WT is the second most common benign tumor of the salivary glands.1,2 It occurs almost exclusively in parotid gland, with occasional involvement of regional lymph nodes. It is characterized by multifocal intraglandular and bilateral parotid involvements.1,6 Its occurrence in other salivary glands is rare. It is relatively common in men aged 50 to 60.7 Both epithelial and lymphoid stromal components of WT are considered benign, but can undergo malignant transformation, with rate of transformation lower than 1% of the cases. The underlying mechanism of malignant transformation has not been fully understood.8
The concurrent detection of malignancy in WT was initially documented in 1954.9 In recent years, there have been reports of WT complicated with cancer, however, WT concomitant with lymphoma is rare. An extensive review of the literature revealed 35 reports of lymphoma concomitant with WT (Table 1). These include totally thirty-nine cases (including the present case) of concurrent WT and lymphoma. Of these, 33 (84.6%) are Non-Hodgkin lymphoma (NHL) and 6 (15.4%) are Hodgkin lymphoma (HL) The cases of WT concomitant with MCL appear extremely rare. Including the present case, MCL comprises only 3 (9%) of 33 total reported NHL cases.10
Table 1:
Summary of malignant lymphoma concomitant with Warthin tumor. (cHL,classical Hodgkin lymphoma; NLPHL, nodular lymphocyte predominant Hodgkin lymphoma; DLBCL, diffuse large B cell lymphoma; SLL/CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia)
Hodgkin lymphoma (n = 6, 15.8%) | Frequency (n) |
CHL, mixed cellularity | 211,12 |
CHL, lymphocyte rich | 113 |
CHL (Not distinguished) | 214,15 |
NLPHL | 116 |
Non-Hodgkin lymphoma (n = 32, 84.2%) | |
Follicular lymphoma | 149,17–26 |
In situ follicular neoplasia | 110 |
DLBCL | 622,27–31 |
SLL/CLL | 48,10,32,33 |
Mantle cell lymphoma | 217,34 |
MALT-type lymphoma | 135 |
Peripheral T cell lymphoma | 136 |
T cell-lymphoblastic lymphoma | 237,38 |
Unclassified | 120 |
Of two reported cases with concurrent WT and MCL, one described MCL occurring within the parotid gland in patients with chronic myoepithelial mumps, secondary to an adjacent small WT, but this lymphoma did not occur within the lymphoid stroma of the tumor as seen in the present case.[17] Furthermore, the diagnosis of that case was based on morphology alone without immunophenotypic support or evidence of t(11; 14) (q13; q32) to confirm it.34
There is a strong correlation between cigarette smoking and WT according to the literature.1 Most scholars believe WT arises from intraparotid lymph nodes or ectopic salivary gland tissue remnant in regional lymph nodes. It has been proposed that benzene and/or other substances in tobacco tar be dissolved in saliva being carried retrograde to the glandular parenchyma via parotid duct, thus acting on the parotid duct epithelium and stromal lymphoid tissue, causing metaplasia and neoplastic transformation of both epithelial and stromal lymphoid components. According to the report, 89.1% of the patients with WT had a history of cigarette smoking and almost 90% were found in males.39 In addition, autoimmune diseases and radiation exposure increase the risk of WT.1,2,6 All these factors have also been associated with lymphomagenesis.
Summary of literature demonstrates history of rapid growth of parotid mass lesions, so was seen in the present case. Therefore, in case of sudden increase in parotid lesion, the possibility of malignant tumor should be raised, and diagnostic procedures, such as radiological evaluation and/or surgical resection with histopathologic examination, should be considered to confirm or rule out the diagnosis.
WT itself is a slow-growing benign tumor. Due to its unique morphological features, the histopathologic diagnosis is not difficult, and surgical resection is generally required for therapeutic purpose. WT concomitant with MCL, however, is quite different in terms of clinical presentation, treatment and prognosis. Thereafter, it is critical to carefully evaluate lymphoid stroma, particularly in cases with stromal expansion, and thus rule out the possibility of lymphomatous involvement.
Theoretically, because the lymphoid stroma may be part of lymphoid tissue throughout the body, existing lymphomas may involve in WT via homing mechanism and systemic dissemination. Of the reported cases of lymphoma within WT, most patients already had a diagnosis of lymphoma or demonstrated significant lymphadenopathy or systemic involvement by clinical staging subsequently to the diagnosis of WT. While MCL in our case appeared to confine to the stroma of WT without involving adjacent normal parotid glandular parenchyma tissue, clinical staging showed the evidence of lymphomatous involvement in multiple lymph nodes, in keeping with majority of the reported cases.
Mantle cell lymphoma (MCL) is mature B-cell lymphoma, with overexpression of cyclin D1 driven by the underlying genomic change, CCND1::IGH fusion.5 Microscopically, tumor cells were small to medium-sized lymphocytes with scant cytoplasm, irregular nuclear contours, condensed chromatin and inconspicuous nucleolus. In general, MCL is considered a highly invasive and incurable disease. The median survival time of patients is 3–5 years. 34 A high proportion of Ki67-positive cells has been reported as a poor prognostic indicator. In the current case, Ki67 proliferation index was estimated at 70%, predicting aggressiveness of the lymphoma.34
Patients with MCL require a comprehensive clinical staging, as most patients have developed the tumor with advanced clinical stages (Ann Arbor III/IV) at the time of diagnosis, accompanied by enlargement of multiple lymph nodes, often involving the spleen, liver, and bone marrow.5 The patient in this case was assigned to stage Iva, in keeping with the high proliferation rate of the tumor by histopathologic evaluation. Nonetheless, given the slow growth of parotid lesions, the case was judged as low to intermediate risk, and close observation was decided for the initial management, with next PET-CT examination scheduled in 6 months.
In the examination and diagnosis of patients with WT concomitant with MCL, CT has been preferred as the initial method because it is easily accessible and provides the location, size, and structures involved in the tumor.31 Magnetic resonance imaging (MRI) may also be useful in the assessment of parotid tumors. 1 A definitive diagnosis relies primarily on histopathological assessment of tissue biopsy, including fine needle aspiration (FNA), core needle biopsy (CNB), and excisional biopsy. FNA plays an important role in the assessment of salivary gland tumors.40 However, since the diagnostic value of FNA may be affected by insufficient cells and a high false negative rate, CNB is considered to be more superior to FNA in the detection of malignant tumors. However, it remain risky to overlook lymphomatous component within the stroma of WT .41 We believe that surgical excision with histopathological examination is necessary for a definitive diagnosis of WT and exclusion of lymphomatous involvement.
In conclusion, collision tumors characterized by WT concomitant with MCL are very rare, with only 2 cases reported in the English literature to date. WT is a slow-growing benign tumor that can be surgically removed. WT concomitant with MCL, however, is quite different in terms of treatment and prognosis. Since most parotid tumors are benign, malignancy is not usually considered as differential diagnosis and is thus often overlooked, once diagnosis of WT is made. Due to distinct treatment approach, overlooking diagnosis of mantle cell lymphoma would lead to delayed treatment and dismal clinical outcome. Pathologists should carefully and thoroughly examine the stromal lymphoid component of WT to identify potential lymphoma hidden in WT so that adequate management can be delivered timely.