|Year : 2015 | Volume
| Issue : 2 | Page : 138-143
Primary extranodal lymphomas - spectrum of distribution and morphology with immunophenotyping: A 3-year institutional study
Chinnam Aparna, Inuganti Venkata Renuka, Muthyala Rajani, Garikapati Sailabala, Parvatala Annapurna
Department of Pathology, Guntur Medical College, Guntur, Andhra Pradesh, India
|Date of Web Publication||13-Mar-2015|
Inuganti Venkata Renuka
Department of Pathology, Guntur Medical College, Guntur - 522 002, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Background: Malignant lymphomas arising in extranodal sites are intriguing. The histological types of lymphomas vary from one site to another. This study is undertaken to diagnose and categorize extranodal lymphomas using histochemistry and immunohistochemistry (IHC). Materials and Methods: Formalin processed paraffin blocks and hematoxylin and eosin stained sections were used for routine histology. IHC was done in all cases. Results: We have encountered 31 cases of extra nodal lymphomas over a period of 3 years. The tumors occurred at different sites, including brain, nasopharynx, nose, gastrointestinal tract, thyroid, bone, testis, breast, lung, vagina, and skin. Majority of the cases were B-cell lymphomas, while four cases were T-cell lymphomas. Among the B-cell lymphomas diffuse large B-cell lymphoma was the most common variant. Conclusion: This study reiterates the key role of IHC particularly when the differential diagnosis includes an undifferentiated epithelial malignancy and a high-grade lymphoma in the extranodal sites as the treatment modalities and prognosis are different.
Keywords: B-cell lymphoma, diffuse large B-cell lymphoma, extranodal, lymphoma, T-cell lymphoma
|How to cite this article:|
Aparna C, Renuka IV, Rajani M, Sailabala G, Annapurna P. Primary extranodal lymphomas - spectrum of distribution and morphology with immunophenotyping: A 3-year institutional study. Med J DY Patil Univ 2015;8:138-43
|How to cite this URL:|
Aparna C, Renuka IV, Rajani M, Sailabala G, Annapurna P. Primary extranodal lymphomas - spectrum of distribution and morphology with immunophenotyping: A 3-year institutional study. Med J DY Patil Univ [serial online] 2015 [cited 2020 Dec 3];8:138-43. Available from: https://www.mjdrdypu.org/text.asp?2015/8/2/138/153137
| Introduction|| |
Non-Hodgkin's lymphomas (NHL) involve extranodal sites during their natural course, and in certain cases multiple sites are simultaneously involved at the time of presentation. However, some NHLs are considered to originate at sites other than lymph nodes or spleen and are referred to as primary extranodal lymphomas (PENHL).  This study is taken up to study the lymphomas arising at extranodal sites.
| Materials and Methods|| |
In the present study, data regarding extranodal lymphomas from March 2009 to March 2012 were analyzed. Formalin fixed paraffin blocks and hematoxylin and eosin stained sections were used for routine reporting. Immunohistochemistry (IHC) was applied selectively from a panel of markers, including leukocyte-common antigen (LCA), HMB45, pan cytokeratin (pan CK), CD99, vimentin, desmin, CD20, and CD3. Ann Arbor staging was performed by physical examination, surgical reports, and ultrasound scan of abdomen, X-ray chest, hemogram, and bone marrow biopsy.
| Results|| |
In the present study, 31 cases of lymphomas in extranodal sites were reported, the most common sites being the nasopharynx, gastrointestinal tract, and skin. Other sites are listed in [Table 1]. The age incidence ranged from 5 to 72 years Males (58%) outnumbered females. None of our cases showed any B symptoms.
| Discussion|| |
Primary extra nodal lymphomas constitute about 24-48% of lymphomas according to the literature.  In the present study, we considered PENHL's originating at a site other than lymph node or spleen. We received 31 cases of PENHL's over a period of 3 years.
A variety of organs were affected encompassing extraocular muscles, nasopharynx, nasal cavity, oral cavity, lung, mediastinum, breast, thyroid, gastrointestinal tract, vaginal wall, testis, skin, bone, and central nervous system (CNS). The age of presentation ranged from 5 to 72 years and male: female ratio was 1.6:1. There were no B symptoms in any of the cases.
Depending on the site of the tumor and also the histological picture, we used a panel of markers such as pan-CK, LCA, CD99, HMB45, chromogranin, vimentin, and desmin. Once the tumors were positive for LCA, we applied markers for CD3 and CD20 to label them as T-cell or B-cell lymphomas.
Two cases were reported in the nasal cavity. One of the cases occurred in a 5-year-old-child, and the differential diagnosis was esthesioneuroblastoma and NHL. However, IHC revealed positivity for LCA and CD20, thus favoring the diagnosis of B-cell NHL. The other case was a human immunodeficiency virus (HIV) positive adult. Histology showed alveolar and nesting patterns leading to the differential diagnosis of PENHL, small cell neuroendocrine carcinoma, alveolar rhabdomyosarcoma, and malignant melanoma. A panel of markers, including LCA, HMB45, pan-CK, CD99, chromogranin and desmin were done [Table 2]. The tumor was positive for LCA and CD3 confirming the diagnosis of PENHL of T-cell origin. This patient died after two cycles of chemotherapy.
In all the five cases seen in the nasopharynx, IHC with high molecular weight cytokeratin was done to exclude a nonkeratinizing undifferentiated carcinoma. The tumors were diffusely positive for CD45 and CD20 [Figure 1]. One case was seen in a 29-year-old female. She presented with difficulty swallowing. On nasal endoscopy, a large bilateral ulceroproliferative growth was seen on both sides occupying roof of nasopharynx, obstructing right Eustachian tube More Details. Cervical group of lymphnodes were also enlarged. Clinically, it was staged as Stage 3a. After starting CHOP regime for 5 months, the patient was relieved of symptoms. Nasal endoscopy showed open eustachian tube, no growth, and no palpable nodes. However, the patient had candidiasis of the mouth, which was treated with antifungal agents. Since February 2012, there was no relapse until date.
|Figure 1: (a) Nasopharyngeal large B-cell lymphoma (H and E, ×400) (b) nasopharyngeal large B-cell lymphoma showing CD20 expression in tumor cells (immunohistochemistry, CD20 ×200)|
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According to the literature intraoral lymphomas constitute only 25% of all lymphomas and 0.6% are seen as gingival tumors.  Among intraoral lymphomas gingiva is the common site. In this study, one case each was observed in the gingiva and the tongue. Both cases presented as a mass in the oral cavity. We considered a differential diagnosis of undifferentiated carcinoma and lymphoma. However, LCA was positive, so these were signed out as NHL.
Primary bone lymphoma accounts for approximately 7% of all primary bone malignancies and 5% of all extranodal lymphomas.  We have reported two cases, one in the vertebra, and the other in the rib. In these cases, multiple myeloma was excluded by morphology, hemogram, urine/serum electrophoresis, and skeletal survey.
Primary breast lymphoma incidence ranges from 0.04% to 0.5% of all breast malignancies.  Lymphomas usually lack the irregular borders of an invasive duct cell carcinoma and exhibit no calcifications in mammography in half of the cases. In this study, one patient presented with bilateral breast masses without involvement of axillary lymph nodes. Medullary carcinoma of breast was excluded as there were no syncytial patterns and pseudo lymphoma was ruled out because the cells were monotonous. The tumor cells were positive for LCA and CD20 clinching the diagnosis of B-cell lymphoma.
Lymphomas of ocular adnexae account for 1-2% of NHL's and 8% of extranodal lymphomas.  In the present case, we considered the differential diagnosis of a small cell neuroendocrine carcinoma and NHL. IHC revealed negativity for CD99 and positivity for LCA and CD20; thus, confirming the diagnosis of lymphoma. As per literature 80% of primary ocular adnexal lymphomas are of marginal zone lymphomas, but the present case turned out to be a diffuse large B-cell lymphoma. 
We reported a NHL of thyroid in the background of hashimoto's thyroiditis in a 50-year-old female. Clinically, she complained of difficulty in deglutition. On fine-needle aspiration, the possibility of an NHL was considered, and in the resected specimen the differential diagnosis included small cell variant of medullary carcinoma, insular carcinoma, and lymphoma. The tumor was negative for calcitonin, but positive for LCA and CD20, indicating lymphoma of B-cell lineage [Figure 2].
|Figure 2: (a) Thyroid B-cell lymphoma (H and E, ×200). (b) Thyroid B-cell lymphoma showing CD20 expression in tumor cells (immunohistochemistry, CD20 ×200)|
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Primary NHL of the brain represents 2% of NHL's and 5% of brain tumors.  As the central neuraxis lacks a resident lymphoid population, the histogenesis of primary NHL of the brain is obscure. AIDS related lymphomas harbor Epstein-Barr virus, but sporadic NHL's of the brain do not. Over 90% of primary CNS lymphomas are diffuse large B-cell lymphomas.  All our cases were seronegative for HIV. Two of the cases were intradural, but one case was extradural infiltrating into the bone. One of the intradural tumors showed a ring enhancing radiological appearance resulting in the inclusion of toxoplasmosis in neurosurgeon's differential diagnosis, but it was ruled out on histopathology.
Primary pulmonary NHL is a rare entity constituting 0.4% of all lymphomas.  In this study, a 19-year-old male presented with a lung mass. The possibility of small cell neuroendocrine carcinoma and primitive neurectodermal tumor was excluded by applying IHC markers CD99, pan-CK, LCA, CD20, and CD3. The tumor was positive for LCA and CD20; thus, confirming the diagnosis of lymphoma.
Gastric lymphomas are derived from the mucosa associated lymphoid tissue (MALT) that is generated by Helicobacter pylori on. In 1994, MALT lymphomas were officially categorized in the REAL classification as extranodal marginal zone lymphomas of MALT type. Stomach is the most common site among the gastrointestinal lymphomas according to the literature.  In this study, three cases were observed in the ileum and colon and one case in the stomach. Clinically, they presented with nonspecific symptoms such as indigestion, heartburn, etc. These cases were positive for CD45 and CD20 confirming their B-cell nature [Figure 3],[Figure 4] and [Figure 5]. Morphologically these were of marginal zone (MALtoma) type, but no associated malabsorption syndromes were observed. In the gastric lymphoma case also, we could not get any evidence of preexistent H. pylori infection. These tumors presented as ulcerated lesions, in contrast to the literature, which suggests multiple lymphomatous polyposis as the most common presentation.  Histologically, all these were low grade MALtomas because they showed small lymphocytes with dark round nucleus along with lymphoepithelial lesions. 
|Figure 3: (a) Gastric large B-cell lymphoma (H and E, x200). (b) Gastric large B-cell lymphoma showing CD20 expression in tumor cells (immunohistochemistry, ×200)|
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|Figure 4: Gastric mucosa showing lymphoepithelial lesion (H and E, ×400)|
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|Figure 5: (a) Ileal non-Hodgkin's lymphoma (H and E). (b) Ileal non- Hodgkin's lymphoma diffusely positive for CD45 (immunohistochemistry, Cd45 ×200)|
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Lymphomas of the mediastinum are commonly seen in the middle portion of the mediastinum, usually in young adult females. In this study, one was a male of 50 years, and the other was female of 55 years. Female patient was previously treated for breast carcinoma. Differential diagnoses included a dysgerminoma and a thymoma. Dysgerminoma was ruled out on morphology. Mediastinal lymphoma was differentiated from thymoma by using IHC marker pan-CK.
Testicular lymphomas comprise 5% of all testicular malignancies. It is the most common testicular tumor in elderly persons and is often bilateral.  It has to be differentiated from a seminoma, plasmacytoma. In this study, a 70-year-old male presented with bilateral enlargement of testes. The tumor was positive for LCA and CD20 favoring the diagnosis of B-cell NHL. No lymph nodes were enlarged even after 6 months of follow-up, so a secondary lymphoma was ruled out.
In the skin, we have reported four cases. One case was diagnosed as mycosis fungoides, as the tumor cells showed characteristic epidermotropism and Pautrier's microabscess [Figure 6]. One case did not show the typical cerebriform nucleus, but was positive for CD3, so our diagnosis was a T-cell lymphoma of unspecified category. Two cases were positive for CD20 and bcl-2 and hence labeled as the primary cutaneous diffuse large B-cell lymphoma.  We have considered differential diagnosis of diffuse lymphoid hyperplasia and lymphoma. However, a monomorphic population of cells favored a diagnosis of lymphoma.
|Figure 6: (a) Cutaneous lymphoma showing epidermotropism (H and E). (b) High power view of epidermotropism (H and E).|
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In the vagina, we have reported two cases of lymphoma, one case being HIV positive. Both were middle-aged females. They presented with bleeding per vagina. Grossly, the tumors were gray white and fleshy. Microscopically, the tumor cells were arranged in nests and alveolar patterns along with discrete cells. Some cells showed clear cytoplasm while others showed abundant eosinophilic cytoplasm. We considered differential diagnosis of alveolar rhabdomyosarcoma, clear cell carcinoma, amelanotic melanoma, and NHL. A panel of markers were applied including desmin, vimentin, CD99, HMB45, LCA, CD20, and CD3. Both tumors were positive for LCA favoring the diagnosis of NHL. One case showed positivity for CD20, while the other showed positivity for CD3. We have not found a single case of primary NHL of vagina, in the literature. Treatment; all patients were given the standard CHOP regime. Cyclophosphamide 750 mg/m 2 intravenously, adriamycin 50 mg/m 2 intravenous (I.V), vincristine 1.4 mg/m 2 I.V, prednisolone 100 mg/m 2 P.O. This was repeated every 3 weeks. Maximum of 6-8 cycles were given. Rituximab 375 mg/m 2 I.V was added for some cases the day before the CHOP regime.
| Conclusion|| |
This study highlights the importance of IHC particularly when there is a diagnostic dilemma between an undifferentiated epithelial malignancy and a high-grade lymphoma. In various extranodal sites, lymphoma has to be excluded using IHC because the treatment modalities and prognosis are completely different from a carcinoma, sarcoma or a melanoma. Sometimes additional studies for monoclonal immunoglobulin heavy chain rearrangement using polymerase chain reaction are also necessary to differentiate lymphoma from reactive lymphoid hyperplasia.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]