ALK-Negative Anaplastic Large Cell Lymphoma With Rare Scalp Involvement: A Case Report and Literature Review

Abstract

Anaplastic large-cell lymphoma (ALCL) is a rare type of T-cell lymphoma characterized by a clonal proliferation of atypical large cells. Here, we describe a 63-year-old man presenting with subcutaneous nodules on the scalp and anterior chest wall, right axillary lymphadenopathy, and systemic B symptoms. Positron emission tomography imaging revealed hypermetabolic activity in the scalp, chest wall, and axillary lymph nodes, suggestive of aggressive lymphoma. Histopathological analysis confirmed lymphoma with atypical large cells, and immunohistochemistry showed that both ALK and CD30 were negative, making the diagnosis atypical. This case illustrates the rarity of scalp involvement in ALK-negative ALCL and underscores the importance of a multidisciplinary approach, integrating clinical, imaging, and histological findings for accurate diagnosis and management.

Introduction

Anaplastic large-cell lymphoma (ALCL) is a type of T-cell lymphoma defined by the clonal expansion of large, pleomorphic cells with abundant cytoplasm and often horseshoe-shaped nuclei. ALCL shows high expression of CD30 and more sinusoidal and cohesive growth. ¹ The 2 main kinds of ALCL are systemic ALCL and primary cutaneous ALCL. Systemic ALCL can further be broken down into breast implant-associated ALCL, ALK-positive ALCL, and ALK-negative ALCL. ²

ALK-negative ALCL, which bears anatomical and clinical similarity to ALK-positive ALCL, does not express the ALK protein or exhibit rearrangements of the ALK gene. ALK-positive ALCL is usually less aggressive, but the ALK-negative type has a worse prognosis and is more aggressive than ALK-positive ALCL and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). ³

ALK-negative point hike in the development of ALCL, primarily targets adults, with a median age of 54 to 61 years and a male to female ratio (0.9:1). ALCL accounts for 3% to 5% of all non-Hodgkin lymphomas (NHLs) and 10% to 20% of lymphomas in children. ⁴

Clinically, most patients have B symptoms (fevers, night sweats, and weight loss), especially those with ALK-negative ALCL. Extranodal involvement is common; the breast is the most frequent site of extranodal ALK-negative ALCL, followed by the skin, bones, and muscles. Scalp invasion in patients with ALK-negative ALCL is extremely uncommon. ⁵

Case Presentation

This report describes a 63-year-old man with a striking clinical presentation of subcutaneous nodules on the scalp and anterior chest wall. The patient reported that these nodules had slowly increased in size over the past few months. He also presented with right axillary lymphadenopathy, characterized by warm, tender, and firm nodes, consistent with lymphatic involvement.

His medical history included hypertension, controlled with medications, and diabetes mellitus, managed with oral hypoglycemics. He had no personal history of cancer, no known exposure to toxins, and denied a family history of cancer or exposure to environmental hazards. Further evaluation revealed significant unintentional weight loss of ~10 kg over the past 3 months. The patient also experienced characteristic B symptoms, including persistent night sweats and low-grade fever. These systemic symptoms raised concerns about an underlying lymphoproliferative disease.

An excisional biopsy was performed on one of the subcutaneous nodules for histological analysis. The biopsy revealed tumor cell infiltration in the dermis and subcutaneous tissue, while the epidermis remained intact. Histological examination showed that the tumor was composed of large atypical pleomorphic cells, some with prominent nucleoli, accompanied by brisk mitotic activity. Immunohistochemical analysis demonstrated that the tumor cells were negative for CD30 and CD20 staining. Weak and focal positivity was observed on IHC staining, appearing brown in color. Furthermore, the tumor cells were diffusely positive for CD4 staining on the left side (Figure 1). Notably, the tumor was ALK-negative, a feature that differentiates ALK-negative from systemic ALCL, making this case uniquely challenging to diagnose.

Figure 1.

Histopathological examination showed (A) HE stains showed that the tumor is composed of large atypical pleomorphic cells, some of them with prominent nucleoli (green arrow). Brisk mitotic figures are also noted (red arrow). (B) The tumor cells infiltrate the dermis and the subcutaneous tissue (blue arrow), while the epidermis is preserved (red arrow). (C) This is CD20 stain is completely negative in the neoplasticism cells in the right side (labeled with green arrow) and also negative in the normally lining squamous epithelium (which labeled with red arrow). (D) This is CD5 IHC stain and showed membranous positive staining result in a part of the large neoplasticism cells as noted (red arrow). (E) This is CD4 IHC stain which showed diffuse cytoplasmic positive result in the neoplastic cells (red arrow). The attached squamous epithelium is negative (green arrow).

The patient underwent evaluation to determine the extent of disease involvement using a positron emission tomography (PET) scan. The PET scan revealed hypermetabolic activity in the bilateral scalp, anterior chest wall, and right axillary lymph nodes, as well as multifocal dermal and subcutaneous soft tissue thickening with high FDG uptake in the form of plaques (Figure 2).

Figure 2.

Red arrow shows hypermetabolic activity in the left posterior focal dermal and subcutaneous soft tissue thickening and plaques of intense FDG uptake: (a) axial PET brain, (b) axial brain CT, (c) brain axial fusion Positron Emission Tomography – Computed Tomography (PET-CT) scan, (d) coronal PET scan, (e) sagittal PET scan. PET, positron emission tomography.

The patient was treated with 6 cycles of Cyclophosphamide, Doxorubicin, Vincristine, Etoposide, and Prednisone (CHOEP), along with supportive care measures, including fluids, allopurinol, and aspirin. Posttreatment imaging demonstrated resolution of hypermetabolic activity in the scalp and chest wall nodules; however, residual activity persisted in the right axillary lymph node, and a new hypermetabolic lesion appeared in the right inguinal lymph node. A biopsy was recommended to evaluate disease progression or response to treatment. Despite these efforts, the patient’s condition deteriorated, and he passed away due to a sudden myocardial infarction.

Discussion

Systemic ALK-negative ALCL is an aggressive and rare subtype of NHL, accounting for around 2% of all NHL cases and ~12% of T-cell lymphomas. ⁶

The diagnosis of ALK-negative ALCL relies on clinical evaluation, histology, and immunophenotyping. Histologically, ALK-negative ALCL typically exhibits a cohesive growth pattern with extensive sinus involvement and is characterized by anaplastic cells that may demonstrate greater anaplasia compared to other T-cell lymphomas. Hallmark cells are present in many cases, though they are generally less frequent. Immunophenotypically, ALK-negative ALCL is characterized by CD30 expression, with variable results for CD15 and BCL-2, the latter being absent in in ALK-positive cases. ⁷ Other features include aberrant T-cell markers, often accompanied by the loss of pan-T-cell antigens such as CD3. Clusterin expression can help differentiate ALK-negative ALCL from other T-cell lymphomas, such as PTCL-NOS. Additionally, CD30 expression is not always definitive for diagnosing ALK-negative ALCL, as some cases may be CD30-negative. ⁸ In our case, the tumor was also CD30-negative, which makes the diagnosis more challenging and highlights the complexity in differentiating ALK-negative ALCL from other T-cell lymphomas with overlapping histologic and immunophenotypic features.

Lymphoma primarily affects adults, with a median age of 54 to 61 years and a male-to-female ratio of 0.9. At presentation, ALK-negative ALCL is often in stages III to IV and is associated with B symptoms, high International Prognostic Index (IPI) scores, and elevated Lactate dehydrogenase (LDH) levels in more than 50% of cases. The disease typically follows an aggressive course. Lymph node involvement is observed in ~50% of cases, while extranodal spread occurs in about 20%. These findings reaffirm that the clinical manifestations of ALK-negative ALCL tend to be unpredictable, ⁹ with the breast being the most common site of extranodal involvement. ⁵ Scalp involvement in ALK-negative ALCL is rare. ¹⁰ In our case, a 46-year-old male patient presented with subcutaneous nodules on the scalp and anterior chest wall, accompanied by right axillary lymphadenopathy and classic B symptoms. These features are consistent with the clinical presentation of ALK-negative ALCL. PET revealed hypermetabolic activity in the bilateral scalp, anterior chest wall, and right axillary lymph nodes, confirming the extent of the disease and supporting the diagnosis.

The prognosis of ALK-negative ALCL is generally poorer compared to its ALK-positive counterpart due to its aggressive clinical course. ¹¹ Patients often present with advanced-stage disease (stages III-IV), B symptoms, and high-risk IPI scores, all of which are associated with poorer outcomes. The overall survival rates are significantly lower, with 5-year survival rates of only 40% to 60% compared to 70% to 90% for ALK-positive ALCL. ¹²

While overall survival rates for ALK-positive ALCL have been reported as 70% to 90%, the overall survival rates for ALK-negative ALCL are markedly lower, at <50%. CD8 expression in ALCL correlates with noncommon morphologic variants and T-cell antigen expression suggesting biological differences with CD8-negative ALCL. ¹³

The prognosis of ALK-negative ALCL depends on clinical scores and biomarkers. The PIT score, incorporating age, performance status, LDH, and bone marrow involvement, predicts survival. ¹⁴ Poor outcomes are linked to extranodal disease, elevated β2-microglobulin, liver involvement, low albumin, and high IPI scores. CD56 expression and bone marrow infiltration also indicate worse survival. These factors highlight its aggressive nature and the need for tailored treatment strategies. ⁹

There is no known optimal therapy for ALK-negative ALCL due to disease rarity, heterogeneity of clinical presentation, and lack of randomized trials focused on this lymphoma. The standard first-line treatment for systemic ALCL is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The standard therapy for patients with relapsed or refractory disease has not been established. ¹⁵ Newer approaches include targeted therapy such as brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate used for relapsed/refractory systemic ALCL. ¹⁶

Our literature review indicates that scalp lymphoma, particularly ALCL, is rarely reported in the literature, as summarized in (Table 1). Cases span a wide age range, from children as young as 13 months to adults, predominantly between 50 and 70 years. Treatment typically involves chemotherapy (eg, CHOP, HyperCVAD, Brentuximab vedotin, Cyclophosphamide, Doxorubicin, and Prednisone (BV-CHP)), with radiation therapy used for localized lesions and surgical excision for extensive scalp involvement. Additional therapies include photochemotherapy (Psoralen and Ultraviolet A (PUVA)) for cutaneous lesions and autologous stem cell transplantation for consolidation in remission cases.

Table 1.

Review of 11 Cases of ALCL.

Title	Date of publication	Age of presentation	Treatment and outcome	References
Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma manifesting as a scalp hematoma after an acute head injury—a case report and literature review	April 2016	84 y	Chemotherapy with bendamustine and dexamethasone, radiation therapy (45 Gy in 29 fractions); outcome: death due to pneumonia and sepsis within 2 mo	Yeung et al 5
Posttransplant primary cutaneous Ki-1 (CD30)+/CD56+ anaplastic large cell lymphoma	August 2004	56 y	Initial reduction in immunosuppressive therapy, radiation therapy (5000 rad for 4 wk), chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone; outcome: complete remission for 6 mo after 6 cycles	Kim et al 17
Carcinoma and multiple lymphomas in one patient: establishing the diagnoses and analyzing risk factors	July 2009	62 y	Sequential treatment including chemotherapy (rituximab, ifosfamide, carboplatin, etoposide), radiotherapy, and nonmyeloablative allogeneic stem cell transplant; outcomes: mixed responses to various malignancies, including periods of remission and progression	Cannizzo et al 18
Neutrophil-rich anaplastic large cell lymphoma of T-cell lineage: a report of two cases arising in HIV-positive patients‏	Unspecified	41 y 44 y	Both patients receive CHOP chemotherapy: 2 cycles for patient 1 and 4 cycles for patient 2. Both patients died duo to infection within 6 mo	Jhala et al 19
Anaplastic lymphoma kinase-negative primary systemic anaplastic large cell lymphoma mimicking a ruptured epidermal cyst of the scalp: a case report and literature review	October 2024	77 y	Wide surgical excision followed by skin grafting, and chemotherapy with BV-CHP regimen; outcome: no recurrence or complications at 6-mo follow-up	Ahn et al 20
DUSP22-IRF4 rearrangement in AIDS-associated ALK-negative anaplastic large cell lymphoma	September 2019	53 y	HyperCVAD chemotherapy followed by brentuximab vedotin monotherapy; outcome: complete remission sustained for 1 y with improved immune profile	Wang et al 21
CD30-positive primary cutaneous anaplastic large cell lymphoma with coexistent pseudocarcinomatous hyperplasia	2018	75 y	PUVA photochemotherapy; outcome: almost complete clearance of lesions but patient lost to follow-up	Kreuter et al 22
Primary cutaneous histiocyte and neutrophil-rich CD30+ and CD56+ anaplastic large-cell lymphoma	2006	57 y	6 Cycles of CHOP chemotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation; outcome: complete remission sustained for more than 6 y	Boudova et al 23
Cutaneous anaplastic large T-cell lymphoma with invasion of the central nervous system	2017	74 y	CHOP chemotherapy; outcome: regression of lesions but death due to pneumonia during pancytopenic period	Seo et al 24
Primary cutaneous CD30-positive anaplastic large cell lymphoma in childhood	2005	13 mo	Excision of scalp tumor followed by intravenous chemotherapy; outcome: clinical remission for 6 mo, then relapse with multiple skin lesions	Kumar et al 25
Anaplastic large cell lymphoma—a great mimic on cytology	2017	19 y	The patient was started on chemotherapy and lesions regressed (not provided any details about the treatment), the patient succumbed 8 mo after diagnosis	Agnihotri et al 26

Abbreviations: ALCL, anaplastic large cell lymphoma; BV, brentuximab vedotin; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; PUVA, psoralen ultraviolet A.

Treatment outcomes for scalp ALCL vary widely. While some patients, such as a 53-year-old treated with chemotherapy and BV, achieved sustained remission, others experienced relapses, as seen in a 13-month-old child who relapsed within 6 months. Complications, particularly infections such as pneumonia and sepsis, were common and often fatal, especially in patients undergoing aggressive chemotherapy or stem-cell transplantation. Older patients, like an 84-year-old, had poorer prognoses with shorter survival times due to these complications. This highlights the critical importance of managing infections and immune suppression during ALCL treatment.

Scalp ALCL poses significant treatment challenges, with outcomes influenced by age, treatment approach, and complications. While remission is achievable, the risks of infection and relapse are substantial, particularly in elderly or immunocompromised patients. Further research is needed to optimize treatment, enhance survival, and reduce infection-related mortality.

Conclusion

This case illustrates the diagnostic challenge of ALK-negative ALCL, an uncommon and aggressive form of NHL. Scalp involvement, subcutaneous nodules, and systemic B symptoms in the presentation are extremely rare. Atypical large cells were identified on histology, but other features were absent, as immunohistochemistry showed both ALK and CD30 negativity. PET imaging revealed extensive disease. This case highlights the crucial need to combine these modalities with histology and immunophenotyping to guide diagnosis and management.