Painful purpura from intravascular large B-cell lymphoma cutaneous variant

Abstract

Intravascular large B-cell lymphoma is a rare disease that often goes unnoticed and is repeatedly diagnosed during autopsy. Patients present with a wide variety of nonspecific symptoms, which makes the diagnosis challenging. This case presents a patient who was initially diagnosed with fever of unknown origin but later developed a retiform purpuric rash that prompted the diagnosis.

Intravascular large B-cell lymphoma (IVLBCL) is a rare presentation of non-Hodgkin’s lymphoma that selectively affects cells in small blood vessels’ lumina, causing a neoplastic growth. IVLBCL has been mostly described in the elderly population, and most patients have advanced disease at the time of presentation.¹ In the US, the incidence of the disease from 2000 to 2013 was estimated to be 0.095 cases per million.² This is a rare disease that has mostly been documented by case reports.

CASE PRESENTATION

A 62-year-old man with known chronic kidney disease stage III and recently diagnosed panhypopituitarism presented with a painful purpuric rash and swelling on both lower extremities. Two months earlier, he had presented to the hospital for persistent fever and hypotension. At that time, he was admitted to the intensive care unit for sepsis and was initially placed on vasopressors and broad-spectrum antibiotics. Laboratory values for that admission are shown in Table 1. Eventually, his fever resolved; however, an infectious workup was negative. He was ultimately discharged with a diagnosis of panhypopituitarism.

Table 1.

The patient’s laboratory results during three hospital visits

Variable	Reference range	2 Months before	1 Week before	During presentation
Lactate dehydrogenase (U/L)	313–618	2786.3
D-dimer (μg/mL)	0.00–0.50	0.84
Haptoglobin (mg/dL)	30–200	<20		117
Parvovirus B19 IgG (IV)	≤0.90	3.78
Parvovirus PCR	ND	ND
Thyroid-stimulating hormone (ulU/mL)	0.47–4.68	<0.01		<0.01
Free T4 (ng/dL)	0.78–2.19	0.45		1.92
Total T3 (ng/mL)	0.97–1.69	0.39
Free T3 (pg/mL)	2.77–5.27	1.32		1.29
HIV 1 & 2 antigen and antibody	Neg	Neg
Prolactin (ng/mL)	2.1–17.7	26.2
Total testosterone (ng/dL)	300–720	<3
Free testosterone (pg/mL)	47–244	<1
Luteinizing hormone (IU/L)	1.7–8.6	0.7
Insulin-like growth factor 1 (ng/mL)	51–209	44
Adrenocorticotropic hormone (pg/mL)	7.2–63.3	5.2
Cryptococcal antigen	Neg		Neg
Fungitell beta–D glucan	Neg		Neg
Coccidioides Ab IgG by ELISA (IV)	≤0.9		1.7
Coccidioides Ab IgM by ELISA (IV)	≤0.9		0.0
Typhus fever Ab, IgG	<1:64		<1:64
Typhus fever Ab, IgM	<1:64		<1:64
Babesia species by PCR	ND		ND
Histoplasma galactomannan antigen	ND		ND
Myeloperoxidase Ab (AU/mL)	0–19			0
Proteinase 3 Ab (AU/mL)	0–19			0
SSB–La ENA IgG Ab (AU/mL)	0–40			0
SSA 60 (Ro) (ENA) Ab, IgG (AU/mL)	0–40			0
SSA 52 (Ro) (ENA) Ab (AU/mL)	0–40			1
Cryoglobulin typing and quant IgG	Neg 72 h			Neg 72 h
Double-strand DNA Ab (IU)	≤25.000			0.565
Smith Ab (AU/mL)	0–40			0
Histone Ab IgG (U)	0.0–0.9			0.3

Ab indicates antibody; ELISA, enzyme-linked immunosorbent assay; ENA, extractable nuclear antigen; ND, not detected; Neg, negative; PCR, polymerase chain reaction; quant, quantitative.

One month after being discharged and 1 week before the presentation under discussion, he returned to the hospital for the same complaint of intermittent fever associated with chills and malaise. During admission, his temperature was 36.5°C. Physical examination was again unremarkable except for 1+ edema on his lower extremities. Laboratory results are shown in Table 1. The patient was again treated empirically with broad-spectrum antibiotics. Thorough evaluation for rheumatologic, infectious, and hematologic causes for persistent fever was negative. He ultimately became afebrile and was discharged with a diagnosis of fever of unknown origin.

One week after being discharged from his second hospitalization, he presented to the same hospital with new onset of a painful purpuric rash on his upper and lower extremities. His only new medication was trimethoprim/sulfamethoxazole for Pneumocystis jiroveci prophylaxis since he was on chronic steroids for panhypopituitarism. Physical examination showed pitting edema of the abdomen and bilateral lower extremities. Painful purpuric exanthem (Figure 1a–c) was seen on the upper and lower extremities. His purpuric rash enlarged and formed bullae and some skin sloughing (Figure 1d–f) during his hospitalization. A skin biopsy showed clonal lymphocytes in the lumina of blood vessels with an increased nuclear-to-cytoplasmic ratio, prominent nuclei, and multiple mitotic figures. Combined with the immunohistochemical stains for CD20, these findings confirmed a diagnosis of IVLBCL.

Figure 1.

Retiform purpuric rash (a–c) during the initial physical exam, on the thigh, forearm, and hamstring, and (d–f) 1 week after onset, showing formation of bullae, the sloughing of skin, and progression of the rash in the lower extremities.

The patient completed one cycle of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). He later developed infection of skin lesions and was discharged to a postacute facility to complete antibiotic treatment and recover from the prolonged hospital stay and debilitating skin lesions.

DISCUSSION

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. As with other presentations of non-Hodgkin lymphoma, B symptoms such as fever and weight loss are very common, along with elevated lactate dehydrogenase. Patients present with involvement of a single or multiple organs, such as kidney, thyroid, lung, spleen, skin, and pituitary, among others.³ Our patient was diagnosed with panhypopituitarism and had brain imaging suggestive of pituitary macroadenoma vs cyst, but no atypical lymphoid cells were noted on cerebrospinal fluid or bone marrow examination.

Definitive diagnosis is made by histology showing neoplastic cells with a high nuclear-to-cytoplasmic ratio and immunophenotypes showing a high CD20 expression, as seen in Figure 2.^4,5 To our knowledge, no study has been able to identify a correlation of immunophenotype presentation and patient outcomes.

Figure 2.

Skin tissue biopsy showing (a) areas of fibrin thrombi within the vessels; (b) highly atypical cells with an increased nuclear-to-cytoplasm ratio, irregular nuclear contours, prominent nuclei, and multiple mitotic figures; and (c) positive immunohistochemical staining for CD20.

Three clinical variants of IVLBCL have been described: classic, hemophagocytic syndrome-associated, and cutaneous.⁶ Our patient met criteria for the cutaneous variant based on his skin presentation. An array of skin lesions have been described with the cutaneous variant, ranging from painful erythematous papules to poorly differentiated nodular discolorations, ulcerated nodules, and desquamative plaques, among others.⁷ Ferreri et al stated that some presentations of cutaneous variant cases were isolated to the skin, while others also had neurological or B symptoms.⁷

No large trial has been done to determine treatment efficacy for IVLBCL; therefore, treatment is extrapolated from lymphoma treatment and based on evidence from case reports. The first line of therapy is anthracyclines, with the use of CHOP.⁸ However, recent case reports have shown better outcomes with the addition of rituximab to the initial therapy.^9,10 Overall, the addition of rituximab to CHOP treatment has improved the poor outcome seen in previous cases.^10,11 Rituximab has also shown the potential for reversing pituitary involvement of IVLBCL.¹¹