Primary Cutaneous CD8(+) CD30(+) Anaplastic Large Cell Lymphoma: An Unusual Case with a High Ki-67 index-A Short Review.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a part of the spectrum of CD30(+) cutaneous lymphoproliferative disorder, characterized by variable degrees of CD2, CD3, CD4 and CD5 expression by lymphoid cells. PCALCLs with an expression of cytotoxic phenotype (CD8(+)) and cytotoxic proteins are uncommon. Cutaneous CD8(+) CD30(+) lymphoproliferative lesions are difficult to classify, diagnose and may be the cause of misdiagnose. CD8(+) PCALCL must be distinguished from CD8(+) mycosis fungoides, lymphomatoid papulosis type D and primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma. Usually CD8(+) PCALCL is an indolent disease with a favorable prognosis, except few cases can show poor outcomes. The high Ki-67 index points toward advanced PCALCL. Treatment modalities include surgical excision, radiotherapy and clinical monitoring. Chemotherapy is reserved for disseminated disease. We report a 59-year-old male presented with rapid development of multiple painful reddish-brown plaques and nodular ulcerative skin lesions over the left thigh region since 2 months. A diagnosis of CD8(+) PCALCL with a high Ki-67 index was made on the basis of histology and immunohistochemistry, in co-relation with clinical presentation.

What was known?

The majority of CD30+ PCALCL has CD4+/CD8– immunophenotype. CD8+ CD30+ PCALCL is a rare cutaneous T-cell lymphoproliferative disorder. Its distinction from other CD8+ CD30+ cutaneous lymphoproliferative disorder is difficult. The importance of Ki-67 has not been mentioned in primary cutaneous anaplastic large cell lymphoma (PCALCL).

Introduction

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a well-defined CD30+ lymphoproliferative disorder with a relatively good prognosis and response to treatment.[12] CD8+ PCALCL is an uncommon and difficult to diagnose, because of the large number of differential diagnoses involving the entire spectrum of cutaneous CD8+ CD30+ lymphomas.[123] Ki-67 has an important prognostic and therapeutic implications in cutaneous lymphoid malignancies.[45] To the best of our literature search, 34 cases of CD8+ PCALCLs have been reported in the literature, but a high Ki-67 index in these cases has not been mentioned.[12367891011] Herein, we describe a case of CD8+ PCALCL, with a high Ki-67 index and its differential diagnosis. To the best of our knowledge, this is the first reported case of CD8+ PCALCL with an increased proliferation rate.

Case Report

A 59-year-old male presented with a diffuse swelling over the left inguinal region and subsequent development of itchy skin lesions over the left thigh region since 2 months. Lesions were progressively increasing in size and number with few areas of ulceration for the past 1 month. There was no history of fever, weight loss or night sweats. Past medical history and family history were unremarkable. Physical examination revealed multiple reddish-brown, shiny, firm to hard, mildly tender papules and nodules, ranging from 0.2 to 1.7 cm size over the ventral aspect of the left thigh region. Total size of the lesional area was 20 × 10 cm. Few nodules showed ulceration and sero-sanguinous discharge with crust formation [Figure 1]. The skin overlying the lesions could not be pinched. There were no similar lesions elsewhere on the body. The patient had multiple discrete, firm, non-tender inguinal lymph nodes 1 × 1 cm to 3 × 2 cm in size. There was no pallor or jaundice. There was no cervical and axillary lymphadenopathy and hepatosplenomegaly. The other systemic examinations were unremarkable. Routine investigations revealed a normal hemogram and urine examination. Liver and renal function tests were within normal limits. A serology test for the human immune deficiency virus was negative. The patient underwent a skin biopsy.

Figure 1

Clinical Image: Multiple reddish-brown shiny plaques, papules and nodules, are ranging from 0.2 to 2.2 cm size over the ventral aspect of the left thigh region. Few nodules show ulceration with sero-sanguinous discharge and crusting. Total size of the lesional area is 20×10 cm

Histologic examination

A skin biopsy showed a dense, diffuse sheet-like infiltrate, composed of markedly atypical large tumor cells in the superficial and reticular dermis and in the subcutaneous tissue. The tumor cells showed irregularly folded nuclei, marked nuclear pleomorphism, prominent nucleoli and abundant eosinophilic cytoplasm. Frequent atypical mitoses were noted. Necrosis was not seen. Although the tumor cells were clearly demarcated from the epidermis, focally mild epidermotropism was seen [Figure 2]. On immunohistochemistry, over 95% of the tumor cells showed diffuse strong reactivity for CD30. The tumor cells were also positive for CD8 and CD3. Few background small lymphocytes were positive for CD5. The tumor cells were negative for CD4, CD15, CD20, S-100, HMB-45, ALK and EMA. The Ki-67 index was high (75%) [Figure 3]. The final histopathologic diagnosis was CD8+ PCALCL.

Figure 2

Skin Biopsy, H and E stained Histology: (a) Diffuse dense infiltrate of tumor cells in superficial and reticular dermis and subcutis. Mild epidermotropism is seen (×40); (b) perivascular infiltration of atypical lymphoid cells in the dermis (×100); (c) periadnexal infiltration of atypical lymphoid cells in dermis and subcutaneous tissue (×200); (d) tumor compose of markedly atypical, large, pleomorphic epithelioid-like cells with marked nuclear pleomorphism, prominent nucleoli, and eosinophilic cytoplasm, along with immature cells resembling immunoblasts. Neural entrapment is seen (×400)

Figure 3

Skin biopsy, IHC: (a) Strong and diffuse CD30 positivity in more than 95% of atypical lymphoid cells (×200). (b) CD8 positivity in more than 80% of atypical lymphoid cells (×40) [inset figure: ×200]. (c) CD3 positive in numerous atypical lymphoid cells (×100). (d) CD5 is positive in few mature lymphoid cells (×200). (e) CD20 is negative in lymphoid cells (×200). (f) Ki-67 index is high (75%) (×200).

The patient was subjected to thorough investigations in the form of flow cytometry analysis of peripheral blood, bone marrow biopsy, CT scan of the chest and abdomen, which were all found to be normal. Unfortunately, probably because of financial constraints, the patient had not taken chemotherapy. On telephonic tracing of the patient, we found that the patient died within 2 months.

Discussion

The spectrum of cutaneous CD30+ lymphoproliferative disorders encompasses lymphomatoid papulosis (LYP), “borderline cases,”’ systemic anaplstic large cell lymphoma (ALCL) with cutaneous involvement and PCALCL.[12] While most of the CD30+ T-cell lymphoproliferative disorders of the skin are CD4+/CD8–, CD8+/CD4– lesions are uncommon.[12367891011] Cutaneous CD8+ CD30+ lymphoproliferative lesions are difficult to classify and encompass entities that follow a benign course to overt lymphoma.[3] PCALCL is defined as the presence of cutaneous lesions without nodal and/or visceral involvement after complete staging procedures.[112]

Clinical features

CD8+ PCALCL commonly affects older aged (>50 years) patients, with a male preponderance.[1367] CD8+ PCALCL has not been described in the pediatric population.[12367891011] Prior history LYP is common.[12] The lesions usually occur on the trunk, face, extremities, buttocks, back, chest and eyebrows. The disease usually presents as a rapidly growing, solitary, minimally pruritic reddish-brown nodule or plaque, with or without ulceration.[12378910] Less common presentations include multiple, localized nodules or multicentric tumors at disseminated sites.[12310] Rare cases of CD8+ PCALCL can present with hemophagocytic syndrome and a giant ulcerated skin lesion.[9] Mucosal lesions are extremely rare.[11] Partial or complete spontaneous regression is reported in 25% to 66% of cases.[2] Regional lymphadenopathy is uncommon in CD8+ PCALCL.[12367891011] Concomitant history of other lymphoid malignancy is rare.[12367891011] In general, there is no apparent difference of clinical presentation, course and prognosis between CD8+ and CD8– PCALCL.[12]

Histology

PCALCLs are characterized by a broad cytomorphologic spectrum and a large variety of histopathologic presentations. Recognition of these variants is important, as they deviate considerably from the common morphological appearance of PCALCL, thus being a potential cause of misdiagnosis and wrong treatment of the patients. Even different lesions from a single patient may show variable histopathologic patterns and cell morphologies.[12] Concerning the predominant cell morphology, large anaplastic cells are almost as frequent as large pleomorphic and small to medium-sized cells.[12] Histopathological findings of a common variant include a nodular or diffuse, non-epidermotropic infiltrate with cohesive sheets of atypical lymphoid cells with an anaplastic or pleomorphic cytomorphology. Classically anaplastic tumor cells show round, oval, or irregularly-shaped/embryonic nuclei, prominent eosinophilic nucleoli and abundant cytoplasm. Immunoblastic morphology is uncommon.[178912] Neutrophils (“inflammatory-type” pattern), lymphocytes (“lymphohistiocytic” pattern), or even eosinophils can predominate in the infiltrate of PCALCL.[712] Cases with signet-ring cell morphology have also been reported.[712] There is no correlation between particular subtypes and clinical appearance.[12] Necrosis are sometimes seen.[12] Reed-Sternberg-like pleomorphic cells are uncommon.[1212] Focal epidermotropism can be seen.[1212] Other histological features are epidermal ulceration, prominent vascular proliferation, pseudoepitheliomatous hyperplasia, myxoid changes and vascular infiltration by neoplastic cells.[212] Granulomatous infiltrates are observed in a few cases.[2] Some cases are characterized by an increased number of mitosis and apoptosis with considerable apoptotic debris.[2]

Immunohistochemistry

Lymphoid cells in conventional cases of PCALCL express CD30 (more than 75% of cells) and variable degree of CD2, CD3, CD4, and CD5, and are usually negative for CD8, CD20, CD56, HSV, Epstein–Barr virus (EBV) and cytotoxic proteins.[1268910] According to recent literature, frequent expressions of cytotoxic proteins (granzyme B, T-cell restricted intracellular antigen-1 (TIA-1), perforin) are not uncommon.[1267] According to Massone et al., approximately one third of the cases of PCALCL present with profound T-cell phenotypic aberrations, which are more common than previously reported, thus representing a diagnostic pitfall and may be the cause of misdiagnoses.[6] A study by Massone et al. showed that 18% of PCALCL had a T-cytotoxic phenotype (CD4–/CD8+).[6] Although usually PCALCL are not positive for epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK), few cases can show positivity for EMA and ALK.[12713] Rare cases of PCALCL have previously reported to express CD56. CD56 expression has not been associated with an adverse clinical course.[27] In cutaneous T-cell lymphomas, the Ki-67 index is significantly higher in the high-grade group than the intermediate-grade group, and in the intermediate-grade group than the low-grade group. The high Ki-67 index is inversely proportional to survival period, biological behavior and clinical prognosis.[4510] The Ki-67 index not only correlates with the type and extent of skin involvement and clinical stage, but is also an independent adverse prognostic factor.[4510] DNA hybridization analysis indicates the proliferation of clonal T lymphocytes.[278]

Differentials

CD8+ CD30+ immunophenotype can be seen in other lymphomas, such as LYP type D, mycosis fungoides (MF), primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, systemic lymphomas involving the skin and primary cutaneous peripheral T-cell lymphoma, unspecified.[1261014] These entities are not included as distinct entities in the World Health Organization-European Organization for Research and Treatment of Cancer for cutaneous lymphomas. The distinction of different CD8+ CD30+ cutaneous lymphoproliferative disorder may not be possible on histopathologic ground alone. Clinico-pathological co-relation remains the cornerstone for specific diagnosis.[1261014] CD8+ LYP is clinically characterized by cyclic eruptions of small erythematous papulonodular lesions followed by spontaneous healing and scar formation. Histologically, CD8+ LYG shows epidermal changes of ulceration, spongiosis and parakeratosis, moderate to marked epidermotropism, epidermotropic small and large lymphocytes and wedge-shaped or diffuse sheet-like dermal infiltrate without extension to the subcutaneous tissue. The large atypical lymphocytes are fairly monomorphic and immunoblastic appearing cells with the background population of small lymphocytes. Interstitial, perivascular, perinuerial and periadnexal infiltrate of lymphoid cells are common. Lichenoid and nodular infiltrative patterns are uncommon. Vasculitis changes are strikingly common. Prominent histiocytic infiltrate imparting a granulomatous reaction can be seen. Dermal fibrosis is not strikingly common. Biopsies containing many eosinophils, neutrophils and plasma cells are uncommon. The CD30 positivity is found in 50% to 75% of cells in LYP.[123614] In MF, lesions are usually generalized. CD8+ MF with CD30 expression cases show a lichenoid pattern of infiltrate by small and large lymphoid cells with moderate to marked epidermotropism, perivascular accentuation and vacuolar interface change. Cellular atypia is of mild to moderate degree. Eosinophils, neutrophils and plasma cells are conspicuously absent. Dermal fibrosis is not seen. CD30 expression is focal and in less than 50% of cells in MF.[123614] Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a high-grade lymphoma characterized by generalized/multiple plaques and tumors that can sometimes ulcerate and can have mucosal involvement with an aggressive clinical course. Histologically, it presents with a nodular diffuse infiltrate with prominent epidermotropism by small and medium sized atypical cells. Perivascular and periadnexal infiltrate are common. A naïve CD45 RA phenotype is characteristic. CD30 is usually negative, but CD30 positivity might occur rarely.[123614] Primary cutaneous CD8+ T-cell lymphoma, unspecified, characteristically shows loss of T-cell markers but rarely express CD30 in the majority of neoplastic cells. Lack of epidermotropism and usually diffuse nodular (perivascular) infiltrate of atypical cells along with a rapidly progressive clinical course favors peripheral T-cell lymphoma, unspecified.[6] PCALCL differs from the systemic ALCL based on its clinical features, site of involvement and the absence of EMA and ALK-1 expression.[127] In the present case, systemic lymphoma was ruled out as the patient had no generalized lymphadenopathy, systemic involvement, B symptoms, and was negative for EMA and ALK. In the presence of the ALK expression, it is imperative to exclude systemic disease. Systemic ALCL can initially present as isolated cutaneous disease, even if no extracutaneous disease is found at presentation, so a close follow-up is mandatory in the presence of positive ALK.[1315]

Prognosis

Prognosis is generally excellent for CD30+ PCALCL, with a 5-year survival rate between 76% and 96%. CD8+ expression alone cannot be a hallmark for a poor prognosis.[1714] The outcome has been indicated to be the same as CD4+ PCALCL.[12367891011] The isolated cases of CD8+ PCALCL that follows an aggressive clinical course may need to be re-categorized under the category of CD30+ variant of aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma.[129] PCALCL with ALK-1 positive cases also show good prognosis.[1315] CD30– PCLCL is a much more aggressive neoplasm, with a 15% 5-year survival.[1714] It is necessary to closely monitor these patients because of the potential risk of dissemination, recurrence of the disease or even development of other malignancies.[1714]

Management

The standard management modalities for PCALCL include observation, surgical excision, or local radiation.[27] Large tumor burden, rapid progression of cutaneous lesion, and extracutaneous dissemination require systemic chemotherapy. Multifocal PCALCL tends to relapse after systemic chemotherapy and is generally considered more prone to progress to systemic disease.[11]

Conclusion

The diagnosis of PCALCL rests on early biopsy, good clinicopathological correlation including immunophenotyping. The cytotoxic cell-related proteins like CD8 should be included in the routine panel of antibodies that used to diagnose PCALCL. CD8+ PCALCL should be distinguished from other cutaneous CD8+ CD30+ T-cell lymphomas on the basis of histology, immunophenotyping and appropriate clinical context, which influences the management and prognosis. The high Ki-67 index is inversely proportional to survival period and clinical prognosis. Though CD8+ PCALCL has a good prognosis, it is necessary to closely monitor these patients because of the potential risk of recurrence, extracutaneous dissemination or even development of other malignancies.

What is new?

This article highlights and summarizes the histopathologic features and immunophenotype of CD8+ CD30+ PCALCL, which help its differentiation from other CD8+ CD30+ cutaneous lymphoproliferative disorders. Ki-67 is an independent prognostic marker in PCALCL. Strict clinico-pathologic correlation is mandatory before making a specific diagnosis of cutaneous lymphomas.