Primary gastrointestinal T-cell lymphomas: concepts and diagnostic insights

The gastrointestinal tract represents the most common site of extranodal non-Hodgkin lymphoma. Malignant lymphomas represent up to 4% of all malignant neoplasms of the GI tract. Overall, lymphomas of B-cell lineage predominate. T-cell lymphomas are uncommon and account for 6% of all GI tract lymphomas. Intestinal T-cell lymphomas comprise a heterogeneous group of lymphoproliferative neoplasms with distinct morphologic, immunophenotypic, and genetic features. Based on the recently revised 2017 WHO classification, intestinal T-cell lymphomas are categorized into four distinct entities: Enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (METL), intestinal T-cell lymphoma, not otherwise specified (ITCL, NOS) and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Herein, we aim to create awareness of these uncommon neoplasms with emphasis on key diagnostic points.     

Recent advances upper gastrointestinal lymphomas: molecular updates and diagnostic implications

Approximately one‐third of extranodal non‐Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A few entities, especially diffuse large B‐cell lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T‐cell neoplasms and the recommended diagnostic approach to aggressive B‐cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases.     

The histopathological differential diagnosis of gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs), initially presumed to be of "true" smooth muscle origin, encompass a heterogeneous, and as yet incompletely understood, group of mesenchymal tumours with respect to their origin, cellular differentiation, and prognosis. Cellular morphology ranges from predominantly spindle shaped to epithelioid in character, whereas differentiation pathways, as determined primarily by immunohistochemistry and ultrastructure, can vary from indeterminate to myoid and/or neural. Recent work has indicated that the interstitial cells of Cajal, a complex cellular network postulated to act as pacemaker cells of the gastrointestinal tract, which exhibit both myoid and neural features, could be candidates for tumour histogenesis. This would provide a plausible and attractive explanation for the variable differentiation pathways identified in the GIST category to date. Nevertheless, the occasional but undisputed location of GISTs outside the gastrointestinal tract (omentum, peritoneum, and retroperitoneum) might mitigate against such an origin, and their histogenesis remains open to debate. The c-kit proto-oncogene, encoding a growth factor receptor with tyrosine kinase activity, has been postulated to play an important role in tumorigenesis because "gain of function" mutations in this gene, localised to chromosome 4q11-21, are being increasingly identified in hereditary and sporadic cases. Monoclonal and polyclonal antibodies directed at the c-kit gene product expressed on the cell surface (CD117/c-kit) appear to be increasingly helpful in resolving the histopathological differential diagnosis between GISTs and true gastrointestinal smooth muscle neoplasms, schwannomas, and other far less frequently occurring mesenchymal tumours at this site. Although tumours with a clinically benign course appear to be more common than their malignant counterparts, no specific histological criteria have as yet been identified to enable an unambiguous prediction of biological behaviour. Increasing tumour size and mitotic activity favour aggressive tumour behaviour, whereas the prognostic value of germline and somatic mutations within the c-kit proto-oncogene remains to be elucidated further. It is the aim of this synopsis to highlight the relevant fundamental and diagnostic developments with respect to this complex group of neoplasms.     

New diagnostic modalities in the histopathological diagnosis of hydatidiform moles

Hydatidiform moles represent a fascinating group of trophoblastic proliferative disorders with unique genetic compositions and often challenging morphologic features for diagnosis. While conventional histomorphology remains the cornerstone of the diagnosis of molar gestations, there has been an ongoing search for the past three decades for new diagnostic modalities to aid the pathologist. In this review first we will discuss the histopathologic features of molar gestations and their mimics, including non-molar hydropic abortions, chromosomal trisomy syndromes, digynic non-molar triploidy and placental mesenchymal dysplasia. Then we will focus on the conventional and novel ancillary techniques – ploidy analysis, fluorescent in situ hybridization, immunohistochemistry and molecular genotyping – and their role in the diagnostic algorithm.     

Rhinoscleroma: a detailed histopathological diagnostic insight

Rhinoscleroma (RS) is a chronic specific disease of nose and upper respiratory passages caused by Klebsiella rhinoscleromatis bacilli. It is endemic in Egypt and in sporadic areas worldwide. Diagnosis of RS depends on identification of the pathognomonic Mickulicz cells (MCs) which is most prominent during granulomatous phase but spares or absent during catarrhal or sclerotic phases of the disease. This study aimed to identify the potential diagnostic features of nasal RS when MCs are absent. Nasal biopsies from 125 patients complaining of chronic nasal symptoms were retrieved for this study; including 72 chronic non specific inflammatory lesions and 53 RS diagnosed by PAS and Geimsa stains. The detailed histological differences among the two groups were measured statistically. RS was frequently a bilateral disease (P < 0.05) of young age (P < 0.001) with a female predominance (P < 0.05) and usually associated with nasal crustations (P < 0.001). Five strong histological indicators of RS were specified by univariate binary logistic regression analyses including squamous metaplasia (OR 27.2, P < 0.0001), dominance of plasma cells (OR 12.75, P < 0.0001), Russell bodies (OR 8.83, P < 0.0001), neutrophiles (OR 3.7, P < 0.001) and absence of oesinophiles (OR 12.0, P < 0.0001). According to Multivariate analysis, the diagnostic features of RS in absence of MCs can be classified into major criteria including dominance of plasma cells infiltration and absence of oesinophiles and minor criteria including young age, female gender, bilateral nasal involvement, nasal crustation, squamous metaplasia, Russell bodies, and neutrophiles. The diagnostic model using the two major criteria confirmed or excluded RS in 84.3% of the investigated cases.     

Primary cutaneous B-cell lymphomas and pseudolymphomas: review of histopathological features

The terminology and classification of lymphoproliferative disorders in the skin remains a source of confusion for clinicians and pathologists. More than 25 types of malignant lymphoid neoplasms may involve the skin. These either arise primarily or represent secondary cutaneous involvement due to the spread of node-based lymphomas, other extracutaneous lymphomas or leukemias. In addition, there is a variety of cutaneous pseudolymphomatous reactions. This article addresses the histopathological features of primary cutaneous B-cell lymphomas and B-cell pseudolymphomas and presents a modern approach to the diagnosis of these lymphoid neoplasms.     

The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma

Summary In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the small-specimen technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the large-specimen techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed.     

Nodal aggressive B-cell lymphomas: a diagnostic approach

The diffuse aggressive B-cell lymphomas, as recognised in the 2001 WHO classification, represent a clinically and biologically heterogeneous group of neoplasms that require very different therapeutic approaches and have very different outcomes. They should be diagnosed using a multiparameter approach that emphasises morphological and immunophenotypic studies, and in at least some cases, relies on cytogenetic and/or genotypic studies. Incorporation of clinical data may be important as well. There is also current interest in going beyond the basic diagnosis and providing pathological prognostic information when possible. Whereas the diagnosis of some cases will be relatively easy, the differential diagnosis in others is very difficult, with some cases in a grey zone between two different well defined categories.     

Microscopic mimicry of lymphomas: diagnostic pitfalls.

A common, critical challenge for the pathologist is the distinction between lymphoma and lymphoma simulators. Ancillary studies are effective in making this distinction and should be used in descending order of their likely reliability according to the particular differential diagnostic consideration at hand. Clinical case information is essential to avoid misinterpretation. Lymphoma simulators can be grouped into several major categories: nonlymphoid neoplasms, usually high-grade, simulating high-grade lymphomas; chronic lymphoid hyperplasias simulating low-grade lymphomas; and acute lymphoid hyperplasias simulating high-grade lymphomas.     

The histopathological diagnosis of malignant mesothelioma v. pulmonary adenocarcinoma: reproducibility of the histopathological diagnosis

In a randomized design we examined the interobserver variation in the histopathological diagnosis of adenocarcinoma of the lung and malignant mesothelioma. In three rounds, three pathologists assessed slides from 42 tumours originally diagnosed as adenocarcinomas, malignant mesotheliomas or benign lesions in the pleura. In the first round the assessments were made on haematoxylin and eosin (H & E) stained sections; in the second, on H & E sections plus sections stained with histochemical mucin stains; and in the final round, the diagnoses were made on H & E sections and sections stained with a panel of antibodies against various antigens (cytokeratin, EMA, CEA, Ber-EP4, B72.3, Leu-M1, vimentin and S-100 protein) said to be of value in the differential diagnosis. The overall interobserver agreements for the three rounds were 0.659, 0.802 and 0.817; the kappa values were 0.461, 0.681 and 0.690. It is concluded that differentiation between adenocarcinoma of the lung and malignant mesothelioma should be made on sections stained with H & E and mucin and/or immunohistochemical staining reactions, including antibodies against B72.3. Ber-EP4 and CEA.     

Sarcoidosis: histopathological definition and clinical diagnosis.

Sarcoidosis is best defined in histopathological terms as 'a disease characterised by the presence in all of several affected organs and tissues of non-caseating epithelioid-cell granulomas, proceeding either to resolution or to conversion into hyaline connective tissue'. Although the defining characteristics are thus histopathological, diagnosis during life depends largely upon clinical, radiological, and immunological findings. The amount of support required from histology varies greatly from case to case. Though histology from one site cannot in itself establish the diagnosis of sarcoidosis, a generalised disease, detailed histological study of biopsy tissue makes an important and often essential contribution. In many instances, complete lack of necrosis, an intact reticulin pattern, and failure to demonstrate infective agents permit an unequivocal statement of compatibility with this diagnosis; however, a compatible clinical picture and absence of evidence of known causes of local granulomatous reactions or of other generalised granulomatous diseases are required for definitive diagnosis. In some, the histological pattern deviates in some particular from the accepted 'typical' pattern; there may be a little necrosis, the follicular pattern of the granuloma may be less than perfect, and exclusion of known infective agents can never be absolute. In such instances, subsequent surveillance, including possible response to treatment, may show a clinical course justifying a diagnosis of sarcoidosis, and necropsy may establish it; but it must be recognised that in a few cases, particularly those in which the clinical evidence of disease is confined to one organ, diagnosis is likely to remain in doubt for long periods. Reports on the histology of the Kveim test should be made without knowledge of clinical findings and in terms of the presence and quality of granulomatous response. A granulomatous reaction to a validated test suspension makes a contribution to diagnosis similar to the finding of granulomas in an additional organ or tissue.     

Immunohistochemistry of primary gastrointestinal lymphomas: a study of 76 cases

A retrospective study of 76 primary gastrointestinal lymphomas utilizing an avidin: biotinylated horseradish peroxidase complex (ABC) technique demonstrated 22 B-cell lymphomas, including two associated with alpha-heavy chain disease. Seven cases were classified as true histiocytic lymphomas based on a positive reaction for one or more of three histiocytic enzyme markers utilized, predominantly alpha-1-antitrypsin and alpha-1-antichymotrypsin. However, in 20 cases, an intense admixture of reactive histiocytes was noted and these cells stained preferentially for the enzyme, lysozyme. Twenty cases, which stained for both kappa and lambda light chains and positively or negatively for albumin, could not be classified and 27 cases failed to stain with any of the antisera utilized.     

Meckel syndrome: what are the minimum diagnostic criteria?

Two sibs are described, the first of whom presented the classic Meckel syndrome triad of encephalocele, postaxial polydactyly, and characteristic renal cystic changes. The second sib had none of these abnormalities, but did show urethral atresia and preaxial polydactyly, two features previously described in some patients with Meckel syndrome. The two cases illustrate both the wide phenotypic spectrum of Meckel syndrome and the difficulty of attempting to define minimum diagnostic criteria for the disorder. The clinical implications arising from this problem are discussed.