The over diagnosis of diffuse mesothelioma: An analysis of 311 cases with recommendations for the avoidance of pitfalls.

BACKGROUND: The diagnosis of mesothelioma may be challenging. We investigated a large database of cases in order to determine the frequency with which a diagnosis of mesothelioma was made incorrectly and the most frequent causes of error. DESIGN: A database including more than 4000 consultation cases of histologically confirmed mesothelioma was examined to identify cases in which mesothelioma was diagnosed by at least one pathologist when the available information pointed towards a different diagnosis. RESULTS: There were 311 cases misdiagnosed as mesothelioma. The most common category was metastatic carcinoma to the pleura or peritoneum (129 cases: 73 lung carcinomas, 15 renal cell carcinomas). The next most common category was primary lung cancer (111 cases: 55 sarcomatoid carcinoma, 56 pseudomesotheliomatous carcinoma). The third most common category was primary malignancies arising from or near the serosal membranes (33 cases). The fourth most common category was fibrous pleurisy (38 cases). The most common errors were failure to consider important radiographic information regarding the gross distribution of tumor, lack of awareness or consideration of another malignancy, overreliance on certain immunohistochemical results, and failure to perform certain diagnostic histochemical, immunohistochemical, or ultrastructural studies. CONCLUSIONS: There are a number of diagnostic pitfalls that can lead to the over diagnosis of mesothelioma. Careful attention to clinical and radiographic information as well as performance of appropriate ancillary tests can help to prevent such misdiagnoses. Detailed examples will be presented to assist in the avoidance of these pitfalls with emphasis on the most commonly observed errors.

Primary histiocytic sarcoma of the clivus with focal extension into central nervous system and neurologic manifestations: First description at an unusual site with an overwhelming and rapid progression.

Histiocytic sarcoma (HS) is a rare malignant neoplasm of macrophage-dendritic cell lineage that can occur at any site. Primary base of skull involvement is exceedingly rare. We present the case of a previously healthy 56-year-old man who complained of headaches and showed localized neurologic symptoms. Magnetic resonance imaging demonstrated a hyperintense and enhancing mass involving the sphenoid bone and the clivus with an extradural component that compressed the distal pons. The differential diagnosis included chordoma or chondrosarcoma. An endoscopic trans-sphenoidal resection was performed. Microscopically, the tumor showed epithelioid and spindle morphology with atypia, mitoses, and necrosis. No osteoid, cartilaginous, or myxoid matrix was identified. By immunohistochemistry, the tumor was positive for CD68 (KP-1) and lysozyme, variably positive for CD4, CD11c, CD14, CD68 (PGM-1), CD45, and CD163, and negative for markers of epithelial, melanocytic, lymphoid, myeloid, muscle, and dendritic cell origin. Expression of PD-L1 by immunohistochemistry and BRAF V600E mutation analysis by PCR were negative. Tumor recurrence developed after radiation treatment with overwhelming progression into a largely infiltrating mass within 2 weeks with clinical deterioration, and the patient died 3 months later. To our knowledge, this represents the first case of primary HS of the clivus reported to date in the English literature, further expanding the spectrum of neoplasms seen at this site as well as the sites where HS can be seen. The overall prognosis of HS in the skull base is poor, with no standard treatment. Further research is warranted to develop effective treatment approaches, which in the future may rely on the expression of checkpoint inhibitors and/or specific molecular markers.

Breast implant-associated anaplastic large cell lymphoma: clinical follow-up and analysis of sequential pathologic specimens of untreated patients shows persistent or progressive disease.

Breast implant-associated anaplastic large cell lymphoma (ALCL) is a distinctive type of T-cell lymphoma that arises around textured-surface breast implants. In a subset of patients, this disease can involve surrounding tissues, spread to regional lymph nodes, and rarely metastasize to distant sites. The aim of this study was to assess sequential pathologic specimens from patients with breast implant-associated ALCL to better understand the natural history of early-stage disease. To achieve this goal, we searched our files for patients who had breast implant-associated ALCL and who had undergone earlier surgical intervention with assessment of biopsy or cytologic specimens. We then focused on the patient subset in whom a definitive diagnosis was not established, and patients did not receive current standard-of-care therapy at that time. We identified a study group of ten patients with breast implant-associated ALCL in whom pathologic specimens were collected 0.5 to 4 years before a definitive diagnosis was established. A comparison of these serial biopsy specimens showed persistent disease without change in pathologic stage in three patients, progression in five patients, and persistence versus progression in two patients. Eventually, six patients underwent implant removal with complete capsulectomy and four underwent partial capsulectomy. Seven patients also received chemotherapy because of invasive disease, three of whom also received radiation therapy, two brentuximab vedotin after chemotherapy failure, and one allogeneic stem cell transplant. Eight patients achieved complete remission and two had partial remission after definitive therapy. At time of last follow-up, six patients were alive without disease, one had evidence of disease, one died of disease, and two patients died of unrelated cancers. In summary, this analysis of sequential specimens from patients with breast implant-associated ALCL suggests these neoplasms persist or progress over time if not treated with standard-of-care therapy.

Mediastinal Lymphoproliferative Disorders.

Lymphoproliferative disorders comprise 50% to 60% of all mediastinal malignancies in both children and adults. Primary mediastinal involvement is rare (∼5%), whereas secondary mediastinal involvement by systemic disease is more common (10% to 25%). Primary mediastinal disease is defined as involvement by a lymphoproliferative disorder of mediastinal lymph nodes, the thymus, and/or extranodal mediastinal organs without evidence of systemic disease at presentation. In this review, the clinical, radiologic, histopathologic, immunohistochemical, and genetic features of some of the most characteristic mediastinal lymphoproliferative disorders are presented. The entities discussed here include: classic Hodgkin lymphoma with emphasis on nodular sclerosis and mixed cellularity types, and non-Hodgkin lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, mediastinal gray zone lymphoma, mediastinal diffuse large B-cell lymphoma, thymic marginal zone lymphoma, mediastinal plasmacytoma, T-lymphoblastic lymphoma, and anaplastic large cell lymphoma. Although not a malignant process, hyaline vascular Castleman disease is also discussed here as this disorder commonly involves the mediastinum. Despite multiple advances in hematopathology in recent decades, the day-to-day diagnosis of these lesions still requires a morphologic approach and a proper selection of immunohistochemical markers. For this reason, it is crucial for general pathologists to be familiar with these entities and their particular clinicoradiologic presentation.

A proposal for pathologic processing of breast implant capsules in patients with suspected breast implant anaplastic large cell lymphoma.

Breast implant anaplastic large cell lymphoma is an entity recently recognized by the World Health Organization. The tumor arises around textured-surface breast implants and is usually confined to the surrounding fibrous capsule. Currently, there are no recommendations for handling and sampling of capsules from patients with suspected breast implant anaplastic large cell lymphoma without a grossly identifiable tumor. We analyzed complete capsulectomies without distinct gross lesions from patients with breast implant anaplastic large cell lymphoma. The gross appearance of the capsules as well as the presence, extent and depth of tumor cells on the luminal side and number of sections involved by lymphoma were determined by review of routine stains and CD30 immunohistochemistry. We then used a mathematical model that included the extent of tumor cells and number of positive sections to calculate the minimum number of sections required to identify 95% of randomly distributed lesions. We identified 50 patients with breast implant anaplastic large cell lymphoma who had complete capsulectomies. The implants were textured in all 32 (100%) cases with available information. Anaplastic large cell lymphoma was found in 44/50 (88%) capsules; no tumor was found in six (12%) patients who had lymphoma cells only in the effusion. The median number of sections reviewed was 20 (range, 2-240), the median percentage of sections involved by tumor was 6% (range, 0-90%), and the median percentage of sections involved by lymphoma was 10% (range, 0-90%). Invasion deep into or through the capsule was identified in 18/50 (36%) patients. In patients with breast implant anaplastic large cell lymphoma without a grossly identifiable tumor we identified a spectrum of involvement and we propose a protocol for handling, sampling and reporting these cases. The number of sections to exclude the presence of lymphoma with more than 95% certainty was supported by a mathematic rationale.

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study.

Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3-9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.

Analysis of primary central nervous system large B-cell lymphoma in the era of high-grade B-cell lymphoma: Detection of two cases with MYC and BCL6 rearrangements in a cohort of 12 cases.

High-grade diffuse large B-cell lymphoma (HG-DLBCL) refers to DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit DLBCL) that exhibits poor prognosis. Double-expressor DLBCL (c-myc+/bcl-2+) has intermediate prognosis when compared to HG-DLBCL. Primary central nervous system lymphoma (PCNSL) has distinct pathophysiology (frequent non-germinal center-like subtype and double-expressor) and has worse prognosis than systemic DLBCL. By fluorescence in situ hybridization (FISH), 25-30% of PCNSLs harbor BCL6 abnormalities with rare alterations in MYC, BCL2, double-hit or triple-hit events. We describe the clinicopathologic features and status of MYC, BCL2 and BCL6 in 12 PCNSLs (7 women, 5 men; median age 63 years; range: 28-79). Six cases showed focal starry-sky pattern. Immunohistochemically, all (100%) were of non-germinal center-like subtype, and 8/10 (80%) cases were double-expressors. Ki-67 ranged from 70 to 100%. FISH was positive in 9/12 (75%) cases: 4 (33%) harbored a BCL6 rearrangement, 3 (25%) had a gain of BCL2, 2 (17%) cases each had a gain of BCL6 and gain of IGH, and gain of MYC and deletion of MYC were observed in 1 case each (8%). Two (16%) cases were MYC/BCL6 double-hit PCNSLs. No MYC/BCL2 or triple-hit cases were identified. Eleven (92%) patients received chemotherapy and one also received whole brain radiation. The median time of follow-up was 4.4 months (range, 0.3-40.3). Seven (58%) patients are alive, 4 (33%) have died, and 1 (8%) had no follow-up. Five alive patients are in remission, including one MYC/BCL6 double-hit PCNSL. Our results add two new cases of rare double-hit PCNSL to the literature.

Breast implant-associated anaplastic large cell lymphoma: a review.

Breast implant-associated anaplastic large cell lymphoma is a newly recognized provisional entity in the 2017 revision of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. It is an uncommon, slow growing T-cell lymphoma with morphology and immunophenotype similar to anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. However, the presentation and treatment are unique. Breast implant-associated anaplastic large cell lymphoma often presents as a unilateral effusion confined to the capsule of a textured-surface breast implant, a median time of 9 years after the initial implants have been placed. Although it follows an indolent clinical course, breast implant-associated anaplastic large cell lymphoma has the potential to form a mass, to invade locally through the capsule into breast parenchyma or soft tissue and/or to spread to regional lymph nodes. In most cases, an explantation with a complete capsulectomy removing all disease, without chemotherapy is considered to be curative and confers an excellent event free and overall survival. Here we provide a comprehensive review of breast implant-associated anaplastic large cell lymphoma, including history, epidemiology, clinical features, imaging and pathology findings, pathologic handling, pathogenic mechanisms, model for progression, therapy and outcomes as well as an analysis of causality between breast implants and anaplastic large cell lymphoma.

Focal Rosai-Dorfman disease coexisting with lymphoma in the same anatomic site: a localized histiocytic proliferation associated with MAPK/ERK pathway activation.

Rosai-Dorfman disease is a rare histiocytic disorder shown to have gene mutations that activate the MAPK/ERK pathway in at least one-third of cases. Most patients with Rosai-Dorfman disease present with bulky lymphadenopathy or extranodal disease, but rarely Rosai-Dorfman disease is detected concomitantly with lymphoma in the same biopsy specimen. The underlying molecular mechanisms of focal Rosai-Dorfman disease occurring in the setting of lymphoma have not been investigated. We report 12 cases of Rosai-Dorfman disease and lymphoma involving the same anatomic site. There were five men and seven women (age, 23 to 77 years) who underwent lymph node (n = 11) or skin (n = 1) biopsy; the lymphomas included nodular lymphocyte predominant Hodgkin lymphoma (n = 6), classical Hodgkin lymphoma (n = 4), small lymphocytic lymphoma (n = 1) and extranodal marginal zone lymphoma (n = 1). The foci of Rosai-Dorfman disease in all cases had S100 protein-positive histiocytes undergoing emperipolesis. No patients had Rosai-Dorfman disease at other anatomic sites at initial diagnosis and at last follow-up (median, 40 months). We performed immunohistochemical analysis to assess activity of the MAPK/ERK pathway in the Rosai-Dorfman disease foci. We also micro-dissected disease foci and analyzed 146 genes using next-generation sequencing in four cases with adequate DNA; the panel included genes previously reported to be mutated in Rosai-Dorfman disease. All cases were negative for gene mutations. Nevertheless, all cases were positive for cyclin D1 and most cases showed p-ERK expression indicating that the MAPK/ERK pathway is active in the histiocytes of focal Rosai-Dorfman disease. We conclude that focal Rosai-Dorfman disease coexisting with lymphoma is a clinically benign and localized histiocytic proliferation. These data also indicate that the MAPK/ERK pathway is active in focal Rosai-Dorfman disease although we did not identify activating mutations. These findings suggest that the pathogenesis of focal Rosai-Dorfman disease is different from that of usual cases of Rosai-Dorfman disease.

Primary Mediastinal Nodal and Extranodal Non-Hodgkin Lymphomas: Current Concepts, Historical Evolution, and Useful Diagnostic Approach: Part 2.

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ∼5% of all non-Hodgkin lymphomas (NHLs) and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal (PM) large B-cell lymphoma and T-lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both Epstein-Barr virus positive), and pleural and/or pericardial primary effusion lymphoma (human herpesvirus-8 positive/Epstein-Barr virus positive). We review the historical aspects, epidemiology, clinicoradiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of the remaining mediastinal B-cell lymphomas, including primary thymic marginal zone lymphoma of the mucosa-associated lymphoid tissue type, other PM small B-cell lymphomas, PM plasmacytoma, and the most relevant PM T-cell lymphomas.

Primary Mediastinal Nodal and Extranodal Non-Hodgkin Lymphomas: Current Concepts, Historical Evolution, and Useful Diagnostic Approach: Part 1.

Primary mediastinal non-Hodgkin lymphomas (PM-NHLs) represent ~5% of all NHLs and comprise lymphomas of B-cell and T-cell origin. PM-NHLs are defined as involvement of mediastinal lymph nodes, thymus, and/or mediastinal organs (heart, lung, pleura, pericardium) by NHL without evidence of systemic disease at presentation. The clinical scenario is variable and depends on the lymphoma subtype. The radiologic presentation is also variable ranging from a mediastinal mass with or without superior vena cava syndrome, a pleural or a cardiac mass associated with an effusion, or as an effusion only. The diagnosis of PM-NHLs can only be established by microscopic evaluation, and therefore, general pathologists should be aware of these tumors and familiar with their diagnostic approach. The most common anterior mediastinal NHLs (90% to 95%) are primary mediastinal large B-cell lymphoma and T lymphoblastic lymphoma. Thymic marginal zone lymphoma and mediastinal gray zone lymphoma are very rare. The remainder PM-NHLs involving middle or posterior mediastinum include diffuse large B-cell lymphoma (DLBCL) and rare cases of T-cell lymphoma, including anaplastic large cell lymphoma and breast implant-associated anaplastic large cell lymphoma extending to the anterior mediastinum. Primary pleural and cardiac NHLs are mostly DLBCLs. Other rare subtypes of PM-NHLs include DLBCL associated with chronic inflammation/pyothorax-associated lymphoma, fibrin-associated DLBCL (both EBV), and pleural and/or pericardial primary effusion lymphoma (HHV-8/EBV). We review the historical aspects, epidemiology, clinico-radiologic features, histopathology, immunohistochemistry, differential diagnosis, and relevant cytogenetic and molecular features of PM (thymic) LBCL, PM "nonthymic" DLBCL, BCL, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma (mediastinal gray zone lymphoma), DLBCL associated with chronic inflammation (pyothorax-associated lymphoma), fibrin-associated DLBCL, and primary effusion lymphoma. This review represents the first part of 2 manuscripts covering PM-NHLs.

Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease.

Rosai-Dorfman disease is a histiocytic disorder with a poorly defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3-82). In all, 13 had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 vs 53 years, P=0.0347) with more pediatric patients (4/7 vs 1/14, P=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated vs 1/14 (7%) unmutated cases (P=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (P=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7-352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contribute to the understanding of the biology of Rosai-Dorfman disease and point to potential diagnostic and therapeutic targets.

Langerhans cell histiocytosis associated with lymphoma: an incidental finding that is not associated with BRAF or MAP2K1 mutations.

Langerhans cell histiocytosis is characterized by a localized or systemic proliferation of Langerhans cells. BRAF mutations have been reported in 40-70% of cases and MAP2K1 mutations have been found in BRAF-negative cases, supporting that Langerhans cell histiocytosis is a true neoplasm, at least in mutated cases. In a small subset of patients, Langerhans cell histiocytosis is detected incidentally in a biopsy involved by lymphoma. These lesions are usually minute and rarely have been assessed for mutations. We assessed for BRAF and MAP2K1 mutations in seven cases of Langerhans cell histiocytosis detected incidentally in biopsies involved by lymphoma. We performed immunohistochemical analysis for phosphorylated (p)-ERK. There were four men and three women (median age, 54 years; range, 28-84). The biopsies included lymph nodes (n=6) and chest wall (n=1). The lymphomas included five classical Hodgkin lymphoma, one mantle cell lymphoma, and one angioimmunoblastic T-cell lymphoma. All cases were negative for BRAF V600E and MAP2K1 mutations. Nevertheless, three of seven cases showed ERK activation as shown by expression of p-ERK. We performed mutation analysis using a panel of 134 commonly mutated genes (including BRAF and MAP2K1) by next-generation sequencing on three cases, including two cases positive for p-ERK by immunohistochemistry. No mutations were detected in any of the three cases assessed. Six patients received therapy appropriate for their lymphoma. With a median follow-up of 21 months (range, 6-89), no patients developed disseminated or recurrent Langerhans cell histiocytosis. We conclude that lymphoma-associated Langerhans cell histiocytosis is a clinically benign process that is not associated with BRAF V600E or MAP2K1 mutations and, as suggested by others, the designation Langerhans cell hyperplasia may be more appropriate. Nevertheless, the expression of p-ERK in three cases suggests that the RAS-RAF-MAP2K-ERK pathway is activated, perhaps by non-mutational mechanisms induced by the presence of lymphoma or lymphoma-microenvironment interactions.

Concomitant Cutaneous Langerhans Cell Hystiocytosis and Leukemia Cutis.

Leukemia cutis develops in <4% of all acute leukemias. Concurrent acute myeloid leukemia (AML) and Langerhans cell histiocytosis (LCH) is rare, with most cases involving lymph nodes or spleen, and no cutaneous involvement. We report the case of a 59-year-old man who presented with fever, malaise, and fatigue. The CBC showed leukocytosis (30.4 × 10/L, 9% blasts), anemia, and thrombocytopenia. Bone marrow biopsy was diagnosed with AML, not otherwise specified, with mutations of FLT3 and IDH2 (R140Q). The patient developed skin rash on the right flank with the clinical differential diagnosis of herpes simplex virus or varicella-zoster virus infection/reactivation versus leukemia cutis. A skin biopsy showed leukemia cutis in mid and deep dermis. Immunohistochemistry positive for CD4, CD33, CD117, and myeloperoxidase (MPO) supported myeloid and monocytic differentiation. Clusters of Langerhans cells positive for S100, CD1a, CD4, langerin and aberrant CD33 and MPO were found admixed with the AML cells. Langerhans cells were negative for BRAF V600E by immunohistochemistry. The diagnosis of leukemia cutis and concomitant LCH was established. The aberrant expression of CD33 and MPO shared by AML and LCH suggests a possible relationship among these 2 lesions. No LCH or Langerhans cell differentiation was found in the bone marrow. The patient achieved complete remission 4 months after chemotherapy and the skin lesions resolved. To our knowledge, we present for the first time a case of concomitant cutaneous LCH and leukemia cutis.

Primary Mediastinal Classical Hodgkin Lymphoma.

Primary mediastinal Classical Hodgkin lymphoma (CHL) is rare. Nodular sclerosis CHL (NS-CHL) is the most common subtype involving the anterior mediastinum and/or mediastinal lymph nodes. Primary thymic CHL is exceedingly rare. The disease typically affects young women and is asymptomatic in 30% to 50% of patients. Common symptoms include fatigue, chest pain, dyspnea and cough, but vary depending on the location and size of the tumor. B-symptoms develop in 30% of cases. By imaging, primary mediastinal CHL presents as mediastinal widening/mediastinal mass that does not invade adjacent organs but may compress vital structures as bulky disease. Histopathology is the gold standard for diagnosis. Primary mediastinal NS-CHL consists of nodules of polymorphous inflammatory cells surrounded by broad fibrous bands extending from a thickened lymph node capsule. The cellular nodules contain variable numbers of large Hodgkin/Reed-Sternberg cells, required for diagnosis. Primary thymic CHL may exhibit prominent cystic changes. The histopathologic recognition of NS-CHL can be challenging in cases with prominent fibrosis, scant cellularity, artifactual cell distortion, or an exuberant granulomatous reaction. The differential diagnosis includes primary mediastinal non-HLs, mediastinal germ cell tumors, thymoma, and metastatic carcinoma or melanoma to the mediastinum. Distinction from primary mediastinal non-HLs is crucial for adequate therapeutic decisions. Approximately 95% of patients with primary mediastinal CHL will be alive and free of disease at 10 years after treatment with short courses of combined chemoradiotherapy. In this review, we discuss the history, classification, epidemiology, clinicoradiologic features, histopathology, immunohistochemistry, differential diagnosis, and treatment of primary mediastinal CHL.

Primary Pulmonary Lymphomas.

Primary lung lymphoma (PLL) is a rare disease that comprises <0.5% of all primary lung tumors. It is defined as lymphoma confined to the lung with or without hilar lymph node involvement at the time of diagnosis or up to 3 months thereafter. Patients with PLL may be asymptomatic or manifest nonspecific clinical symptoms, for example, cough, chest pain, and dyspnea. Some individuals may be immunosupressed or have an autoimmune disorder. Radiologically, PLL can mimic pneumonia, lung carcinoma, or metastasis, and therefore, histologic confirmation is mandatory for definitive diagnosis. Primary lung marginal zone lymphoma of mucosa-associated lymphoid tissue type comprises 70% to 80% of cases. Less common B-cell lymphomas include diffuse large B-cell lymphoma, lymphomatoid granulomatosis (LyG), plasmacytoma, and other small lymphocytic lymphomas. PLLs of T-cell origin, largely represented by anaplastic large cell lymphoma, are extremely rare. LyG is an Epstein-Barr virus (EBV)-driven B-cell lymphoid neoplastic proliferation rich in T cells that produces vasculitis. The disease may present at different stages of progression. Differential diagnosis of PLL varies according to the lymphoma subtype: pulmonary mucosa-associated lymphoid tissue lymphoma should be distinguished from reactive inflammatory conditions, whereas high-grade lymphomas may resemble poorly differentiated lung carcinoma, metastatic disease, and other lymphomas. LyG can resemble inflammatory, infectious, and other lymphoid neoplastic processes. A panel of immunohistochemical markers, flow cytometry, and molecular methods are necessary to confirm the diagnosis in the majority of cases. In this article we review the clinical, radiologic, pathologic, and molecular characteristics of several B-cell and T-cell PLLs with exception of Hodgkin lymphoma and posttransplant lymphoproliferative disorder.