ALK-negative anaplastic large cell lymphoma mimicking a soft tissue sarcoma.

Anaplastic lymphoma kinase protein (ALK)-negative anaplastic large cell lymphoma (ALCL) has a vast morphologic spectrum and may mimic many other types of malignancies both cytologically and histologically. There are only a few published case reports/series describing the cytomorphologic features of ALCL on fine-needle aspiration (FNA) biopsy specimens. We describe a case of ALK-negative ALCL mimicking a high-grade soft tissue sarcoma of the thigh in a 62-year-old man. The characteristic morphologic findings on FNA and core biopsy along with the immunophenotypic profile are described and reviewed. The diagnosis of ALCL on FNA biopsy may be difficult, but can be done successfully with the use of ancillary tests. Therefore, it must be considered in the differential diagnosis of lesions with pleomorphism, anaplasia, and wreath-like or horseshoe-shaped nuclei to ensure that adequate material is obtained for ancillary studies.

Introduction

Anaplastic lymphoma kinase protein (ALK)-negative anaplastic large cell lymphoma (ALCL) is defined by the World Health Organization (WHO) as a CD30-positive T-cell lymphoma that is morphologically indistinct from ALK-positive ALCL.[1] As opposed to ALK-positive ALCL which typically occurs in children and young adults, the ALK-negative neoplasm occurs more commonly in adults with a median age of 58 years and has a worse prognosis.[2] It can involve lymph nodes and extranodal sites including skin, soft tissue, and the gastrointestinal tract.[2] The tumor is composed of large pleomorphic cells, some with prominent nucleoli and multinucleation, and shows a variable number of “hallmark” cells with horseshoe-shaped or kidney-shaped nuclei.[1] Morphologically, ALCL may mimic other types of lymphoma and may grow in a cohesive pattern mimicking nonhematologic malignancies such as sarcomas, carcinomas, germ cell tumors, and melanoma. Because the morphologic spectrum is so vast, the diagnosis of ALCL on fine-needle aspiration (FNA) cytology may pose a challenge to pathologists. We describe a case of ALCL mimicking a high-grade sarcoma on FNA cytology.

Case Report

The patient is a 62-year-old man with a history of type-2 diabetes mellitus, hypertension, chronic inflammatory demyelinating polyneuritis, and Cushing's disease secondary to incomplete resection of a pituitary adenoma. He presented with deep vein thrombosis of the left leg with a subsequent episode 1 month later. At that time, a soft tissue mass was noted in the left thigh.

On physical examination, there was an approximately 6 cm mobile, irregular, firm mass located in the medial left thigh. Inguinal adenopathy and organomegaly were absent. Magnetic resonance imaging showed a lobular 6.3 × 5.4 × 3.4 cm mass in the medial subcutaneous fat of the proximal/mid left thigh. The mass was slightly hyperintense to muscle and demonstrated homogenous enhancement with a small area of hypoenhancement, suggestive of necrosis. It displaced the underlying musculature posterolaterally and appeared to extend to the skin. The differential diagnosis included synovial sarcoma, malignant fibrous histiocytoma (MFH), dermatofibrosarcoma protuberans, and nerve sheath tumor with malignant degeneration.

An ultrasound-guided FNA biopsy of the mass was performed using a 22-gauge needle. Four smears were fixed in 95% ethanol and stained using the Papanicolaou method, and four smears were air-dried and stained with modified Giemsa (Diff-Quik) (Differential Stain Kit, Newcomersupply, Middleton, WI). A compact cell block was prepared. A concurrent 18-gauge core needle biopsy (CNB) was also performed. Additional material was submitted for flow cytometry (FC) using standard techniques.

The FNA smears showed numerous discohesive, atypical round to polygonal to spindled cells with pleomorphic nuclei [Figure 1]. Scattered cells had abundant cytoplasm with multinucleation and prominent nucleoli best visualized on Papanicolaou stains. There were a few cells with nuclei with a wreath-like appearance [Figure 2]. Scattered mitotic figures were present. Inflammatory cells and lymphoglandular bodies were not identified. A high-grade sarcoma with a differential diagnosis of rhabdomyosarcoma and MFH was favored. Other diagnoses entertained were metastatic poorly differentiated carcinoma, melanoma, and high-grade non-Hodgkin lymphoma including anaplastic lymphoma.

Figure 1

Smear shows discohesive cells with pleomorphic nuclei and varying amounts of cytoplasm. Mitotic figures are noted by arrows (Diff-Quick stain, ×400)

Figure 2

Smear shows a cell with a wreath-like nucleus in the center. Prominent nucleoli are noted (Papanicolaou stain, ×400)

The concurrent CNB [Figure 3] showed dense connective tissue with a nodular and diffuse infiltrate composed of large cells with amphophilic cytoplasm and single, bi-, and multinucleation. Several horseshoe-shaped nuclei were noted. There were numerous mitotic figures. This was similar to the material obtained on the cell block preparation.

Figure 3

Section of the core needle biopsy shows cells with abundant amphophilic cytoplasm and pleomorphic nuclei, some with horseshoe-shaped and wreath-like nuclei (center) (H and E, ×500)

Immunohistochemistry (IHC) showed that the neoplastic cells were focally positive for CD2 and strongly positive for CD30 [Figure 4] with weak positivity for granzyme-B. The cells were negative for CD3, CD15, CD20, EMA, and ALK-1. FC detected a large population of atypical T-cells that were positive for CD2 and negative for CD3, CD4, CD8, CD38, CD138, and B-cell, monocytic, and myeloid markers. The final diagnosis was ALK-negative T-cell ALCL.

Figure 4

Immunohistochemical staining for CD30 shows strong cytoplasmic staining in the neoplastic cells (IHC, ×400)

Discussion

There are only a few case reports/series describing the cytomorphologic features of ALCL on FNA biopsy.[3-6] The largest series reported by Rapkiewicz et al.[3] reviewed 37 patients with ALCL of which only 13 cases were diagnosed initially as ALCL on FNA cytology specimens. The remainder of the diagnoses included non-Hodgkin lymphoma, Hodgkin lymphoma, nondiagnostic, atypical lymphocytes, and malignant neoplasm with a broad differential diagnosis of lymphoma, anaplastic carcinoma, and sarcoma. There was a variable degree of cellular pleomorphism and number of anaplastic cells on the FNA smears. The characteristic hallmark cells were found in only 11 of 20 reviewed aspiration specimens, of which eight cases had wreath-like multinucleated giant cells. Lymphoglandular bodies were not present in non-lymph node specimens. The study concluded that although difficult, ALCL can be accurately diagnosed on FNA specimens when aided by ancillary studies such as IHC.[3]

Our case showed similar cytomorphologic findings as some of the previously reported cases. A definitive diagnosis was established with FC and IHC. In general, FC and IHC can both be easily performed on aspirated material or concurrent CNB, depending on the preference of the individual laboratory. In our laboratory, CNB is the preferred method for the first time diagnosis of suspected lymphoid lesions based on immediate on-site evaluation of the aspirated material. Therefore, although the cell block was adequate, IHC was done on the concurrent CNB in this case.

In summary, diagnosing ALCL on FNA cytology is difficult given the spectrum of cytomorphologic findings but may be successfully done with the aid of ancillary tests, such as IHC and FC. The cytomorphologic features and immunocytochemical profiles of the most common entities in the differential diagnosis of ALCL on FNA cytology are listed in Table 1. It is important for cytopathologists to consider ALCL in the differential diagnosis of lesions characterized predominantly by discohesive, pleomorphic cells especially when anaplasia and/or horseshoe-shaped or wreath-like nuclei are present, and it is therefore essential to obtain adequate material for ancillary testing at the time of the procedure. This can be either in the form of additional passes for FC and cell block for FNA samples or concurrent CNB.

Table 1

Cytomorphologic and immunocytochemical features of the differential diagnoses of anaplastic large cell lymphoma