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Extranodal Hodgkin lymphoma is rare at first presentation, especially NLPHL. A recent review (Ma et al. 2014), however, indicated 42% of 26 cases of extranodal Hodgkin lymphoma occurred in the lung.
Hodgkin lymphoma has been described as being a disease of the young. However, in recent years it is found in the 15–35 years age group still, but also in older patients as well as children. Personal experience would suggest extranodal disease is more common in the older cohort.
There is no recognized predominance of one sex in CHL although men more often harbor NLPHL.
Hodgkin lymphoma arises most often in lymph nodes in the neck. Mediastinal nodes are often involved and may be the only site of disease, and thus it is likely that many so-called pulmonary cases reflect direct spread from the mediastinum or disease in intrapulmonary lymph nodes. Schild et al. (2014) observed that most cases of pulmonary HL were diagnosed before the advent of PET/CT scanning, further questioning the origin in pulmonary parenchyma.
Given the rarity of pulmonary HL, accurate estimates of outcome are hard to find (Schild et al. 2014). Best practice following diagnosis is thus likely to rely on standard staging and prognostic indices. A recent review of data from 1,402 CHL patients concluded that expected outcome is excellent if there is a 2-year event-free interval following treatment, regardless of risk prior to treatment (Hapgood et al. 2016).
Tumors form masses at the hilum and associated with the mediastinum. Solitary masses in the parenchyma at presentation are most uncommon although may well be a feature of advanced stage or recurrent disease. The disease has a cream-white cut surface, often firm and fibrous and sometimes with zones of necrosis.
Hodgkin lymphoma can be the easiest and yet sometimes the most difficult diagnosis in hematopathology. Cytological (e.g., endobronchial ultrasound – EBUS) and biopsy material may provide diagnosis although an open biopsy is likely to provide the most accurate diagnosis and avoid misclassification. The characteristic finding in CHL (see Stein et al. 2008) is of Hodgkin and Reed-Sternberg cells with their well-documented features. The background is variable and can include admixed population of variably mixed lymphoid cells, plasma cells, macrophages (occasionally aggregated to form granulomas), neutrophil, and eosinophil polymorphs. Fibrous stroma is variable. Nodularity is usual in the nodular sclerosing type. The difficulty arises on cytology because several lymphomas can mimic HRS and background cell morphology and also with small biopsies where architectural features are not apparent and the sample size limits the opportunity to make vital diagnostic observations.
In NLPHL, bizarre, large, often isolated NP cells with convoluted nuclei are surrounded by small lymphoid cells in expansile, “space-occupying” nodules (see Popema et al. 2008 for a full description).
The immunocytochemical features of CHL are well documented and of B-cell lineage (Stein et al. 2008), being no different in the lung. HRS cells are CD30 positive with a strong paranuclear dot as well as membrane and/or cytoplasmic staining. CD15 is often positive, frequently with a “grainy” texture, variable intensity within and between tumors, and sometimes negative. The cells stain positively with MUM-1(IRF4) and Ki67. PAX5 is positive but weakly in comparison to nearby B cells. OCT-2 and BOB-1 are expressed singly or neither is positive. HRS cells are generally negative with CD45 and CD20 although some focal or weak staining may be seen. CD10, BCL6, and ALK are negative. CD79a is said to be positive in rare cases, as are EMA and T-cell markers, especially CD2. Light chain staining is said to represent passive uptake of these molecules by the tumor cells. LMP1 is occasionally positive – overall in CHL, around 15–25% are positive; however EBER-ISH is more sensitive (25–40% approximately).
While cytogenetic and molecular features are variable, it has been recognized recently that many of the lesions seen in CHL influence the NFΚB and the JAK/STAT pathways and genes relevant to major histocompatibility complex expression (Mathas et al. 2016).
The differential diagnosis of CHL includes NLPHL, T-cell-rich B-cell lymphoma which is a variant of diffuse large B-cell lymphoma, EBV-positive large B-cell lymphoma (of the elderly, now: “not otherwise specified”; Swerdlow et al. 2016), and, in the lung, primary mediastinal (thymic) large B-cell lymphoma and lymphomatoid granulomatosis. Tumors with overlapping characteristics can be classified as B-cell lymphoma and unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. Anaplastic large cell lymphoma should be excluded, and, in certain clinical circumstances, it may be necessary to think about Hodgkin-like posttransplant lymphoproliferative disorders, not to mention granulomatous diseases with necrosis and EBV infection.
The differential can be elucidated with reference to the clinical and radiological features and knowledge of ongoing disease. Immunocytochemistry will generally be helpful. The large LP cells of NLPHL are CD20, CD79a, CD45, BCL6, OCT-2, and BOB-1 positive and negative with CD30 and CD15. EBV is negative. Differentiating this, especially in its diffuse form, from T-cell-rich B-cell lymphoma is problematic; however the large B cells in the latter tend to be more frequent than in NLPHL. EBV-positive large B-cell lymphoma, not otherwise specified, is a diffuse process with bizarre large cells and a heterogeneous background. This tumor is CD20, CD79a (usually), CD30, MUM-1, and EBER-ISH positive but CD15 negative. Older age and immunocompromised status are generally associated with this tumor type. Mediastinal large B-cell lymphoma has a characteristic fibrous stroma with packed or trabeculated cells enmeshed in collagen. It is CD30, CD20, and usually MUM-1 (IRF4) and CD23 positive, but CD15 negative. Lymphomatoid granulomatosis tends to present with systemic symptoms, some of which may resemble the “B” symptoms of CHL. Lung nodules tend to be multiple and variable in size. The histopathology is of angiocentric nodules with vascular damage. The background can be polymorphous, but the immunocytochemistry is helpful because the large cells are CD20, CD30, and usually EBER-ISH positive, but negative with CD15. Anaplastic large cell lymphoma (ALCL) is CD30 and CD4 positive, often MUM-1 positive, but negative with B-cell lineage markers. Clonality studies looking for IgH and light chain rearrangements may be helpful, as may clonality of the TCR gene in ALCL.
References and Further Readings
- Hapgood, G., Zheng, Y., Sehn, L. H., Villa, D., Klasa, R., Gerrie, A. S., Shenkier, T., Scott, D. W., Gascoyne, R. D., Slack, G. W., Parsons, C., Morris, J., Pickle, T., Connors, J. M., & Savage, K. J. (2016). Evaluation of the risk of relapse in classical Hodgkin lymphoma at event-free survival time points and survival comparison with the general population in British Columbia. Journal of Clinical Oncology, 34, 2493–2500.CrossRefPubMedGoogle Scholar
- Ma, J., Wang, Y., Zhao, H., Lui, S., Ii, Q., Lin, L., Yue, Y., Wang, X., Zhao, Z., Yu, Y., & Zhang, Y. (2014). Clinical characteristics of 26 patients with primary extranodal Hodgkin lymphoma. International Journal of Clinical and Experimental Pathology, 7, 5045–5050.PubMedPubMedCentralGoogle Scholar
- Popema, S., Delsol, G., Pileri, S. A., Stein, H., Swerdlow, S. H., Warnke, R. A., & Jaffe, E. S. (2008). Nodular lymphocyte predominant Hodgkin lymphoma. In S. H. Swerdlow et al. (Eds.), WHO classification of tumours of haematopoietic and lymphoid tissues (pp. 323–325). Lyon: IARC. isbn:978-92-832-2431-0.Google Scholar
- Stein, H., Delsol, G., Pileri, S. A., Weiss, L. M., Popema, S., & Jaffe, E. S. (2008). Classical Hodgkin Lymphoma, introduction. In S. H. Swerdlow et al. (Eds.), WHO classification of tumours of haematopoietic and lymphoid tissues (pp. 326–329). Lyon: IARC. isbn:978-92-832-2431-0.Google Scholar
- Swerdlow, S. H., Campo, E., Pileri, S. A., Harris, L. N., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G. A., Zelenetz, A. D., & Jaffe, E. S. (2016). The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood, 127, 2375–2390.CrossRefPubMedPubMedCentralGoogle Scholar