Identification of extranodal lymphomatous involvement is prognostically important in management [4]. PET-CT is a hybrid technique that provides both anatomical and functional data.
We aimed at this study to evaluate the added value of PET/CT over diagnostic CT in the detection of extranodal lymphomatous involvement. There was poor agreement between these two modalities (k = 0.32). This result denotes that CECT should not replace PET/CT in the staging of lymphoma. These results are different from Omur et al.’s study, where agreement was fair (k = 0.6). In the current work, disagreements were frequently depicted between these two modalities regarding the bone marrow, spleen, and liver, while in Omur et al.’s study, there was disagreement regarding spleen, marrow, thyroid, and prostate[5].
In the current study, PET study detected infiltration in 36 sites that were negative by CECT. Most of them showed either diffuse splenic or marrow uptake by PET images while were normal by CECT. This resulted in up staging in 10% of cases, because in the remaining cases there were other CT detected sites of extranodal involvement.
CECT showed five positive lesions at the liver and marrow; however, FDG uptake was only present in lymph nodes. Benign nature of these five lesions was confirmed by biopsy or MRI. Accordingly, PET/CT resulted in down staging of 5% of cases. This percentage was notably higher than that of Omur et al. where percentages of cases downstaged and upstaged based on PET-CT were 1.8% and 5.4% respectively [5].
In a prospective study made by Luminari et al. [6] that was conducted on 142 patients, PET/CT helped in upstaging and downstaging of 11% and 1% of patients respectively.
In Le Dortz et al.’s [7] study, which was a retrospective study on 45 patients, upstaged and downstaged cases were 8% and 0 % respectively.
Cheson et al. [8] found that PET/CT resulted in a change in staging in 10–30% of cases.
If there is diffuse increased FDG uptake in any organ, it should be investigated for the presence of lymphoma either by MRI or biopsy [5].
SUVmax values for hottest LNs and extranodal organs were measured in patients with secondary lymphoma. Pearson’s correlation was done and revealed significant positive moderate correlation (r = 0.45). On the other hand, in Omur et al.’s [5] study, they found a high positive correlation between SUVmax of highest FDG accumulating lymph node and extranodal sites (r = 0.67).
The importance of this data is that the highest SUVmax value of the lymph nodes can support the diagnosis of extranodal organ involvement by lymphoma over other benign conditions like inflammation or infection especially if the FDG is seen accumulated in the extranodal organ without mass effect. Organs with SUVmax that is close to the SUVmax of maximum 18FDG accumulating LN can be diagnosed as lymphomatous.
In the current work, the maximum FDG uptake was seen at NHL (DLBCL) followed by (large B cell lymphoma), while in HD, the maximum uptake was seen in HD interfollicular followed by HD nodular sclerosis. These results were in agreement with Schroder et al. [9], where the DLBCL, nodular sclerosis types showed the highest FDG avidity.
In NHL, the spleen is considered an extranodal organ while in HD, it is nodal. In the present study, the most commonly involved organ was the spleen (Fig. 2) seen in 30% of cases (22% focal and 8% diffuse infiltration). Ten out of these 30 cases (30%) only were positive by CECT while the remaining were negative. These results clarify the importance of PET/CT in identification of splenic lymphoma in normal size and morphology spleen by CT. These results are keeping with the study made by Omur et al. [5] where CECT detected only 42% of all PET/CT detected cases.
In the current study, the second commonly involved extranodal after the spleen was head and neck. PET/CT discriminated between true infiltration and physiological FDG uptake at tonsils in two cases (2%) (physiological uptake is bilateral, symmetrical, of low grade, and without corresponding abnormalities on diagnostic CT). PET/CT depicts intense focal FDG uptake even in normal size tonsils and can differentiate between lymphoma and nasopharyngeal carcinoma, as the latter has predilection for transforaminal cranial extension. PET/CT can identify this extension [4].
Thyroid gland lymphoma was depicted in 2% of cases (1% secondary and 1% primary). The important differential is anaplastic carcinoma which has strong avidity to FDG and heterogeneous enhancement in diagnostic CT [1]. According to Sin et al. [1], diffuse but low-grade thyroid FDG uptake can be seen in other non-lymphomatous conditions such as reactive uptake, Hashimoto thyroiditis, and post-chemotherapy.
In the current study, the only involved salivary gland was the parotid (2%). There are FDG avid benign lesions in the salivary glands that show uptake even more than malignant lesions which are Whartins tumor and pleomorphic adenoma [10]. Sjogren’s syndrome and lymphoepithelial sialadenitis predispose to lymphoma [4].
Orbital lymphoma was depicted in 2% of cases seen as FDG avid lesions involving the lacrimal glands bilaterally infiltrating the extraocular muscles sparing the optic nerve (Fig. 3). This agrees with Das et al.’s [4] study as they reported that optic nerve is not involved in lymphoma. Orbital lymphoma rarely erodes the bone [11, 12]. Interpretation of ocular lymphoma by PET/CT is challenging because of the physiological uptake of the nearby brain and the small volume of the lesion [13].
In the present study, 12% of cases showed pulmonary affection; all were NHL (Fig. 4a, b). This is keeping in agreement with Das et al. [4]; they reported that HD of the lung is rare and usually due to direct extension from a mediastinal or hilar mass. On the other hand, Metser et al. [14] found that lymphoma of the lung is three times more frequent in HD more than NHL. Differentials include granulomatous disease or even second primary malignancy.
In the current study, PET/CT enabled discrimination between reactive and lymphomatous pleural effusion in 2% of cases. Active pleural effusion is seen as FDG avid focal pleural thickening, pleural plaques, or bulky masses. According to Sarah and Rodney [15], reactive effusion is more common and occurs secondary to lymphatic or venous obstruction by mediastinal lymph nodes and seen as a non-FDG avid pleural lining.
In the present study, we had 1% case with chest wall muscle lymphoma. According to Das et al. [4], chest wall invasion may be due to direct extension from internal mammary or mediastinal adenopathies [3, 4]. Chest wall lymphoma mandates aggressive treatment because of the high rate of recurrence [16].
One case (1%) presumed to have an intra-atrial thrombus; however, on combined PET/CT, it was seen as large hypermetabolic hypodense soft tissue mass within the right atrium encroaching upon the AV valve reaching the right ventricle (Fig. 4c, d). These findings are in agreement with Mahajan et al., as they reported that the right atrium is most frequently involved. It is an oncologic emergency due to its rapid progression [17]. The interpretation of cardiac lymphoma is challenging as physiological uptake of FDG by the myometrium mask lymphomatous infiltration [18].
FDG avidity on PET/CT discriminates between cardiac lymphoma and other benign conditions including lipomatous hypertrophy of the interatrial septum, cardiac sarcoidosis, and myocarditis [17]. Presence of FDG avid pericardial effusion indicates lymphomatous infiltration [18].
The thymus is a nodal organ, so its involvement by lymphoma does not change the stage of the disease [2]. However, PET/CT is crucial in the differentiation between rebound thymic hyperplasia that develop following completion of chemotherapy (seen as low level FDG uptake anterior mediastinal mass with no active disease elsewhere in the body) from true active thymus lymphomatous infiltration (seen as focal intense FDG uptake). Thymic lymphoma retains the shape of the gland while enlarged mediastinal lymph nodes are lobulated [4].
In the current study, we found two cases (2%) of secondary breast lymphoma NHL (DLBCL subtype) seen as bilateral multiple masses associated with axillary lymph nodes and subcutaneous nodules (Fig. 5). According to Even et al., PET/CT is helpful in identification of breast lymphoma, because CT alone is not accurate for breast pathology and mammography is not routinely done in lymphoma staging [13]. According to Das et al. [4], age distribution of lymphoma has two peaks; one during pregnancy and lactation and is often high grade, the other is around the age of 50 and is usually solitary.
Normal physiological bowel uptake is a problem during interpreting PET/CT; however, higher uptake than the liver favors lymphoma [4]. GIT lymphoma is associated with risk factors like parasitic infection and inflammatory bowel disease [19]. In the current study, GIT was involved in 15% of cases. Four (4%) were primary lymphoma (3% NHL and 1% HD), and 11% were secondary lymphoma (10% NHL and 1% HD). These findings were in agreement with Sin et al. [1] who reported that secondary GIT lymphoma is relatively common while primary small bowel lymphoma is rare.
Gastric lymphoma was found in 8% of cases (7% NHL seen as diffuse mural thickening and 1% HD seen as exophytic masses) (Fig. 6a, b). This agrees with Paes et al. [2], who reported that the stomach was the most common involved part of the GIT.
In the current study, small bowel lymphoma was detected in 6% of cases [ileum (4%), jejunum (1%), and duodenum (1%)]. This was in agreement with Das et al. [4] who found that the incidence of involvement decreases proximally. Metser et al. reported that primary bowel lymphoma can be identified by intense FDG uptake in a short segment and in draining lymph node, while in secondary lymphoma, multiple segments are involved [3]. Peritoneal lymphomatous infiltration was seen in 1% of cases (Fig. 6c, d).
MALT lymphoma has predilection to the stomach while enteropathy-associated T cell lymphoma has predilection to the jejunum [1]. We encountered a case (1%) of the later type, which is commonly seen with celiac disease [20].
In the current study, all cases with hepatic lymphoma were secondary lymphoma. This is in agreement with Das et al. [4], where secondary lymphoma was more common. In the present study, two cases showed hepatic focal lesions based on CECT; however, no FDG activity was detected, and accordingly, these two cases were downstaged.
In the present study, we encountered one case (1%) with pancreatic lymphoma. According to Metser et al. [3], the presence of a large mass below the renal veins associated with peripancreatic lymph nodes suggests lymphoma rather than pancreatic adenocarcinoma.
Although the sensitivity of PET/CT for detection of renal lymphoma is low because FDG is normally excreted by the kidneys; however, the advantage of PET/CT is the ability to detect subtle lesions and the ability to diagnose lymphoma in diffusely enlarged kidney without focal lesions [4]. PET/CT detected lymphoma in 4% of cases (25% of these lesions were not detected on diagnostic CT) (Fig. 7). One case showed concomitant ureteric lymphomatous infiltration. Presence of renal affection indicates an aggressive form. Patterns of renal lymphoma are solitary, multiple hypodense masses, or diffuse infiltration [1].
In our study, PET/CT discriminated adrenal lymphoma from incidentaloma in 1% of cases. Lymphoma patients commonly have non-lymphomatous adrenal hyperplasia [3].
Lymphoma detection in the brain is challenging because of the physiological FDG uptake [4]. We depicted CNS lymphoma in (2%) of cases. Diagnosis of lymphoma is by MRI; however, PET/CT can differentiate it from non-FDG avid lesions like toxoplasmosis in immune-compromised patients and identify recurrence [12].
Primary osseous lymphoma is considered stage 1 disease, while secondary osseous lymphoma is considered stage 4 [2] (Fig. 8). In the current study, we encountered two cases (2%) of primary osseous lymphoma involving the appendicular system (patella 1% and tibia 1%) both were NHL. DLBCL was the most common histological subtype in both primary and secondary lymphoma.
Primary osseous lymphoma arises from flat bones and appendicular system while secondary lymphoma arises from the axial skeleton [4]. Bone marrow involvement is diffuse or focal, mono or polyostotic, the lesions could be lytic, sclerotic, or mixed. Sclerosis may be denovo or following radiotherapy [21]. Diffuse marrow uptake of FDG is seen after chemotherapy mainly by granulocyte colony-stimulating factor (GCSF); this pattern is commonly associated with increased splenic uptake [21].
This study depicted cutaneous lymphoma in 5% of cases seen as FDG avid nodules. A pitfall in the diagnosis of cutaneous lymphoma is T cell lymphoma type, which is associated with mycosis fungoides that shows low FDG avidity [12].
Muscular lymphoma is focal or diffuse. Although Sin et al. found that primary lymphoma of the muscle is more common [1], in the current study, diffuse muscle affection was in 2% of cases and both were secondary lymphomas. The role of PET/CT is the identification of single or multiple foci that guide the biopsy. A pit fall in the diagnosis of muscle lymphoma is diffuse uptake due to vigorous muscle activity prior the study.
In the present study, we encountered testicular lymphoma in 1% of cases that was secondary lymphoma. Secondary lymphoma of the testis is more common than primary and indicates aggressive disease. The detection of testicular lymphoma is challenging due to the physiological uptake of FDG by the normal testis. However, concomitant affection of the spermatic cord, epididymis, skin, and CNS are common that may help the diagnosis of lymphoma [4]. In females, adenxa is more commonly secondary affected by lymphoma than the uterus [4]. In the present study, 1% of cases had adnexal mass proved to be Burkitts lymphoma.
