Mantle cell lymphoma presenting primarily as cutaneous lesions: A case report

Abstract

BACKGROUND

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma that rarely presents with cutaneous involvement, which typically occurs in advanced disease stages. Primary cutaneous manifestations are particularly uncommon and frequently misdiagnosed. We report a diagnostically challenging case of MCL that first appeared as a nodule on the lower leg.

CASE SUMMARY

An elderly female had a painless red nodule on the front of her right lower leg for six months. Positron emission tomography-computed tomography showed a soft tissue mass at the same site and increased activity in the right groin lymph nodes. Skin and lymph node biopsies, along with immunostaining, confirmed MCL. The patient began combination chemotherapy, resulting in a marked improvement of skin lesions and lymphadenopathy after two weeks.

CONCLUSION

Cutaneous manifestations, though uncommon, may serve as the initial clinical presentation of MCL. Dermatologists and pathologists should maintain heightened awareness of this diagnostic possibility when evaluating persistent, atypical cutaneous nodules, particularly in elderly patients. Histopathological evaluation with complete immunophenotypic profiling is paramount for accurate diagnosis.

Key Words: Mantle cell lymphoma; Skin neoplasms; Lymphoma; B-cell; Immunohistochemistry; Case report

Core Tip: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell lymphoma that rarely involves the skin. When cutaneous involvement occurs, it often indicates advanced systemic disease and is associated with a poor prognosis. This case emphasizes the difficulty in differentiating cutaneous MCL from other similar lymphomas, such as diffuse large B-cell lymphoma, leg-type. Accurate diagnosis relies heavily on immunophenotypic markers, particularly cyclin D1 and SOX11. Therefore, a comprehensive approach integrating clinical findings, histopathology, and molecular studies is vital for timely diagnosis, appropriate treatment, and improved patient outcomes.

INTRODUCTION

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma derived from mature B cells, representing 3%-10% of all such cases[1]. While MCL predominantly affects lymph nodes and frequently involves extranodal sites-such as the bone marrow, spleen, and liver-cutaneous manifestations are exceedingly rare[2]. We describe an unusual case of MCL that first presented as a solitary skin nodule on the lower leg. Furthermore, we conducted a review of published cases to summarize the clinical characteristics of MCL with skin involvement.

CASE PRESENTATION

Chief complaints

A 74-year-old Chinese woman presented to the dermatology department with a solitary, asymptomatic red nodule on the front of her right lower leg, present for six months.

History of present illness

The lesion initially was small but progressively enlarged to approximately 6 cm × 4 cm. The nodule had a smooth surface, a firm consistency, and no signs of ulceration, itching, or tenderness.

History of past illness

Seven years earlier, the patient underwent bilateral thyroidectomy for papillary thyroid carcinoma, with subsequent neck lymph node dissection one year later for metastatic disease.

Personal and family history

No relevant family history of malignancy was noted.

Physical examination

On examination, a solitary, asymptomatic red nodule, approximately 6 cm × 4 cm, was found on the front of her right lower leg. The nodule exhibited a smooth surface and firm consistency, without ulceration, itching, or tenderness (Figure 1).

Figure 1 Clinical presentation. A solitary, erythematous nodule measuring 6 cm × 4 cm on the anterior aspect of the right lower leg, demonstrating smooth surface morphology and firm consistency.

Laboratory examinations

No abnormalities were detected in routine blood tests, urinalysis, or liver/kidney function tests.

Imaging examinations

Ultrasound examination identified a 25 mm × 9 mm × 25 mm hypoechoic subcutaneous mass in the mid-right lower leg displaying poorly defined borders and irregular shape. The surrounding area showed enhanced echogenicity with abundant peripheral blood flow signals (Figure 2). Concurrently, imaging studies revealed multiple enlarged lymph nodes in the right inguinal region, with the largest measuring 30 mm × 13 mm. These nodes showed asymmetric cortical thickening and punctate/Linear vascular signals (Figure 2).

Figure 2 Ultrasound imaging of the right lower leg mass and right inguinal lymph nodes. A: A hypoechoic subcutaneous mass (25 mm × 9 mm × 25 mm) in the mid-right lower leg, exhibiting irregular margins and an ill-defined shape; B: The adjacent tissue demonstrates increased echogenicity, accompanied by prominent peripheral vascularity; C: Multiple enlarged lymph nodes are observed in the right inguinal region, with the largest measuring 30 mm × 13 mm and showing asymmetrical cortical thickening; D: Intranodal blood flow appears as punctate/Linear vascular signals.

Positron emission tomography- computed tomography (PET-CT) imaging demonstrating intense fluorodeoxyglucose uptake in both the cutaneous lesion and right inguinal lymph nodes, consistent with lymphoma involvement. There was no abnormal uptake or reduction in other soft tissues or bones (Figure 3).

Figure 3 Positron emission tomography-computed tomography imaging findings. Coronal view demonstrating fluorodeoxyglucose-avid soft tissue mass in the right lower extremity (SUVmax 15.95). Axial view showing multiple hypermetabolic right inguinal lymph nodes (SUVmax 10.54). Both are consistent with lymphomatous involvement.

Further diagnostic work-up

Biopsy of the skin nodule on the right lower leg revealed mild thickening of the epidermal stratum spinosum, with a clear separation between the epidermis and the dermis. The dermis and subcutaneous fat were densely infiltrated by lymphoid cells. These cells exhibited large, irregular nuclei with abnormal features and occasionally underwent cell division. Immunohistochemical analysis demonstrated positivity for CD20, CD79a, PAX5, Bcl-2, CD5, Cyclin D1, and SOX11. Partial positivity was observed for Bcl-6, while C-MYC was positive in scattered small areas. Markers including CD3, CD10, CD21, CD43, and MUM-1 were negative. The proliferation rate, indicated by Ki-67, reached about 60% in the most active areas. Testing for Epstein-Barr virus was negative (Figure 4). Genetic analysis confirmed clonal rearrangements for TCRG, IgH, and IgK.

Figure 4 Histopathological and immunohistochemical results of the nodule. A: Mild thickening of the epidermal stratum spinosum, with a clear separation between the epidermis and the dermis [hematoxylin & eosin (H&E), × 400]; B: The dermis and subcutaneous fat were densely infiltrated by lymphoid cells. These cells exhibited large, irregular nuclei with abnormal features and occasionally underwent cell division (H&E, × 400); C-I: Tumor cells were diffuse positive for (C) CD20 (× 400), (D) CD79a (× 400), (E) PAX5 (× 400), (F) Bcl-2 (× 400), (G) CD5 (× 400), (H) Cyclin D1 (× 400), and (I) SOX11 (× 400); J and K: C-MYC shows scattered small focal areas of positivity (× 400); L: Ki-67 hotspots exhibit approximately 60% positivity (× 400).

A fine needle biopsy of the right inguinal lymph node showed a proliferative lymphoid lesion mainly composed of medium-sized lymphoid cells, some with atypical features. Immunohistochemistry confirmed positivity for CD20, CD79a, CD5, Cyclin D1, and SOX-11, with approximately 70% of cells positive for Bcl-2. Other markers including CD3, CD10, CD21, CD23, CD43, and Bcl-6 were negative. The Ki-67 proliferation index was about 70%. Epstein-Barr virus testing was again negative. Genetic studies identified clonal rearrangements involving IgH and IgK genes.

Bone marrow examination showed no abnormalities.

FINAL DIAGNOSIS

Considering the clinical findings and pathological analysis, the patient was diagnosed with mantle cell lymphoma, classified as Ann Arbor stage IIE/A[3].

TREATMENT

The patient was referred to the Oncology to receive R-CHOP chemotherapy (rituximab 700 mg d1, cyclophosphamide 1300 mg d1, pirarubicin 85 mg d1, vincristine 2 mg d1, prednisone 100 mg d1-5 q3w). However, after two cycles, significant chemotherapy-related side effects prompted a change in therapy to orelabrutinib (150 mg qd). A follow-up PET-CT scan conducted after four months of orelabrutinib treatment showed mixed responses. The lesion in the lower leg demonstrated reduced size and decreased glucose metabolism (Deauville score: 5). Meanwhile, the right inguinal lymph node lesions exhibited a partial increase in size but a reduction in metabolic activity. Additionally, a new lesion emerged near the right external iliac vessels. In response to these findings, the treatment regimen was adjusted to R-Len (rituximab 620 mg d1, lenalidomide 20 mg qd d1-21 q4w). The patient has now completed 2 cycles of this regimen.

OUTCOME AND FOLLOW-UP

Most recent PET-CT evaluation revealed stable disease in the right lower leg tumor lesion (Deauville score: 5), while demonstrating complete metabolic response in both the right inguinal and external iliac lymph node lesions with no detectable F-18 fluorodeoxyglucose avidity, suggesting successful treatment response at these sites. The patient continues regular follow-up monitoring in our outpatient clinic for planned periodic reassessments.

DISCUSSION

This case demonstrates MCL presenting as a smooth, firm, red nodule on the anterior right lower leg of an elderly woman. Such cutaneous manifestations are frequently misdiagnosed as diffuse large B-cell lymphoma, leg-type (DLBCL-LT), given their overlapping clinical and histopathological features. Accurate diagnosis requires careful immunophenotypic analysis. MCL typically expresses B-cell markers (CD20, CD79a, PAX5) alongside CD43, CD5, cyclin D1, and SOX11. While CD10 and BCL-6 are usually negative, they may be present in more aggressive variants. Although CD5 positivity aids in distinguishing MCL from other B-cell lymphomas, approximately 10% of cases lack CD5 expression, necessitating reliance on cyclin D1 as a key diagnostic marker[4]. Cyclin D1 overexpression, driven by the t(11;14)(q13;q32) translocation, is a molecular hallmark of MCL, present in over 95% of cases[5]. SOX11 has emerged as a valuable supplementary marker, particularly in CD5- or cyclin D1-negative cases[6]. Further confirmation can be achieved through fluorescence in situ hybridization to detect CCND1 rearrangements and the t(11;14) translocation[2,7]. In this patient, the diagnosis of cutaneous mantle cell lymphoma was confirmed by pathological examination of both skin and lymph node biopsies alongside typical immunohistochemical findings, underscoring the importance of integrating these methods for accurate diagnosis.

Cutaneous involvement in MCL is rare, occurring in approximately 1% of cases, and typically signifies advanced disease with poor prognosis[2]. A comprehensive review of published English-language cases reveals that MCL can manifest in any area of the skin, most frequently on the trunk, followed by the lower limbs, upper limbs, and face. Cutaneous lesions in MCL may present as solitary or multiple lesions, most commonly appearing as nodules, papules, macules, or plaques. In contrast, bullae[8], ulcers[9], and melanocytic lesions[10] are rare. Most patients already have systemic involvement when skin lesions appear, with only seven reported cases of skin-only MCL without evidence of systemic disease (Table 1). However, due to limited follow-up duration, the existence of primary cutaneous MCL remains to be debated.

Table 1 Skin mantle cell lymphoma have been reported without any evidence of systemic involvement.

Case	Ref.	Sex/age	Localization	Type of skin lesion
1	Bertero et al[13], 1994	Female/78	Breast, back	Nodules
2	Bertero et al[13], 1994	Male/22	Breast	Nodules
3	Sen et al[14], 2002	Male/76	Thigh	Solitary nodule
4	Estrozi et al[15], 2009	Male/72	Temporal region	Nodule
5	Zattra et al[16], 2011	Male/77	All body areas	Nodules, plaques
6	Lynch et al[17], 2012	Male/83	Thighs	Nodules
7	Zheng et al[18], 2020	Male/74	Trunk, scrotum	Nodules, plaques

The current standard care for MCL relies on combination chemotherapy, with common regimens including hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). The addition of anti-CD20 therapy (rituximab) has demonstrated a marked survival benefit in a study of orbital MCL (5-year overall survival rates of 83% vs 8%)[11]. For relapsed or refractory disease, novel therapeutic options such as Bruton’s tyrosine kinase inhibitors, proteasome inhibitors, immunomodulatory drugs, purine analogs, and CAR-T cell therapy have expanded the treatment landscape[12]. However, clinical outcomes remain suboptimal. Among patients with cutaneous involvement, the median overall survival is 69 months, with a median interval of 24.3 months from skin manifestation to death or last follow-up. Notably, survival outcomes do not differ significantly between patients who initially present with cutaneous lesions and those who develop them during disease relapse or progression[10].

CONCLUSION

In summary, MCL represents an aggressive malignancy where cutaneous involvement typically signifies advanced systemic disease and carries an unfavorable prognosis. While exceptionally uncommon, as illustrated by our case, skin manifestations may occasionally serve as the presenting feature. The pathological distinction between MCL and DLBCL-LT poses significant diagnostic challenges, necessitating careful immunohistochemical analysis for accurate differentiation.

ACKNOWLEDGEMENTS

The authors thank the patient and her family for their assistance.