Dermatology Online Journal

Primary cutaneous CD30+ T-cell lymphoproliferative disorder presenting as paraphimosis: A case report and review of the literature
Patricia Moody McNab MD¹, Drazen M Jukic MD PhD², Omie Mills MD¹, Irwin Browarsky MD¹
Dermatology Online Journal 17 (7): 3

1. Department of Pathology and Cell Biology, University of South Florida, Tampa, Florida. pmoody@health.usf.edu
2. James A Haley VA Hospital, Pathology and Laboratory Medicine Section, Tampa, Florida

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Abstract

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma. More specifically primary cutaneous anaplastic lymphoma (PC-ALCL), one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. We report an unusual presentation of PC-ALCL. A 90-year-old, uncircumcised male presented with a 3-week history of painful penile swelling and discharge. The patient was treated with cephalexin and underwent emergent circumcision for paraphimosis. The diagnosis of ALCL was made on microscopic evaluation of the foreskin along with follow-up staging studies. A literature review revealed 31 previously reported cases of penile lymphoma, one of which reported a primary penile CD30+ T-cell lymphoma similar to ours. Only one case report described a lymphoma presenting as paraphimosis. Our case is the second reported case of PC-ALCL of the penis and the first of its kind to present as paraphimosis. Lymphomas must be included in the differential diagnosis of penile lesions and paraphimosis. When present, clinicians should be able to differentiate primary cutaneous lymphoma from lymphomas with secondary skin involvement. All foreskins should be submitted to pathology for proper evaluation of penile lesions.

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Introduction

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma, comprising 30 percent of the total number of cases. More specifically PC-ALCL, one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. There is a spectrum of disease ranging from lymphomatoid papulosis (LyP) to primary cutaneous anaplastic large-cell lymphoma (PC-ALCL). There is also a subset of borderline cases, which comprise the instances in which a clear distinction between PC-ALCL and LyP cannot be made [1, 2, 3].

PC-CD30+ LPD lesions frequently affect the trunk, face, extremities, and buttocks. Although they exhibit similar distribution, lesions of LyP are generally diffuse, whereas those of PC-ALCL are more likely to be solitary. LyP lesions are generally less than 3 cm; PC-ALCL lesions are usually larger [4, 5]. Clinically, the lesions of LyP characteristically come and go (wax and wane) with or without therapy, but the lesions of PC-ALCL show a more protracted course without waxing and waning.

LyP and PC-ALCL exhibit significant overlap, both histologically and immunohistochemically, because each exhibit large atypical T-cells that are positive for CD30. However, there are several markers more commonly expressed in PC-ALCL than in LyP. These include: CD193 (83% vs 38%), CD194 (92% vs 15%), and RANTES (Regulated on Activation, Normal T Expressed and Secreted; 92% vs 54%). Interestingly, CD194 is thought by some to represent a marker for malignant transformation [6]. Conversely, CD184 is observed more often in LyP than in PC-ALCL (85% vs 8%) [7]. Tumor cells in lymphomatoid papulosis have been known to express cytotoxic molecules such as CD56, TIA-1(T-cell-restricted intracellular antigen-1), and granzyme B [8]. Thus, although many of the above markers weigh in favor of PC-ALCL, no one marker is entirely specific.

Ultimately, the discrimination between LyP and PC-ALCL may be artificial; some cases of LyP progress to PC-ALCL. In addition, both processes can spontaneously remit [4, 9]. In either case both diagnoses portend a relatively good prognosis. Patients with LyP have 5-year survival rates near 100 percent. Those with PC-ALCL follow close behind, with 5-year survival rates of 90 percent [10]. Below, we present an extremely rare presentation of a PC-CD30+ LPD.

Results: Report of a Case

A 90-year-old, retired, uncircumcised male with history of diabetes, coronary artery disease, and hypertension, presented with a 3-week history of mildly painful swelling of the penis with minimal discharge and one episode of mild bleeding, which subsided spontaneously. Physical exam revealed an erythematous penis with edema extending to the mid-shaft and a markedly indurated foreskin which could not be retracted during the physical examination. The visible glans was without lesions and there were no palpable testicular masses. No adenopathy was appreciated. Clinically, the patient was diagnosed with balanitis. Cephalexin was administered and the patient underwent emergency circumcision.

Figure 1	Figure 2
Figure 1. A dense nodular infiltrate of atypical lymphocytes involves the dermis and exhibits foci of epidermotropism (H&E, x100). Figure 2. The tumor cells extend into the subcutis and are seen here involving the wall of a blood vessel (H&E, x100).

Figure 3
Figure 3. Large, loosely-cohesive atypical cells with ample cytoplasm, large irregular nuclei, and prominent nucleoli occupy the dermis. Numerous mitoses are present (H&E, x400).

Although gross observation of the foreskin was unremarkable, microscopic evaluation of a frozen section demonstrated a dense lymphoid infiltrate. Permanent sections revealed foci of mononuclear cells, some of which were atypical, involving the epidermis, dermis, and subcutis (Figures 1 and 2). On higher power, the lesion exhibited a dense, loosely cohesive population of predominantly large cells with prominent nucleoli and numerous mitoses (Figure 3).

Figure 4	Figure 5
Figure 4. Immunohistochemical staining with CD30 is positive in approximately 75 percent of tumor cells with minimal background staining. There is little variability in the staining pattern of the positive cells (CD30, x400). Figure 5. Immunohistochemical staining for ALK is negative. CD30+ LPDs do not carry the t(2;5) translocation involving the ALK gene (ALK, x400).

Figure 6
Figure 6. Unlike S-ALCL, most CD30+ LPDs do not express EMA (EMA, x400).

Immunohistochemical staining of the atypical, large, neoplastic cells exhibited CD30 positivity in >75 percent of neoplastic cells (Figure 4). Immunohistochemical stains for pan-keratin, CD20, ALK (Anaplastic Lymphoma Kinase; Figure 5), EMA (Epithelial Membrane Antigen; Figure 6), and CD3 antigen were negative. Additional stains for LCA, CD43 antigen, and Granzyme B were positive, with only weak CD5 positivity. T-cell receptor beta chain gene rearrangement studies were positive. Further clinical work-up revealed no apparent systemic involvement. In light of these unsuspected findings, a diagnosis of PC-CD30+ LPD, most suggestive of PC-ALCL, was rendered. Subsequently, within three months, the patient expired of natural causes unrelated to his lymphoproliferative disorder.

Discussion

1. PC-ALCL

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PC-CD30+ LPD) as a group are one of the more common types of T-cell lymphoma, comprising 30 percent of the total number of cases. More specifically PC-ALCL, one of these lymphoproliferative disorders, is the second most common cutaneous T-cell lymphoma. PC-ALCL has an incidence of 0.1-0.2 patients per 100,000, and occurs more often in males than females (ratio of 2-3:1) [10]. Although typically seen in older adults (median age 60), children may be affected [2]. PC-ALCL is not uncommonly seen in HIV patients [10].

Most PC-ALCL patients present with solitary or localized nodules, plaques, or papules. However, up to 20 percent of patients may have multifocal lesions. Ulceration may or may not be present. Lesions generally occur on the trunk, face, extremities, and buttocks.

Histologically, PC-ALCL is heterogeneous and can be difficult to diagnose. It can be classified according to histologic features (i.e., pleomorphic, immunoblastic, monomorphic, small-cell predominant, Hodgkin-disease related), immunophenotype (i.e., T, null), and clinical features, such as ALCL occurring after another lymphoproliferative disorder (i.e., mycosis fungoides or LyP) or arising in HIV-positive patients [2, 10].

PC-ALCL usually involves the dermis, but can extend into the subcutis, too. Epidermotropism is often identified. Histologically, cohesive sheets of neoplastic cells with anaplastic morphology, including round to irregularly shaped nuclei (often reniform or horseshoe-shaped), prominent nucleoli, and abundant cytoplasm are seen. Twenty to twenty-five percent of lesions exhibit a non-anaplastic, pleomorphic or immunoblastic phenotype. Reactive lymphocytes skirting the periphery of the lesion are often observed as well. When an ulcer is present, it is accompanied by an abundant inflammatory infiltrate consisting of reactive T-cells, neutrophils, eosinophils, and histiocytes [2].

The characteristic finding in this entity is the expression of CD30 in greater than 75 percent of the tumor cells. PC-ALCL also expresses T-cell associated antigens (i.e., CD2, CD3, CD4, CD45RO), activation markers (i.e., CD25, CD30, CD71, HLA-DR), and cytotoxic molecules (TIA-1, granzyme B, perforin). Variable loss of T-cell antigens (CD2, CD3, CD5, CD7) has been reported [10].

There may be difficulty in diagnosing PC-ALCL because histologically it can be indistinguishable from a number of other lymphomas that secondarily involve the skin [10]. CD30 positivity narrows the differential diagnosis to four main entities besides PC-ALCL: systemic ALK+ ALCL (S-ALK+ ALCL), systemic ALK- ALCL (S-ALK- ALCL), peripheral T-cell lymphomas, NOS (PTCL, NOS), and classical Hodgkin lymphoma (CHL). All of the above also exhibit CD30 positivity. While challenging, immunohistochemical staining can aid in differentiation (Table 1) [11].

S-ALK+ ALCL is a T-cell lymphoma that exhibits a broad morphological spectrum, in which all patterns contain varying proportions of large anaplastic lymphoid cells with horseshoe- or kidney-shaped nuclei. Like PC-ALCL and S-ALK- ALCL, these tumor cells express CD30 in greater than 75 percent of tumor cells. However, S-ALK+ ALCL also carries a t(2;5)/NPM-ALK translocation, resulting in expression of ALK protein, allowing for its distinction from the others [2, 10, 11, 12].

Because both S-ALK- ALCL and PC-ALCL lack ALK expression, a detailed clinical work-up is necessary; differences in staging of the former will assist in distinguishing between the two. This is important because the prognosis for PC-ALCL is much better than for S-ALK- ALCL [2, 13].

PTCL, NOS may be indistinguishable from S-ALK- ALCL and PC-ALCL when presentation is limited to skin; even experts may disagree on this subject [13]. PTCL, NOS is a group of highly aggressive lymphomas, which often develop as a generalized lymphoma with involvement of bone, liver, spleen, and even peripheral blood. This entity responds poorly to therapy and exhibits a 5-year survival of 20-30 percent [14]. Clinical correlation is needed.

CHL, rich in neoplastic cells, may mimic PC-ALCL in rare cases that lack T-cell/cytotoxic markers. In these instances, PAX5 will be useful, because weak expression is seen in most CHLs, whereas it is negative in ALCLs. In addition, the demonstration of CD15 positivity should also raise a suspicion for CHL, although PTCL, NOS has been known to express CD15. In this setting, markers for Epstein-Barr virus are helpful, and when positive, strongly suggest CHL [13].

Clonal rearrangement of T-cell receptor genes can be found in approximately 40 percent of LyP lesions, over 90 percent of PC-ALCLs, and most PTCL, NOS cases [2, 10]. Although important, the presence of a T-cell receptor gene rearrangement is a non-specific finding.

PC-ALCL has a favorable prognosis with a 5-year survival rate of 90 percent. In 10-40 percent of cases there is spontaneous remission [10]. Regional lymph node involvement is present in approximately 10 percent of cases. However, if the tumor burden is limited to the skin, survival rates are similar. Factors that portend a favorable prognosis include spontaneous regression and patient age under 60. Extracutaneous disease and higher age predict a worse outcome [10].

2. Literature review of primary lymphomas of the penis

A recent literature search of PubMed using the keywords “lymphomas of the penis” uncovered 31 reports [15-44] of primary lymphomas of the penis (Table 2). Clinically, infections rather than lymphoma were suspected in the majority of cases.

Of the 31 reports, 4 reports described primary penile T-cell lymphomas with CD30 expression [37, 42-44]. One of these cases also expressed ALK, representing S-ALK+ ALCL [42]. Of the remaining three CD30+ lymphomas described, two cases [43, 44], in our opinion, did not meet the updated WHO criteria for a PC-ALCL. The first described mitotically active, highly atypical malignant cells positive for T-cell markers, but CD30 positivity was present in less than 10 percent of neoplastic cells [43]. Lin et al. [44] described a CD30 positive cutaneous neoplasm, but failed to specify the percentage of positive tumor cells or publish a picture highlighting the CD30 positivity of the anaplastic cells. Thus, only one, or possibly, two reports clearly meet(s) the current WHO criteria for PC-ALCL [37].

Additionally, only one case report, published in 2004, described a lymphoma presenting as paraphimosis [35]. This fact may be secondary to the tendency to discard excised foreskin rather than sending it to pathology for diagnostic purposes.

Conclusion

We have presented the second clearly defined case of PC-ALCL presenting on the penis. It is the first of its kind to present as paraphimosis. A literature review of primary penile lymphomas of any type found only 31 previously reported cases. Although uncommon, physicians evaluating penile lesions should be aware of the possible presence of lymphoma. It should also be included in the differential diagnosis when evaluating “infections” that do not respond to antibiotics.

In addition, dermatologists, urologists, and pathologists must learn to recognize and differentiate primary cutaneous lymphoma from secondary involvement by a systemic lymphoma; the clinical implications and prognosis are different. Finally, it is our recommendation that all foreskins from adults be submitted to pathology for microscopic examination in order to avoid missing specific forms of infection or neoplasm.

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