We performed a subtyping of TIL in 20 liver metastases. Using immunohistochemistry, CD20+, CD3+, CD56+, CD4+ and CD8+ lymphocytes, gamma/delta-T-cells and alpha/beta-T-cells in the tumor, the peritumoral region, portal tracts and lobules were investigated. RESULTS: The immune response was highly accentuated in the surroundings of the metastases with only few lymphocytes in the tumor itself. There was a dominance of CD3+(-)CD4+(-)alpha/beta-T-cells with a lower number of CD8+(-)T-cells. The CD4+/CD8+ ratio was 6:1. CD56+(-)NK/NKT-cells and gamma/delta-T-cells were rare. No differences were found between metastases from different primaries or according to the number or diameter of the metastases. CONCLUSION: TIL are part of an interaction between the metastatic tumor and the liver. Among them CD4+ T-cells seem to have a unique independent function in tumor response. The localization of the immune response in the tumor periphery might be a reason for insufficient tumor defense. A defect in the innate immune system could be a reason for the escape of the metastatic tumor cells from tumor surveillance.

Rhinoscleroma associated with Rosai-Dorfman reaction of regional lymph nodes.

Rhinoscleroma is an uncommon chronic, destructive infection of the respiratory mucosa caused by Klebsiella rhinoscleromatis. This coccobacillus can be found in the typical histiocytes, the Mikulicz cells. Extranasal and nodal involvement in this disease is rare, but documented. Rosai-Dorfman disease or sinus histiocytosis with massive lymphadenopathy is also a rare, non-hereditary disorder. Bilateral cervical lymphadenopathy with emperipolesis, as the main histological characteristic, is the most common presentation. It can also occur extranodally. We report a case of rhinoscleroma occurring in a 62-year-old woman since 1984, who developed parotid gland and lymph node involvement. The changes in the nasal mucosa and the parotid gland showed chronic inflammation with Mikulicz cells. In the lymph nodes, features characteristic of Rosai-Dorfman disease were seen. Taking into consideration the literature dealing with both of these diseases, we discuss that Rosai-Dorfman disease could be a special type of lymph node reaction and is not necessarily an entity of its own. Therefore, it should be known as Rosai-Dorfman lymph node reaction. Furthermore, there seems to be an interconnection between Rosai-Dorfman disease and rhinoscleroma.

Cryopreservation of precision cut tissue slices (PCTS): investigation of morphology and reactivity.

Precision cut tissue slices (PCTS) represent a suitable and convenient tool for pharmacological, toxicological and morphological studies. Cryopreservation would enable to overcome the shortage of liver tissue, in particular in settings using human liver tissue. We investigated the potential of cryopreservation of porcine PCTS as a morphological tool by rapid freezing with 10% and 30% dimethyl sulfoxide as cryopreservation agents and with or without medium using a Brendel/Vitron tissue slicer. Incubation after thawing was done in a static incubation system. Slices were cultured for 3 h, 6 h, 24 h and 48 h and assessed histologically and immunohistologically for proliferation (Ki67) and spontaneous as well as induced apoptotic activity (M30Cytodeath). Vitality was tested using the Tox-8 test. After cryopreservation, morphology of PCTS was well preserved up to 24 h. A reduction of vitality rate took place. Compared to non-frozen PCTS, the rate of spontaneous proliferation of Kupffer cells and apoptosis of hepatocytes were significantly reduced independent of the freezing conditions. The reactivity of PCTS to apoptotic stimuli was significantly reduced in tissue slices after cryopreservation. Apoptotic stimuli could not induce the same amount of cell deaths compared to non-frozen sections. Thus, cryopreservation of PCTS does interfere with pathomechanisms of apoptosis in PCTS.

Biliary cytokeratin expression but not CD56 (N-CAM) expression aids in the differential diagnosis of non-neoplastic bile duct diseases.

Non-neoplastic bile duct diseases include several entities with a variety of clinical and histopathologic features. In needle biopsies, however, these may overlap. Here, auxiliary diagnostic markers would be helpful. CD56 (N-CAM) has been reported in bile duct development, liver regeneration, and different liver diseases. This study was performed to evaluate the diagnostic value of CD56 immunohistochemistry compared to biliary cytokeratins in the diagnosis of non-neoplastic biliary liver diseases in liver needle biopsies. Thirty-eight cases (10× PSC; 10× PBC; 10× obstruction; 8× drug-induced liver disease [DILD]) were analyzed using antibodies against CD56/NCAM, CK7, and CK19. Twenty-three of all cases (63.9%) showed a positive CD56 reaction (PSC 6/10; PBC 9/10; obstruction 5/10; DILD 3/8) with no statistical significance between the groups. Biliary cytokeratins visualized the bile ducts in all cases. CK7 highlighted cholangiolar metaplasia in seven cases (3× PSC; 1× PBC; 3× DILD). CD56 cannot be used as a supplementary tool in the differential diagnosis of non-neoplastic biliary diseases. CK7 should be included in the routine assessment of liver biopsies in these settings. Further research is needed to find better targets for immunohistochemical determination of the etiology of bile duct damage.

CD95 and TNFα-induced apoptosis in liver metastases of colorectal carcinoma.

BACKGROUND: Therapeutic options in patients with metastatic colorectal cancer are still limited. As apoptosis contributes to the overall sensitivity to radiotherapy or chemotherapy, a better understanding of the apoptotic process in metastatic tumour tissues is necessary. MATERIALS AND METHODS: Precision cut tissue slices (PCTS) of three human liver metastases were used to investigate the effect of activating CD95 antibodies (concentrations: 0.1 µg/ml, 1 µg/ml and 1 µg/ml and 1 µg/ml actinomycin D) as well as TNFα (concentrations 1 ng/ml; 10 ng/ml and 10 ng/ml and 1 µg/ml actinomycin D) directly in tumour tissue after 6 h, 12 h and 24 h. The apoptotic effect was assessed immunohistochemically. RESULTS: Activating CD95 antibodies combined with actino-mycin D led to a significant increase in apoptosis after 12 h. Using TNFα at a high dosage, a significant increase in the apoptosis rate was observed after 6 h and after 12 h in all dosage groups. CONCLUSIONS: PCTS can be used to investigate the effect of different apoptotic signals directly in human tumour tissues. TNFα is able to effectively induce apoptosis in liver metastases of colorectal carcinoma. Thus, the extrinsic pathway of apoptosis may be a promising target in the development of new therapeutic approaches.

Bednar's aphthae in neonates: incidence and associated factors.

BACKGROUND: Bednar's aphthae can still be found in newborn infants but have nearly disappeared from recent paediatric literature. OBJECTIVES: To find out the incidence of Bednar's aphthae among newborn infants during the first week of life and the factors associated with the ulcers. METHODS: Clinical findings and statistical data were documented of 1,654 infants routinely examined for preventive reasons in two obstetric hospitals in Cologne, Germany. RESULTS: Bednar's aphthae were found in 236 of the 1,494 neonates examined (15.8%) in whom the whole palate could be visualized. They were associated with spontaneous birth at term, nutrition with formula, and mucosal hyperaemia of the typical anatomical location. CONCLUSIONS: Bednar's aphthae are not a rare phenomenon and still commonly occur in neonates.

COX-2 expression and effects of COX-2 inhibition in colorectal carcinomas and their liver metastases.

Nonsteroidal anti-inflammatory drugs are known to reduce the risk and mortality from colorectal carcinoma by inhibiting cyclo-oxygenases (COX). COX-2 expression was investigated immunohistologically in 57 patients with colorectal carcinomas and in the corresponding liver metastases using tissue microarray analysis. Ex vivo COX-2 inhibition with assessment of apoptosis was performed using precision-cut tissue slices of three human liver metastases. Following stimulation with different concentrations of the selective COX-2 inhibitor meloxicam, apoptosis was assessed immunohistochemically after 6 h and 12 h. All primary carcinomas and 56 out of the 57 liver metastases showed various degrees of cytoplasmatic COX-2 expression being with a reduction and in the liver metastases. There was a time- and concentration-dependent change in the number of apoptotic cells in tissue slices, however, this was without statistical significance. COX-2 is constantly involved in the carcinogenesis and metastatic process of colorectal cancer. The antineoplastic effect of COX-2 inhibition may be based on different pathways, including changes in sensitivity to apoptosis.

Liver distribution of gammadelta-T-cells in patients with chronic hepatitis of different etiology.

The gammadelta T cells represent a minor unique T-cell subpopulation long been considered as innate-like immune cells. They are found in increased numbers in tissues from various inflammatory conditions. Their role in chronic hepatitis, however, is still discussed controversially. Fresh frozen tissues from 50 patients (18 cases hepatitis B infection, 25 hepatitis C, three cases with co-infection of hepatitis B and C and four patients with autoimmune hepatitis) were investigated. Immunohistochemistry with primary antibodies detecting alphabeta and gammadelta TCR was used to evaluate their incidence and distribution in the different histological structures of the liver. The inflammatory infiltrate in all cases of chronic hepatitis was dominated by alphabeta T cells and was mainly localized in the portal tracts with formation of an interface hepatitis (95.3%alphabeta T cells; 4.7%gammadelta T cells). There were neither significant differences between inflammatory infiltrate nor the amount or percentage of gammadelta T cells between hepatitis B, C or autoimmune hepatitis. No accumulation of gammadelta T cells could be observed in cases of chronic hepatitis of different etiologies. The immune-mediated phenomena in chronic hepatitis are dominated by alphabeta T cells. Thus, the adapted immune system is responsible for the inflammatory processes in chronic hepatitis.

Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma.

AIM: To investigate the role of tumor infiltrating lymphocytes (TIL) in primary hepatocellular and cholangiolar carcinomas of the liver. METHODS: Immunohistochemical analysis was performed including antibodies to CD3, CD4, CD8, CD20, CD56 and TIA-1 in formalin-fixed and paraffin-embedded tissue of 35 liver resection specimens of hepatocellular or cholangiocellular carcinomas. Semiquantitative evaluation was performed with emphasis on the area of the tumor itself and of the tumor/liver interface. RESULTS: All hepatocellular carcinomas showed infiltration of lymphocytes predominantly around the tumor in the tumor/liver interface consisting mainly of CD3+ CD4+ T lymphocytes [164.3/10 high power fields (HPF)] and in the tumor itself of CD8+ cells (54.9/10 HPF). Cholangiocarcinomas contained a heterogeneous amount of TIL, composed mainly of CD3+ T cells with a predominance of CD8+ cells in the tumor tissue (52.6/10 HPF) and of CD4+ cells in the interface region (223.1/10 HPF). CD56+ cells of the innate immune system were scarce. There was no significant difference between hepatocellular or cholangiolar carcinoma. No correlation with the clinicopathological data was seen. CONCLUSION: Liver TIL consists of intratumoral CD8+ T cells and peritumoral CD4+ T cells independent of histogenetic origin. Different functions of lymphocytes in these regions seem possible.