Volume 20, Issue 2, Pages 105-120 (May 2003)

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Splenic involvement by peripheral T-cell and NK-cell neoplasms

Abstract

In contrast to B-cell lymphomas, the literature on the splenic pathology of peripheral T-cell and NK-cell lymphomas is limited. Several different patterns of splenic involvement can be observed in peripheral T-cell and NK-cell lymphomas: 1) solitary or multiple fleshy nodule, which is seen predominantly in tumors rich in large cells; 2) diffuse red pulp involvement, which is the commonest pattern; 3) colonization of periarteriolar shealth; and 4) patchy haphazard involvement. However, the miliary small nodule pattern commonly observed in low-grade B-cell lymphomas is practically never seen. In hepatosplenic T-cell lymphoma and T-cell large granular lymphocyte leukemia, the pattern of splenic involvement is rather stereotyped, with diffuse red pulp infiltration and preservation of the sinus/pulp cord architecture, and without formation of nodules. The pattern of involvement is variable from case to case in peripheral T-cell lymphoma unspecified, and there can be associated prominent hemophagocytosis or a masking component of epithelioid granulomas. Aggressive NK cell leukemia and extranodal NK/T cell lymphoma show predominatly red pulp involvement, although the tumor cell density can vary from field to field; blood vessel walls are commonly infiltrated and there can be areas of necrosis.

Keywords: Spleen, splenic lymphoma, T-cell lymphoma, NK-cell lymphoma

Article Outline

• Abstract

• Overview on patterns of splenic involvement in peripheral T-cell and NK-cell lymphoid neoplasms

• Solitary or multiple large fleshy nodules

• Diffuse red pulp expansion

• Colonization of the periarteriolar sheath

• Patchy haphazard involvement

• The issue of primary peripheral T-cell or NK-cell lymphoma of the spleen

• Clinicopathologic features of specific types of peripheral T-cell or NK-cell lymphoid neoplasms involving the spleen

• Hepatosplenic T-cell lymphoma

• Clinical features

• Pathologic features

• Immunohistochemical features

• Genetic features

• Problems in diagnosis

• T-cell large granular lymphocyte leukemia

• Clinical features

• Pathology of the spleen

• S100 protein-positive peripheral T-cell lymphoma

• Clinical features

• Pathologic findings

• Peripheral T-cell lymphoma associated with hemophagocytic syndrome

• Peripheral T-cell lymphoma with a masking component of epithelioid granuloma

• Aggressive NK-cell leukemia

• Clinical features

• Pathologic findings

• Differential diagnosis

• Extranodal NK/T cell lymphoma

• Clinical features

• Pathologic findings

• Immunocytochemical and genetic features

• Differential diagnoses

• References

• Copyright

Overview on patterns of splenic involvement in peripheral T-cell and NK-cell lymphoid neoplasms

THE MORPHOLOGIC PATTERNS of splenic involvement by B-cell lymphomas have been quite well studied. Small B-cell lymphomas, such as grade 1 or 2 follicular lymphoma, mantle cell lymphoma and marginal zone B-cell lymphoma, typically replace and expand the white pulp Malpighian corpuscles, with variable spillover into the red pulp. Large B-cell lymphomas often form solitary or multiple large tumor nodules, although they may also rarely involve the red pulp in a diffuse pattern. In contrast, information on the morphologic patterns of splenic involvement by peripheral T-cell and NK-cell lymphoid neoplasms is meager. Even hematopathology book chapters and textbooks on splenic pathology devote only short paragraphs on such pathologic changes.1, 2, 3 The reasons are as follows:

1.Peripheral T-cell and NK-cell lymphomas are much less common compared with B-cell lymphomas. According to the Non-Hodgkin Lymphoma Classification Project, peripheral T-cell and NK-cell lymphomas account for only 10% of all non-Hodgkin lymphomas.4 In a retrospective analysis of the personal consultation files (1983 through 1993) of Dr Henry Rappaport, 108 spleens involved by non-Hodgkin lymphoma were identified, including 43 primary splenic lymphomas, 58 cases of secondary splenic involvement, and 7 cases of hairy cell leukemia.5 Among them, there are only 5 cases of peripheral T-cell lymphoma unspecified and one case of T-cell large granular lymphocyte leukemia. In a review of 1,280 splenectomy specimens encountered over a 10-year period in two tertiary care institutions, there were 130 cases of B-cell lymphoma, but only 6 cases of peripheral T-cell lymphoma.6

2.Immunophenotypic data were not available in the era when splenectomy was commonly performed as part of the staging procedure for lymphomas. However, now that comprehensive immunophenotyping can be readily applied even on paraffin-embedded tissues, splenectomy is rarely performed in patients with known lymphoma except when splenomegaly causes symptoms or complications.

The patterns of splenic involvement by peripheral T-cell and NK-cell neoplasms are variable, and are listed in Table 1. 3, 7 The miliary small nodule pattern produced by selective white pulp involvement, while common in small B-cell lymphomas, is practically never seen in peripheral T-cell and NK-cell neoplasms. A synopsis is presented in Table 2.

Table 1.

Commoner Patterns of Splenic Involvement by Peripheral T Cell and NK Cell Lymphomas/Leukemias

	Solitary or multiple fleshy nodules
	Diffuse red pulp involvement with or without micronodule formation
	Colonization of periarteriolar sheath∗
	Patchy haphazard involvement

∗

This can occur as a sole pattern, or more commonly occurs in combination with the other three listed patterns

Table 2.

A Synopsis of Splenic Involvement by Peripheral T-Cell or NK-Cell Lymphoma

	Knowledge of the splenic pathology in peripheral T-cell and NK-cell lymphomas is limited.
	It is not possible to reliably distinguish T-cell or NK-cell lymphoma from B-cell lymphoma on morphologic grounds alone, with the exception that T- or NK-cell lymphoma is much less likely if a predominantly white pulp expansion pattern is seen. Immunohistochemical staining is required to delineate the cellular lineage.
	Many different patterns of splenic involvement can be seen in peripheral T-cell and NK-cell lymphomas, but the most common pattern is diffuse red pulp infiltration, with preservation of the sinus-pulp cord architecture.
	The same type of peripheral T-cell or NK-cell lymphoma can produce different histologic patterns of involvement in the spleen, with the exception of hepatosplenic T-cell lymphoma and T-cell large granular lymphocyte leukemia, which show fairly stereotypic histologic features
	While angioinvasion and necrosis are characteristic of NK-cell neoplasms, they are by no means specific, because they also be observed in conventional peripheral T-cell lymphomas or even B-cell lymphomas.

Solitary or multiple large fleshy nodules

Some peripheral T-cell lymphomas produce a solitary tumor nodule or multiple separate or coalescent nodules in the spleen. These nodules are often fleshy and tan-white, and necrosis is common. Histologically, the neoplastic cells form compact sheets, causing total destruction of the normal splenic parenchyma in the affected areas (Fig 1). This pattern of involvement is seen predominantly in peripheral T-cell lymphoma unspecified rich in large cells and T/null-cell anaplastic large cell lymphoma.

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Fig 1. Anaplastic large cell lymphoma involving spleen in the form of a solitary large nodule. Histologically, sheets of large lymphoma cells obliterate the normal splenic architecture.

Diffuse red pulp expansion

Diffuse involvement of the red pulp of the spleen results in a beefy red appearance on the cut surface. Histologically, the lymphoma cells infiltrate and expand the red pulp, with preservation of the splenic sinus and pulp cord framework. Preservation of the vasculature of the spleen accounts for the red color in the gross specimen. The lymphoma cells can be individually dispersed within the red pulp, or can show extensive dense infiltrate Fig 2, Fig 3. Sometimes the lymphoma cells are localized predominantly or exclusively in the pulp cord, leaving the sinuses relatively empty-looking. There can be superimposed tight nodular aggregates of lymphoma cells in the red pulp (Fig 4). The white pulp is usually atrophic or lost.

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Fig 2. Peripheral T-cell lymphoma unspecified involving spleen with a diffuse red pulp pattern. The lymphoma cells are loosely dispersed.

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Fig 3. Peripheral T-cell lymphoma unspecified involving spleen with a diffuse red pulp pattern. (A) Compared with Figure 2, the lymphoma cells are more densely packed. (B) Despite the dense lymphomatous infiltration, the sinuses and pulp cords can still be identified.

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Fig 4. Anaplastic large cell lymphoma involving spleen in a diffuse red pulp pattern with superimposed small nodules. (A) The pale-staining areas represent foci of discrete tumor nodule formation. (B) The large lymphoma cells are dispersed in the red pulp, and cellular nodules (right upper field) are also formed.

Diffuse red pulp expansion is the most common pattern of splenic involvement by peripheral T-cell and NK-cell lymphomas.5 Hepatosplenic T-cell lymphoma and T-cell large granular lymphocyte leukemia typically show this pattern of splenic involvement, while peripheral T-cell lymphoma unspecified and NK/T cell lymphoma often but not necessarily involve the spleen in this pattern.

Colonization of the periarteriolar sheath

The periarteriolar sheath of the spleen, which is normally populated by mature T cells, is the T-zone of the spleen. In peripheral T-cell and NK-cell lymphoma involving the spleen, this sheath can be colonized by lymphoma cells (Fig 5). 7 This form of involvement may not produce visible abnormality in the gross specimen, and can be missed on casual examination of the histologic sections. Rarely, there is in addition involvement of the peripheral portion of the marginal zones.7 This pattern of splenic involvement is most commonly seen in combination with other patterns of involvement.

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Fig 5. Peripheral T-cell lymphoma unspecified with periarteriolar sheath colonization in addition to red pulp involvement. (A) At low magnification, there are pale foci around the arterioles (arrows), representing colonization of periarteriolar sheaths by lymphoma cells. (B) Higher magnification shows presence of medium-sized and large lymphoid cells in the periarteriolar zone.

Patchy haphazard involvement

Involvement of the spleen can take the form of focal patchy infiltration of the red pulp, without producing an obvious mass at the macroscopic level. Other areas of the spleen appear normal histologically. This pattern can be observed in occasional cases of peripheral T-cell lymphoma unspecified and NK-cell lymphoma.

The issue of primary peripheral T-cell or NK-cell lymphoma of the spleen

Using a strict definition, primary splenic lymphoma, defined as disease confined to the spleen and/or splenic hilar lymph nodes, is very rare. Using a lenient approach, such as acceptance of presence of bone marrow involvement, primary splenic lymphoma is not so rare.8 The majority of cases of primary splenic lymphomas are of B-lineage, with diffuse large B-cell lymphoma being the commonest.9 True primary peripheral T-cell lymphomas of the spleen (using a strict definition) are on record, but are extremely rare.6, 10, 11, 12

Clinicopathologic features of specific types of peripheral T-cell or NK-cell lymphoid neoplasms involving the spleen

Hepatosplenic T-cell lymphoma

Hepatosplenic T-cell lymphoma is an uncommon but distinctive form of peripheral T-cell lymphoma characterized by uniform medium-sized lymphoma cells expressing T-lineage markers, and exhibiting prominent involvement of the spleen and liver in a sinusoidal pattern.13, 14 This entity was originally known as “hepatosplenic γδT-cell lymphoma” because of consistent expression of γδ rather than αβ T-cell receptor. Since rare cases with similar clinicopathologic and cytogenetic features are shown to express αβ T-cell receptor, the qualifier “γδ” has been dropped from the nomenclature.15, 16, 17, 18

Because of prominent splenomegaly in the absence of readily biopsied lymph nodes, the spleen is not uncommonly removed for initial pathologic diagnosis. While the spleen is always involved, it is never the sole site of disease.

Clinical features

Hepatosplenic T-cell lymphoma most commonly occurs in young patients aged 15 to 35 years. There is marked male predominance.14 The patients present with hepatosplenomegaly, systemic symptoms, and/or thrombocytopenia. There is usually no peripheral lymphadenopathy. There can be small numbers of circulating lymphoma cells. Hepatosplenic T-cell lymphoma occasionally occurs in the setting of immunosuppression, such as organ transplant recipients.19, 20, 21, 22, 23, 24, 25 Rare association with hepatitis B infection has also been reported.26

Hepatosplenic T-cell lymphoma pursues an aggressive clinical course. Despite an initial response to chemotherapy, the disease usually relapses. Almost all patients eventually die from the disease, and the median survival is less than 2 years. Because of the poor survival, alternative forms of therapy have to be considered.14, 27, 28, 29, 30, 31 Sporadic examples of favorable response to bone marrow transplantation or treatment with 2′-deoxycoformycin have been reported, but further studies are required to confirm the effectiveness or value of these therapies.32, 33, 34

Pathologic features

The spleen is usually markedly enlarged, weighing more than 1 kg. The cut surfaces exhibit a uniform beefy red appearance. Histologically, the white pulp is atrophic or lost. The red pulp is expanded by a dense and monotonous infiltrate of medium-sized lymphoma cells, and yet the sinus-pulp cord architecture is not obliterated Fig 6, Fig 7. 28, 29, 30, 31, 35, 36 The lymphoma cells have round, ovoid, or occasionally irregular nuclei, fairly dense chromatin, and a moderate amount of pale to clear cytoplasm (Fig 7B). Mitotic figures are rare. Coagulative necrosis is generally absent.

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Fig 6. Hepatosplenic T-cell lymphoma with diffuse red pulp involvement. The sinuses and pulp cords are infiltrated by uniform medium-sized lymphoma cells.

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Fig 7. Hepatosplenic T-cell lymphoma with red pulp involvement. (A) Compared with Figure 6, this case shows a much denser neoplastic infiltrate in the red pulp. (B) The sinuses and pulp cords are infiltrated by monotonous medium-sized lymphoma cells.

In the liver, the lymphoma typically involves the sinuses rather than the portal tracts (Fig 8). Bone marrow involvement is very common but often subtle, with lymphoma cells being usually confined within the sinusoids (Fig 9). With progressive disease, the infiltrate in the marrow may become more extensive and interstitial in distribution, accompanied by increase in lymphoma cell size.37

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Fig 8. Hepatosplenic T-cell lymphoma involving liver. (A) Note the prominent sinusoidal infiltration. There is no involvement of the portal tracts (not shown). (B) Immunostaining for TIA-1 highlights the lymphoma cells.

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Fig 9. Hepatosplenic T-cell lymphoma with subtle marrow involvement. In a background of normal hematopoietic cells, the sinusoids are packed with medium-sized lymphoma cells (arrows).

Immunohistochemical features

Hepatosplenic T-cell lymphoma is a neoplasm of non-activated cytotoxic T lymphocyte.13, 30, 36 The lymphoma cells express pan-T markers. The majority of cases express γδ T-cell receptor, which requires the use of fresh or frozen tissue for proper demonstration. Some cases express αβ T-cell receptor instead.15, 16, 17, 18 The lymphoma cells usually do not express CD5, CD4, and CD8, although rare cases may express CD8. Among the cytotoxic markers, TIA-1 is frequently positive but not perforin (Fig 8B).30, 36 The NK-associated marker CD56 is commonly expressed.

Genetic features

For cases that express γδT-cell receptor, the γ chain T-cell receptor gene is rearranged, while the β chain T-cell receptor gene is either not rearranged or partially rearranged. For cases that express αβ T-cell receptor, both the γ and β chain T-cell receptor genes are rearranged. One common misconception is that demonstration of γ chain T-cell receptor gene rearrangement supports a diagnosis of γδ T-cell lymphoma. This is not true, because T-cell lymphomas expressing αβ T-cell receptor always show rearrangements of the γ chain T-cell receptor gene as well — in normal T cell development, rearrangements of the γ chain in fact precedes that of αβ chain of the T-cell receptor gene. Thus, a firm diagnosis of γδ T-cell lymphoma depends on demonstration of γδ T-cell receptor expression by immunophenotyping, not by molecular analysis.

Isochromosome 7q is a common and recurrent cytogenetic abnormality of hepatosplenic T-cell lymphoma. Other common alterations are trisomy 8 and loss of Y chromosome.29, 30, 31, 36, 38, 39, 40, 41 An increased number of 7q signals was found in three cases with cytologic features of progression, indicating a tendency of hepatosplenic T-cell lymphoma to multiply the i(7)(q10) chromosome during evolution.42

Epstein-Barr virus (EBV) is negative.29, 30 An exception is the series of three Japanese cases reported by Ohshima et al under the designation “hepatosplenic γδ T-cell lymphoma,” in which all cases were EBV positive.43 Although these cases are clinically and immunophenotypically similar to the cases reported in the literature, the differ in that the neoplastic cells are large to medium-sized and exhibit significant nuclear pleomorphism. In the absence of cytogenetic data, it is currently unclear whether such cases with pleomorphic cytologic features should be classified as hepatosplenic T-cell lymphoma.

Problems in diagnosis

Because the cellular infiltrate in the spleen consists of monotonous medium-sized cells with a moderate amount of cytoplasm, distinction from hairy cell leukemia on morphologic grounds alone is difficult, except that blood lakes are infrequent. Immunohistochemical studies are essential for a firm distinction between hepatosplenic T-cell lymphoma and hairy cell leukemia because the former is a T-cell neoplasm and the latter a B-cell neoplasm.

Peripheral T-cell lymphoma unspecified can also involve the spleen and the liver. Strict criteria should be applied in rendering a diagnosis of hepatosplenic T-cell lymphoma — the infiltrate is predominantly in the red pulp of the spleen, the lymphoid cells should be uniform and medium-sized, and the lymphomas cells should show selective sinusoidal infiltration of the liver.

T-cell large granular lymphocyte leukemia

Clinical features

T-cell large granular lymphocyte leukemia is an indolent disease characterized by persistent increase in circulating clonal large granular T-lymphocytes. The proliferated cells are mature T cells that often show a CD4− CD8+ immunophenotype (80% of cases). The cytotoxic marker TIA-1 is usually positive.44, 45

T-cell large granular lymphocyte leukemia is a disease of older adults. The patients are either asymptomatic or present with complications such as infection (caused by chronic neutropenia) and red cell aplasia.44, 45, 46, 47 Up to 30% of patients show serologic and clinical evidence of rheumatoid arthritis. Physical examination is often unrevealing except for moderate splenomegaly. Splenectomy is occasionally performed in patients with a large spleen, but this does not correct the cytopenia.

Pathology of the spleen

According to the study of Agnarsson et al48 the enlarged spleen weighs 450 to 1650 g, with a median of 600 g. The red pulp is expanded and shows increased cellularity due to selective infiltration of small lymphoid cells in the sinuses and pulp cords (Fig 10). A common accompanying feature is plasmacytosis in the red pulp. In contrast to various lymphoproliferative disorders that infiltrate the red pulp, not only is the white pulp not atrophic but it often shows prominent germinal centers (Fig 10A).48 The diagnosis can be difficult to make in some cases because the neoplastic infiltrate in the red pulp is subtle. Immunostaining for CD3 or CD8 can help to highlight the neoplastic cells (Fig 11).

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Fig 10. T-cell large granular lymphocyte leukemia involving spleen. (A) At low magnification, the white pulp is hyperplastic and shows prominent germinal centers. The neoplastic infiltrate is confined to the red pulp. (B) In the red pulp, small lymphoid cells with dark round nuclei are dispersed in the sinuses and pulp cords.

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Fig 11. T-cell large granular lymphocyte leukemia involving spleen. Immunostaining for CD8 highlights the neoplastic cells. The sinus-lining cells are also weakly stained.

S100 protein-positive peripheral T-cell lymphoma

Clinical features

S100 protein-positive peripheral T-cell lymphoma, also known as S100-positive T-cell lymphoproliferative disorder, is an uncommon form of peripheral T-cell lymphoma. There are only a handful of reported cases in the literature, but the apparent rarity is probably caused by S100 protein immunostaining being rarely performed in the work-up of lymphomas — such cases are probably simply classified as “peripheral T cell unspecified” without information on S100 expression.

S100 protein-positive peripheral T-cell lymphoma typically affects young patients (12 to 62 years, median 31.5 years), who present with fever, marked splenomegaly and thrombocytopenia, but minimal or no peripheral lymphadenopathy. The disease can become leukemic during the clinical course, and sometimes only after splenectomy. This highly aggressive lymphoma usually causes death within one year.49, 50, 51, 52, 53

Pathologic findings

The spleen is markedly enlarged, often weighing more than 1 kg. There is diffuse red pulp infiltration by medium-sized or large lymphoma cells with round or slightly irregular nuclei and distinct nucleoli (Fig 12). Besides staining for T lineage markers and S100 protein, the lymphoma cells are commonly CD56 positive. The commonest T-cell subset immunophenotype is CD4−, CD8−, but rare cases can be CD8+ or CD4+. All 4 cases studied for γδ T-cell receptor expression have given negative results.49 The reported association with human herpesvirus 6 requires confirmation by further studies.54

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Fig 12. S100 protein-positive peripheral T-cell lymphoma. (A) The spleen shows marked expansion of the red pulp. A residual white pulp Malpighian corpuscle is seen in the upper field. (B) The red pulp is infiltrated by medium-sized to large lymphoma cells with distinct nucleoli.

In the liver, the lymphomatous infiltrate is either confined to the sinusoids, or occurs in both the sinusoids and portal tracts. In the lymph node (often intraabdominal), the lymphoma cells show a pure sinusoidal distribution, or show involvement of both the sinusoids and parenchyma.

Peripheral T-cell lymphoma associated with hemophagocytic syndrome

Hemophagocytic syndrome is a reactive but potentially fatal condition characterized by systemic proliferation of histiocytes, which are actively engaged in phagocytosis of hematopoietic cells.55, 56, 57, 58, 59, 60 The patients often present with high fever, constitutional symptoms, hepatosplenomegaly, and pancytopenia. An abrupt drop of the blood counts in the absence of other obvious causes, and elevated serum lactate dehydrogenase level are particularly characteristic. The most common causes of hemophagocytic syndrome are infections and malignant lymphomas; among the latter, peripheral T-cell and NK-cell lymphomas greatly outnumber B-cell lymphomas.61, 62, 63, 64

Some patients with peripheral T-cell lymphomas are complicated by hemophagocytic syndrome at presentation.64, 65 There is slight or no lymphadenopathy, while splenomegaly is often prominent. The disease usually pursues a highly aggressive clinical course. In patients successfully brought into remission, relapse of lymphoma may be accompanied by reappearance of hemophagocytic syndrome.

The spleen is usually markedly enlarged, weighing over 1 kg. Histologically, there is infiltration of the bone marrow, splenic red pulp and liver by lymphoma cells (often large in size), which are admixed with histiocytosis with active hemophagocytosis. The histiocytes can be distinguished from the lymphoma cells by their smaller, bland-looking, eccentrically-placed nuclei, and fine chromatin (Fig 13). Immunostaining for CD68 can highlight the histiocytes, whereas the lymphoma cells are negative.65

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Fig 13. Peripheral T-cell lymphoma unspecified associated with hemophagocytic syndrome. Large lymphoma cells (large size, with coarse chromatin) are dispersed in the splenic red pulp. There are many reactive histiocytes with erythrophagocytosis (arrows).

Peripheral T-cell lymphoma with a masking component of epithelioid granuloma

Some lymphomas involving the spleen are associated with such prominent epithelioid granulomas that the lymphomatous component is obscured (Fig 14). 66, 67, 68 This pattern can be observed in either T-cell or B-cell lymphomas. Immunohistochemical and/or genotypic studies are required for definitive lineage assignment and classification.

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Fig 14. Peripheral T-cell lymphoma unspecified accompanied by granulomatous reaction. (A) Ill-defined granulomas are seen in the spleen. (B) Atypical lymphoid cells (lymphoma cells) are masked by epithelioid histiocytes.

Aggressive NK-cell leukemia

Clinical features

Aggressive NK-cell leukemia most commonly affects young adult patients, who present with fever, systemic symptoms, hepatosplenomegaly, sometimes accompanied by systemic lymphadenopathy. In theperipheral blood, there are circulating large granular lymphocytes which can exhibit variable degrees of atypia. The disease pursues a fulminant clinical course, with most patients dying within days or weeks.69, 70

Pathologic findings

It is extremely rare to encounter a splenectomy specimen from such patients. At postmortem examination, the spleen is always enlarged. Histologically, the neoplastic infiltrate is located predominantly in the red pulp, but the density of neoplastic cells can be highly variable from area to area (Fig 15). The fibrous trabeculae and blood vessel walls are frequently infiltrated, sometimes in a single-file pattern (Fig 15). They are often admixed with many apoptotic bodies. Commonly there are foci of infarction or coagulative necrosis (Fig 15B).

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Fig 15. Aggressive NK cell leukemia. (A) The red pulp shows extensive infiltration, with preservation of the sinus-pulp cord architecture. (B) The upper field shows infiltration of the blood vessel wall by neoplastic cells. The lower field shows a large area of necrosis (infarction).

The typical immunophenotype is CD2+, surface CD3-, CD3ϵ+, CD56+, CD16+/-. Cytotoxic markers are positive. Like the normal counterpart (NK cells), the T-cell receptor genes are not rearranged. EBV is almost always positive.69, 70

Differential diagnosis

Aggressive NK cell leukemia must not be confused with indolent NK cell large granular lymphoproliferative disease, an NK cell proliferation that pursues a nonprogressive course. The main distinguishing features of the latter are lack of clinical symptoms, absence of hepatosplenomegaly and lack of EBV association.

T-cell large granular lymphocyte leukemia is morphologically similar to aggressive NK-cell leukemia in the peripheral blood or bone marrow. It differs from the latter in the following features: indolent clinical course, surface CD3 expression, presence of clonal T-cell receptor gene rearrangements, EBV negativity, less destructive or permeative infiltrate in the spleen, and extreme rarity of necrosis or infarction in the spleen.

Extranodal NK/T cell lymphoma

Clinical features

Extranodal NK-/T-cell lymphoma is a putative NK-cell lymphoma that almost always presents in extranodal sites. It affects mostly adults, with a median age of 53 years, and male predominance. Nasal NK-/T-cell lymphoma presents in the nasal cavity and nasopharynx, with variable extension to the surrounding anatomic sites, producing extensive ulcerative lesions (midfacial destructive disease) or a mass lesion. Most patients have stage I or II stage disease. The clinical outcome is variable, with some patients apparently cured by radiation therapy, but others showing early local or systemic relapse despite aggressive treatment. The overall survival rate is about 30%.70, 71, 72

Nasal-type (extranasal) NK-/T-cell lymphoma presents with disease outside the upper aerodigestive tact, with predilection for the skin, gastrointestinal tract, and testis. Most patients have stage III or IV disease, and systemic symptoms are common. The disease pursues a highly aggressive course, with the majority of patients dying within 6 months.70, 72, 73

Pathologic findings

Clinical evidence of splenic involvement in NK-/T-cell lymphoma is rare, and it is extremely uncommon to encounter a splenectomy specimen in such patients, except when the spleen is removed with other involved intraabdominal organs such as stomach. The following description is based on the limited personal experience of the author. The spleen is of normal size or only slightly enlarged. There is patchy or diffuse infiltration of the red pulp by lymphoma cells (Fig 16). The cytologic spectrum is variable, ranging from small cells to medium-sized and large cells. The nuclei are often irregularly folded. The cytoplasm is usually pale or clear.

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Fig 16. Nasal NK-/T-cell lymphoma relapsing in the spleen. (A) This field shows involvement of the red pulp. (B) The lymphoma cells are more often located in the pulp cords than the sinuses.

In addition, the lymphoma cells can also colonize some periarteriolar sheaths (Fig 17). The walls of blood vessels often show infiltration by lymphoma cells (Fig 17).

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Fig 17. Nasal NK-/T-cell lymphoma relapsing in the spleen (same case as Figure 16). (A) Immunostaining for CD3 highlights atypical cells in the periarteriolar sheath, indicating involvement of this zone. (B) Note infiltration of the subintima of blood vessels by lymphoma cells.

Immunocytochemical and genetic features

The most common immunophenotype is: CD2+, surface CD3−, cytoplasmic CD3ϵ+, CD56+. Cytotoxic markers such as TIA1, granzyme B and perforin are commonly expressed. The T-cell receptor genes are not rearranged, and there is a very strong association with EBV.70, 72, 73

Differential diagnoses

Infectious mononucleosis can involve the spleen, sometimes presenting as splenic rupture, necessitating splenectomy. The marked increase in lymphoid cells and presence of many large lymphoid cells can lead the unwary to an erroneous diagnosis of lymphoma (Fig 18). This diagnostic difficulty is further compounded by the frequent presence of large lymphoid cells infiltrating the vascular walls (Fig 18). The young age of the patient, a positive Monospot test, presence of a spectrum of lymphoid cells with apparent maturation towards plasma cells, lack of frank nuclear atypia, and presence of a mixture of T and B cells on immunohistochemical studies should led to serious consideration of infectious mononucleosis.

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Fig 18. Infectious mononucleosis involving spleen. (A) There is a worrisome increase in lymphoid cells, including many activated large lymphoid cells. (B) The lymphoid cells even infiltrate the subintima of blood vessels.

Systemic mast cell disease involving the spleen may mimic T-cell lymphoma histologically because the mast cells form clusters and sheets of medium-sized cells with indented nuclei, clear cytoplasm and inconspicuous granules (Fig 19). This disease can be distinguished from clear cell-rich peripheral T-cell lymphoma by the presence of many admixed eosinophils and delicate to coarse sclerosis. The diagnosis can be readily confirmed by Leder, toluidine blue or Giemsa stain, or by immunoreactivity for tryptase or CD117 (c-kit).

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Fig 19. Systemic mast cell disease of the spleen may be mistaken for peripheral T-cell lymphoma. The neoplastic cells have medium-sized nuclei and abundant clear cytoplasm. The clues to the correct diagnosis are the admixed eosinophils (most abundant in right field) and the delicate sclerosis.

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a Department of Pathology, Queen Elizabeth Hospital, Hong Kong, S.A.R. China

Address reprint requests to John K.C. Chan, MD, Department of Pathology, Queen Elizabeth Hospital, Wylie Road, Kowloon, Hong Kong, S.A.R. China

PII: S0740-2570(03)00013-3

doi:10.1016/S0740-2570(03)00013-3

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