Diagnosing a Questionable Rash in an Elderly Man

 A 73-year-old man presented to our office for what he described as a “rash” on his right leg. The patient had reported that the problem disseminated and persisted on his right leg for approximately 3 weeks (Figure). At the time, the patient was experiencing dryness, irritation, itching, rash, and redness on the affected area. The patient said that he did not have any allergies. He had expressed symptoms of fatigue and low energy but noted no decrease in appetite. He had a history of chronic cough and hypertension. The mass was firm to palpation. He had no history of trauma to that area. He was not taking any medications. We performed a biopsy and asked the patient to return for a follow-up of the biopsy results.

Figure. Photograph shows pruritic rash on patient’s right leg.

Based on the case description and the photograph, what is your diagnosis?

A. Hodgkin disease

B. B-cell lymphoma

C. Anaplastic large cell lymphoma

D. Metastatic carcinoma

 Click next page for the answer and a discussion>>

Diagnosis: Anaplastic large cell lymphoma (C)

Discussion

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma. It is most frequently diagnosed in children and young adults, but it does occur in people in the later decades of life.^1,2 This highly aggressive form accounts for approximately 2% of all lymphoma-related cases, and is twice as likely to be found in men than in women.² The lymphoma itself is typically composed of T-lymphocytes; other cases, where the composition of the lymphoma is questionable, the cancerous cells are labeled as a null-cell type. There are two main forms of ALCL: systematic ALCL and primary cutaneous ALCL.² It can localize in both nodal and extranodal regions, normally manifesting itself at a later stage with the onset of systemic symptoms.³ The cause and determinant of ALCL are unclear. Similar to other types of cancer, this form of lymphoma is not contagious and cannot be transmitted to another individual.

We determined that our case patient had stage IIE ALCL. Stage II of this lymphoma indicates that multiple groups of lymph nodes are involved. However, the affected groups are confined to either the superior or inferior half of the body, with the diaphragm acting as the center marker. Since the letter “E” denotes the stage, the lymphoma is classified as extranodal, or originating from a region located outside the lymph nodes.⁴

Typically, patients with ALCL first notice a painless area of inflammation located in the neck, armpit, or groin; this bulge is composed of swollen lymph nodes. To complicate matters further, the lymphoma can affect other organs, such as the skin, lungs, liver, and bone marrow. Multiple groups of nodes are typically involved during the onset. Some patients have reported inexplicable feelings of satiety and loss of appetite, which can lead to dramatic weight loss. Other systemic symptoms include fatigue and nighttime-related diaphoresis.^5,6 

The condition is diagnosed by performing a biopsy on a swollen lymph node. Further tests, including blood work, radiographs, and bone marrow specimens, may be needed to illustrate additional information about the disease, including whether it has metastasized.⁶

Histological Findings
The biopsy on the enlarged lymph nodes should yield the appearance of typical hallmark cells (and variants), along with immunopositivity for CD30 and often for the anaplastic lymphoma kinase protein (ALK; only for 7 out of 10 cases, however).^3,7 An ALK immunostain can help to discriminate between the primary and systematic forms of CD30 ALCL.³ Determination of ALK positivity is absolutely critical, as this feature would define future treatment strategies and goals of care.¹ Therefore, it is advised that every case of suspected ALCL must be assayed for ALK. Typical hallmark cells are moderate in dimension and encompass a profuse amount of cytoplasm, kidney-shaped nuclei, and a paranuclear eosinophilic region.^8,9 The cytoplasm within the cells may be clear in complexion, amphophilic, or eosinophilic. Clusterin is a marker that is used to confirm that the lymphoma is not Hodgkin-related; it illustrates a specific Golgi staining pattern amid neoplastic cells.¹⁰ The biopsy of our patient’s lesion yielded the appearance of typical hallmark cells that are CD30+ on immunostaining and showed ALK positivity.

Approaches to Treatment
First line treatment of ALCL typically involves the use of intensive chemotherapy, such as the 4-drug regimen of cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone, also known as CHOP therapy.^3,11,12 ALK-positive ALCL can be cured with chemotherapy, but ALK-negative ALCL is rarely cured with chemotherapy.^3,13 According to a study by Savage and colleagues¹³ involving 181 patients, the 5-year overall survival rate for patients with ALK-positive ALCL was approximately 70%, compared with 49% for patients with ALK-negative ALCL. However, this study also showed no difference in outcome of patients younger than 40 years of age, suggesting that age may be an important prognostic factor in deciding patient outcome.¹³

Patients with ALCL, especially those who are ALK-positive, often respond well to CHOP therapy.¹⁴ Stem cell transplants may be considered for patients who lack the ALK protein or if the lymphoma returns after initial treatment. The use of monoclonal antibodies are being investigated.¹⁴  

As we did with our patient, it is important that patients diagnosed with these rare disorders be referred for evaluation at a tertiary care center for frontline treatment and possible clinical trials as well as evaluation for allogeneic stem cell transplant.

Our patient was referred to a cancer treatment center for follow-up. Primary care physicians who encounter this presentation should ensure timely referral to a dermatologist for evaluation and management, as well as timely biopsy for suspicious lesions. It is important for healthcare providers to recognize the probability of malignancy and refer patients to the appropriate specialist, regardless of the type of lymphoma suspected.

Ruling Out the Other Diagnoses

What follows is a discussion of some of the other possible diagnoses, which were ruled out for our case patient.

Hodgkin Disease
Hodgkin disease, also called Hodgkin lymphoma, is a cancer of lymph tissue found in the lymph nodes, spleen, liver, and bone marrow. The disease is rare and the cause is unknown, but besides an enlarged lymph node, which is typically the first sign in an affected individual, its symptoms are nonspecific. The symptoms include painless swelling in the neck, armpits, and groin; fever and chills; itchiness; nighttime diaphoresis; loss of appetite; and weight loss.¹⁵ A diagnosis of Hodgkin lymphoma relies on biopsies, which can be taken from the lymph nodes and bone marrow, showing proteins such as CD15 and CD30 on the surface of Reed-Sternberg cells.¹⁶

B-Cell Lymphoma
B-cell lymphoma comprises between 80% and 90% of cases of non-Hodgkin lymphomas, and the median age at presentation is older than 50 years.¹⁷ B-cell lymphomas are divided into two categories: precursor B-cell neoplasms and mature B-cell neoplasms. Symptoms of low-grade B-cell lymphomas can include fever, fatigue, and pruritus; whereas symptoms of advanced, high-grade lymphoma can include high fever, tachycardia, respiratory distress, purpura, petechiae, and ecchymoses. Upon taking a biopsy, B-cell lymphoma can be ruled out if the cells test negative for markers of B-cell lineage. Additional tests may be required due to the fact that B-cell lymphomas may test positive for the ALK protein.¹ However, B-cell non-Hodgkin lymphomas are much less commonly associated with skin involvement than are the T-cell non-Hodgkin lymphomas.¹⁸

Metastatic Carcinoma
Metastatic carcinoma can resemble ALCL because it can display the same type of hallmark cells and growth patterns.¹⁸ Upon biopsy studies, the presence of a negative cytokeratin marker will rule in favor of ALCL in this circumstance. The expression of CD30 in virtually every cell is rarely seen in other lymphomas.¹⁹ If metastatic carcinoma is suspected, patients should be referred to an oncologist for further diagnostic work-up and treatment.

The authors report no relevant financial relationships.

References

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