An Autopsy Case of an Elderly Patient with Classic Hodgkin Lymphoma Presenting with a Plethora of Clinical Symptoms and Signs

Background

Hodgkin lymphomas (HLs) are lymphoid neoplasias that usually affect lymph nodes. Although primary extranodal involvement is rare, dissemination to more than one organ, such as the liver, bone marrow, or lungs, is associated with advanced (stage IV) disease [1]. Owing to advances in chemotherapy and radiation therapy, outcomes for patients with early-stage HL are excellent, and prognosis in advanced-stage disease is also very good [2–4].

Nevertheless, the 5-year survival rate of elderly patients (60 years or older) is much worse than that of younger patients (15 to 39 years old) [5,6]. In elderly individuals, HLs are characterized by aggressive disease and unfavorable prognostic features including advanced age, advanced stage, comorbidity, histological sub-type, Epstein-Barr virus (EBV) positivity, the number of macrophages and programmed death-ligand 1 (PD-L1)-positive cells, and serum levels of interleukin (IL)-6 [7–11]. Thus, the choice of treatment for HL in the elderly is a major challenge [4,7].

Despite a low rate of autopsies, a few recent reports describe HL cases that were diagnosed after death [12–14]. An autopsy study for unrecognized HL revealed a number of unfavorable prognostic factors that are common findings among patients who died of HL [15]. We found advanced HL at autopsy in an elderly patient in whom acute cholangitis and sepsis had been suspected. The patient had also exhibited worsening diabetes mellites and an elevation of tumor markers such as CA19-9 and carcinoembryonic antigen (CEA). This case had almost all the adverse prognostic factors mentioned above.

In this report, we discuss the prognostic factors that may have adversely affected the course of the patient. We also discuss the pathophysiological relation of HL with worsening diabetes mellites and suspected cholangitis. HL is a rather common, but vicious disease in elderly individuals [7,11]. However, screening methods to identify elderly patients with HL are lacking [16–18]. A new modality of the effective screening method is needed to ameliorate poor prognosis and adverse outcomes for elderly individuals with HL.

Case Report

AUTOPSY FINDINGS:

Macroscopic inspection revealed many swollen lymph nodes up to 3×3 cm in size in the mediastinal, retroperitoneal, hepatic hilar, and peripancreatic regions. These lymph nodes were grayish white in color and had an elastic consistency. The inspection also detected numerous white to brownish white nodules in the liver (915 g) and spleen (151 g) that were a few millimeters in size (Figure 3A, 3B). Both lungs had more than a dozen nodules of several millimeters in size (left: 297 g, right: 420 g). The right kidney had 2 nodules (7×7 mm) in the cortex, while the left kidney had no tumors. There was an elevated mucosal tumor (2×3 cm) at the base of the gall bladder. We did not observe any tumors or nodules in the pancreas. The pacemaker terminal was implanted in the right ventricle, and the stent was in the anterior descending branch of the left coronary artery. All 3 main branches of the coronary artery had severe atherosclerosis, with 65% to 90% occlusion of the lumens. Cut sections of the heart (285 g) showed an infarction scar (5.5×1.0 cm) in the posterolateral area of the left ventricle and a few smaller scars affecting the septum and anterior area. Yellow and translucent anasarca was seen: ascites of 700 mL, pleural effusions of 350 mL (left) and 300 mL (right), and pericardial effusion of 60 mL. Mild to moderate broncho-pneumonia was observed in the lungs.

Histology of the lymph nodes, liver, spleen, lungs, right kidney, and bone marrow similarly demonstrated scattered infiltration of atypical large cells with a dense admixture of inflammatory cells including small lymphocytes, plasma cells, and macrophages (Figure 4A). The atypical cells had large single nuclei or multiple nuclei with pale chromatin and prominent eosinophilic nucleolus. Neither geographical necroses nor angiocentric or angiodestructive lesions were seen. Immunohistochemically, the atypical cells were diffusely positive for CD15, CD30, and Mum1 (Figure 4B–4D); focally positive for CD138; and negative for CD3, CD4, CD8, CD20, and CD79a. We diagnosed the case as mixed-cellularity classical HL (MCCHL). We performed immunostaining with PAX5 (Leica 1EW) twice and could not obtain the proper immunohistochemical results owing to no positive staining of Hodgkin and Reed/Sternberg (HRS) cells and the background lymphocytes.

In situ hybridization analysis with Epstein-Barr virus-encoded RNA (EBER; Leica BOND EBER probe) showed strong positivity for many HRS cells (Figure 5A). Many macrophages in the tumor microenvironment were positive for CD-68 (Agilent KP1; Figure 5B). HRS cells positively stained strongly for PD-L1 (Ventana SP142; Figure 5C) and IL-6 (Leica 10C12; Figure 5D), moderately for LMP1 (Dako CS.1–4) and granzyme B (Leica 11F1), and weakly for tumor necrosis factor (TNF)-α (Abcam P/T2). A large number of the inflammatory cells were also positive for PD-L1 and IL-6 (Figure 5C, 5D). Monoclonal or oligoclonal proliferation of plasma cells was not seen with immunohisto-chemistry of kappa and lambda light chains of immunoglobulin.

In the liver, HRS cells and the reactive components heavily infiltrated the portal tracts (Figure 6A). Many hepatic bile ducts were positive for CA 19-9 (Figure 6B) but not for CEA. The gall bladder tumor was histologically identified as adenoma with severe dysplasia/carcinoma in situ, and the neoplastic cells were immunohistochemically positive for CEA.

Discussion

In a surveillance study with more than 21 500 HL cases, multivariate analyses suggested that adverse prognostic factors included age (>19 years old), histologic subtypes (mixed cellularity and lymphocyte-depleted), stage IV, presence of B symptoms, no reported use of radiation, and non-white race [19]. In the International Prognostic Score, only age (≥45 years) and hemoglobin level retained independent significance in multivariate analyses of advanced-stage HL [20]. Elderly patients (≥60 years of age) with HL have disproportionately worse survival rate compared with younger patients [21]. Net survival gradually decreases with age, and the 5-year survival is the highest (over 90%) in the youngest individuals (15 to 39 years), approximately 50% in patients aged 70 to 79 years, and less than 30% in those aged 80 years or older [5]. Accordingly, age is considered as one of the most important prognostic factors in HL, and it is intrinsically associated with HL biology [22].

According to van Sporsen et al. [23], 21% of HL patients younger than 60 years have serious comorbid conditions compared with 58% of the older patients. Comorbid conditions chiefly comprise cardiovascular disease, hypertension, chronic obstructive pulmonary disease, and diabetes. In multivariate analyses of elderly HL patients, comorbidity, but not age (60 or older), was regarded as a significant factor of overall survival, whereas the presence of a comorbidity, stage, and presence of B symptoms were each independently correlated with inferior survival [24]. The presence of comorbidity as an independent prognostic factor is particularly relevant for older patients. Moreover, the presence of severe comorbidity may distract the patient, clinician, or both, such that the early symptoms of tumor growth may go unnoticed, leading to delayed diagnosis [25]. Our patient had actually undergone percutaneous coronary intervention and pacemaker implantation for acute coronary syndrome and sinus arrhythmia, respectively, 7 months earlier. She did not present with any symptoms and signs of HL at that time. In addition, there is no true consensus for treatment of elderly patients with HL, primarily owing to intolerance of curative treatment caused by comorbidities. Therefore, the choice of treatment is a major challenge [4,7].

It has been recognized that the number of tumor-infiltrating CD68+ and CD163+ macrophages constitutes a major biomarker that is predictive of inferior progression-free and overall survival [8,26]. Several studies have confirmed this observation [27–29]. CD68 and CD163 expression in classical HL (CHL) is related to increased age, EBER positivity, and MCCHL [28]. Old age is associated with a high frequency of presence of EBV and MCCHL [22,30]. Immunosenescence may be an explanatory factor for the presence of EBV in older patients [22,30]. MCCHL has a close relationship with EBV infection [1], and older patients with EBV-positive HL have significantly poorer outcomes compared with those with EBV-negative HL [30,31].

The natural function of signaling between PD-1 and PD-L1 is to limit certain T-cell-mediated immune responses. T-cell exhaustion is essential to the pathogenesis of HL [32,33]. Nonetheless, PD-L1 and PD-L2 on HRS cells have no prognostic significance [34]. In several tumor types, especially CHL and other tumors with a marked inflammatory infiltrate, a major component of PD-L1 expression within the total cellularity is supposed to derive from tumor-infiltrating macrophages [9,33,35]. Thus, in addition to the CD68 and CD163 expression, the number of PD-L1-positive cells in formalin-fixed paraffin-embedded tissue can be considered as an adverse prognostic factor for elderly patients with HL [9,36].

IL-6 expression in HRS cells, as detected by immunohistochemistry, correlates with B symptoms [10,37]. The expression in background cells independently predicts poor response and freedom from treatment failure in pediatric HL [38]. Although we could not examine serum IL-6, we believe that it was probably elevated in the serum because HRS cells and many inflammatory cells immunohistochemically showed strong positivity for IL-6. The serum level of IL-6 as well as those of IL-1 and TNF-α offers an unfavorable prognosis [10,39]. In addition, patients with increased IL-6 and IL-2R have a significantly higher risk of early relapse and death [10]. However, further studies are needed to clarify virus-associated cytokine effects on poor prognosis in elderly patients with HL [30].

On the other hand, the serum level of TNF-α or IL-6 increases when glucose tolerance is impaired in diabetics compared with nondiabetics [40–42]. Worsening of glucose control positively and linearly correlates with high levels of IL-6 and leptin [43]. There are a few reported cases with IL-6-producing tumors, including lung cancer and adrenal pheochromocytoma, that exacerbated glucose tolerance in diabetic or non-diabetic patients [44–46]. Worsening of glucose tolerance in our patient may have been caused by excess production of IL-6 by HRS cells and inflammatory cells. Nonetheless, the relationship between IL-6 production and abnormal glucose tolerance in HL patients remains to be unraveled with more cases.

While liver diseases occur as a hepatic manifestation of paraneoplastic syndrome in HL [47–49], the frequency of direct involvement with HL ranges from 2% to 20% at the time of diagnosis [1,50,51] and up to two-thirds of the cases at autopsy or necropsy [15,52]. The portal tracts are the most common site for HL involvement [52]. The involvement more typically manifests as miliary lesions (<1 cm) than as masses on CT [47]. Hence, enhanced CT and positron emission tomography (PET) imaging may be required to detect them. The lesions are more frequently seen in portal areas than in hepatic parenchyma in liver biopsy [53]. The histology of portal involvement sometimes suggests acute cholangitis and nonspecific large (≥1 mm) inflammatory infiltrates [53]. The frequency of liver involvement differs in subtypes of CHL. Lymphocyte-depleted CHL (LDCHL) has involvement of the bone marrow (11%) and liver (19%) significantly more often than the other subtypes [50]. Although LDCHL has a much poorer prognosis than the other subtypes, LDCHL and MCCHL are viewed as 2 grades of a single disease entity, often occurring in the setting of HIV infection and conferring a significantly worse prognosis [39].

Finally, HL is not a very rare disease among elderly individuals. The percentage of patients aged over 60 years ranges between 15% and 35% [7,11]. Cases in this population are characterized by aggressive disease and unfavorable prognostic features, which many authors have reported. An effective screening method to detect HL in elderly patients at an early stage and in younger patients is expected in the near future [17,18]. Less toxic and effective therapies are also needed [6,11], in addition to next-generation strategies to prevent and treat EBV infection as a means to control EBV-associated diseases [54–56]. These efforts will result in filling the disproportionately large gap between young and older patients in terms of the effectiveness of treatment and disease prognosis.

Conclusions

We reported an autopsy case of HL in an elderly woman. Such reports are very rare probably because of a low rate of autopsies. We suspected excessive production of IL-6 as the cause of worsening diabetes mellites in our case. Study of a larger number of cases is needed to unravel the relationship between IL-6 production and abnormal glucose tolerance in HL patients. HL may often involve the liver as miliary lesions occur along the portal tracts, which can be confused with cholangitis. Thus, enhanced CT and PET imaging may be required to detect them.

Elderly patients with HL usually have more adverse prognostic factors than younger patients. We discussed the adverse factors, including comorbidity, CD68+ macrophages, EBV infection, and PD-L1 and IL-6 expression in the cells of tumor microenvironment. All of these factors appear to be closely connected with advanced age and pose a major challenge in the clinical management of elderly patients. A new modality of screening for HL in elderly individuals is needed.