DIAGNOSIS OF CASE 2

Discussion


The axial images of the CT urograph, as well as the associated sagittal reformation, demonstrated a large filling defect in the right renal pelvis. The filling defect extended into and replaced most of the right renal pelvis, resulting in a mass effect and a relative delay in the kidney's enhancement during the nephrographic phase (Figures 2-3). The combination of this radiographic appearance with a history of painless hematuria and positive urine cytology was indicative of upper-tract urothelial carcinoma.
Upper-tract urothelial carcinoma refers to malignant changes of the urothelial cells lining the urinary tract from the renal calyces to the ureteral orifice. Upper urinary tract urothelial carcinomas are relatively uncommon, only accounting for about 5-7% of all renal tumors and about 5% of all urothelial tumors. It appears that the true incidence of upper-tract tumors is increasing as the population ages. Upper-tract cancer is typically seen at an older age than bladder cancer; it rarely presents before the age of 40 years, and it has an average age of presentation of 65 years. The incidence of upper-tract tumors is 10 cases per 100,000 population per year. The highest incidence, however, appears to occur in Balkan countries, where urothelial cancers represent 40% of all renal cancers. The likelihood of developing upper-tract tumors among men is about twice that of women. Whites have a 2:1 risk of developing upper-tract tumors when compared with blacks; however, data indicates that disease-specific annual mortality is greater in black men than in white men (7.4% versus 4.9%) and greater in women than in men (6.1% versus 4.4%). Proposed etiologies for developing upper-tract urothelial carcinoma are similar to that of bladder cancer and include environmental factors (cigarette smoking), occupational exposures (aniline dyes), and treatment with anti-inflammatory (phenacetin) or chemotherapy (cyclophosphamide, ifosfamide) agents. A familial association has been identified in patients with Balkan nephropathy, although an unidentified environmental trigger may be the underlying etiology in these cases.[1,2,4]
The most common presenting symptom or finding that leads to the diagnosis of upper-tract urothelial tumors is hematuria, which occurs in 56-98% of patients. The second most common symptom is flank pain, which occurs in 30% of cases. The pain may vary from a dull sensation resulting from gradual obstruction of the collecting system to an acute pain mimicking renal colic, believed to result from an acute obstruction by a thrombus. About 15% of patients are asymptomatic at presentation and are diagnosed incidentally by an imaging study performed for a different indication. Patients presenting with advanced disease may suffer from loss of appetite, weight loss, a flank or abdominal mass, and bone pain. Traditionally, intravenous pyelography (IVP) was used to diagnose upper-tract tumors; however, CT urography (CT with a delayed urographic phase) is now becoming the primary diagnostic modality. Using CT urography, the sensitivity for detecting upper-tract malignant disease has been reported to approach 100%, with a specificity of 60% and a negative predictive value of 100%. CT urography does, however, expose the patient to higher doses of radiation and requires intravenous administration of contrast material. Radiolucent filling defects, obstruction or incomplete filling of a part of the upper tract, and nonvisualization of the collecting system are the typical findings suggestive of an upper-tract tumor. Filling defects may represent stones, blood clots, external compression, or a fungus ball. Stones can be ruled out by detecting calcifications on renal ultrasonography or a noncontrast CT scan. The clinician should always asses the contralateral kidney for possible bilaterality and to determine its functioning.[1,2]
If the diagnosis remains in question or the treatment plan may be adjusted based on a ureteroscopic evaluation, endoscopy with or without biopsy should be performed. Ureteroscopy provides a valuable tool in the evaluation of upper-tract urothelial carcinoma. As a result of advancements in optics, flexible ureteroscopes and endoscopic equipment, visualization and sampling of the tumor have improved. The greatest prognostic factors in the management of upper-tract urothelial carcinoma are pathologic grade and stage. Histologic correlations of up to 90% have been established between the initial ureteroscopic biopsy and the final pathologic specimen; however, because of the small size of the biopsy specimen and the depth of tissue sampling, outcomes with tumor stage have not demonstrated such a strong correlation. In 40 urothelial tumors staged in one series, 45% of tumors thought to be pathologic Ta were upstaged to T1-T3 at the time of complete resection. Ureteroscopic biopsy cannot reliably predict tumor stage; therefore, a combination of tumor grade, endoscopic visual appearance of the tumor, and radiologic appearance are required for the best prediction of tumor stage.[1,2,4]
Because voided urine cytology is nonspecific, the usefulness of it is limited. Even when using selectively obtained ureteral cytologies, the diagnostic yield is still only 60% accurate. Improved diagnostic yield has been demonstrated with the use of saline washing or brush biopsy, with an approximate sensitivity of 90% and a specificity near 90%.[2]
The standard treatment for upper-tract urothelial carcinoma has been nephroureterectomy with excision of a cuff of bladder. Advancements in percutaneous and endoscopic techniques, however, have allowed more conservative nephron-sparing procedures for patients with solitary kidneys or those who are otherwise not ideal candidates for extirpative surgery. Considered the "gold standard", radical nephroureterectomy with resection of a bladder cuff is the treatment of choice for large, high-grade, single or multifocal, noninvasive or invasive renal pelvis or proximal ureter tumors. The risk for multifocality and a high incidence of ipsilateral recurrence following partial resection are the reasons for the preference of this radical approach. Several approaches may be used, including totally open, totally laparoscopic, or a combination of both (eg, laparoscopic nephroureterectomy combined with an open distal intramural ureteral resection).[1,2,3,4]
Patients with a solitary kidney, bilateral disease, renal failure, or significant comorbidities preventing a large abdominal surgery are candidates for endoscopic resection. An additional group of patients who may benefit from endoscopic treatment are those with a small, low-grade lesions in the presence of a normal contralateral kidney. Tumors located at the distal ureter may be treated with a rigid ureteroscope, whereas those situated in the upper-urinary tract may be reached by a flexible ureteroscope or by an antegrade percutaneous approach. Initially, biopsies are taken, and then ablation is achieved using electrocautery or laser energy. Historically, open nephron-sparing surgery for upper-tract urothelial carcinoma was used in patients with a large renal pelvis tumor in a solitary kidney or in cases of synchronous bilateral tumors. Advancements in endourologic techniques, particularly percutaneous antegrade renal surgery, have largely replaced this approach for the conservative management of renal pelvis tumors. Segmental (partial) ureteral resection with end-to-end anastomosis or bladder reimplantation is performed in cases with low-grade, noninvasive tumors of the proximal or mid ureter that cannot be managed endoscopically when nephron-sparing is crucial for the preservation of renal function.[1,2,4]
The recurrence pattern following treatment of upper-tract urothelial carcinoma may be divided into vesical and extravesical recurrence. The higher the grade and stage of the upper-tract urothelial carcinoma, the higher the risk for extravesical recurrence. The recommended follow-up for patients treated for upper-tract urothelial carcinoma should consist of periodic history and physical examination, urinary cytology, and surveillance cystoscopy (occurring every 3 months for the first 2 years after treatment, every 6 months for the next 2 years, and yearly thereafter if the patient is free from disease recurrence). In cases of high-grade urothelial carcinoma, radiographic studies, including chest radiography and abdominopelvic CT scanning, should be performed every 6 months for the first 2 years and then yearly thereafter. Ipsilateral endoscopy for patients who undergo organ-sparing treatment should occur every 6 months for the first 2-3 years and then yearly thereafter, provided that the patient is free of disease. Bone scans should only be performed if the patient has symptoms of bone pain or for an elevated alkaline phosphatase level.[1,4,5]
In this patient, a cystoscopy was performed upon admission which showed a normal bladder without any exophytic tumor. The combination of a large filling defect in the right renal pelvis seen on CT urography and positive urine cytology made the diagnosis of upper-tract urothelial carcinoma. The patient received a comprehensive explanation of the available treatment modalities and elected to undergo nephroureterectomy. The surgery involved a combined laparoscopic and open approach. The right kidney and ureter were removed entirely, including a bladder cuff around the right distal ureter. The postoperative phase was uneventful and the patient was discharged on the seventh postoperative day. She is now under surveillance after surgery, with no evidence of recurrence.

CASE 2 Painless Bloody Urination in a 60-Year Old Woman

A 60-year-old woman is referred to the emergency department (ED) because of a recent event of painless macroscopic hematuria. She reports having experienced several similar episodes during the past year, all of which resolved spontaneously. She regards these episodes as being of gynecologic origin because she is 5 years postmenopausal. She describes a general feeling of malaise in the days preceding the current episode, but she denies having any fever, dysuria, or increased frequency or urgency of urination. The patient also describes an unintentional weight loss of 11 lb (5 kg) during the past 2 years. The patient's previous medical history includes hypothyroidism that was treated medically with thyroxine, and her surgical history includes 2 treatments of dilatation and curettage (D&C) and a tonsillectomy. She has no known drug or food allergies, and she denies smoking, drug use, or alcohol consumption. She has no previous history of kidney stones or recurrent urinary tract infections.
On physical examination, the patient appears well. She has a temperature of 98.8°F (37.1°C), a pulse rate of 71 bpm, and a blood pressure of 150/86 mm Hg. The head and neck examination is normal. Lung auscultation reveals normal breath sounds bilaterally, without wheezing or crackles. Her heart sounds are regular, with a 2/6 systolic murmur maximally auscultated over the right second intercostal space. The abdomen is nondistended and nontender, no masses are palpated, and there are no signs of peritoneal irritation. No peripheral edema is noticed, peripheral pulses are palpated, and the neurologic examination is normal. A gynecologic evaluation that includes a speculum examination and transvaginal ultrasonography is performed, which reveals no pathologic findings.
A laboratory analysis, including a complete blood cell (CBC) count, coagulation studies, and a basic metabolic panel, shows a normal hemoglobin level, normal platelet count, and no coagulopathy. No electrolyte abnormalities are present. A urine dipstick test shows no signs of hematuria, and a urine culture is negative. Urine cytology is positive for malignant cells. Cystoscopy is performed, which demonstrates a normal urethra leading to a urinary bladder covered by normal mucosa, with no exophytic lesions and no active bleeding. A computed tomography (CT) examination of the abdomen and pelvis with intravenous contrast is obtained (see Figure 1).





FIGURE 1

CRYOGLOBUNEMIA

Definition   
Cryoglobulinemia is the presence of abnormal proteins in the blood. These abnormal proteins become thick or gel-like in cold temperatures.

Causes   
Cryoglobulins are antibodies. It is not yet known why they become solid at low temperatures. When they do thicken or become somewhat gel-like, they can block blood vessels throughout the body. This may lead to complications ranging from skin rashes to kidney failure.


Cryoglobulinemia is part of a group of diseases that cause vasculitis -- damage and inflammation of the blood vessels throughout the body. The disorder is grouped into three main types, depending on the type of antibody that is produced:
• Cryoglobulinemia type I
• Cryoglobulinemia typeII
• Cryoglobulinemia type III
Types II and III are also referred to as mixed cryoglobulinemia.
Type I cryoglobulinemia is most often related to cancer of the blood or immune systems.
Types II and III are most often found in people who have a chronic (long-lasting) inflammatory condition, such as an autoimmune disease or hepatitis C. Most patients with mixed cryoglobulinemia have a chronic hepatitis C infection.
Other conditions that may be related to cryoglobulinemia include:
• Leukemia
• Multiple myeloma
• Mycoplasma pneumonia
• Primary macroglobulinemia
• Rheumatoid arthritis
• Systemic lupus erythematosus


Symptoms   
Symptoms vary depending on the type of cryoglobulinemia and the organs that are affected. In general, symptoms may include:
• Difficulty breathing
• Fatigue
• Glomerulonephritis
• Joint pain
• Muscle pain
• Purpura
• Raynaud's phenomenon
• Skin death
• Skin ulceration


Exams and Tests   
The doctor will perform a physical exam. There may be signs of liver and spleen swelling.
Tests for cryoglobulinemia include:
• Complete blood count (CBC)
• Complement assay -- numbers will be low
• Cryoglobulin test -- may show presence of cryoglobulins
• Liver function tests -- may be high
• Rheumatoid factor -- positive in types II and III
• Skin biopsy
• Urinalysis -- may show blood in the urine if the kidneys are affected

Other tests may include:
• Angiogram
• Chest x-ray
• ESR
• Hepatitis C test
• Nerve conduction tests, if the person has weakness in the arms or legs
• Protein electrophoresis - blood


Treatment   
Treatment of mild or moderate cryoglobulinemia depends on the underlying cause. Treating the cause will often treat the cryoglobulinemia.
Mild cases can be treated by avoiding cold temperatures.
Standard hepatitis C treatments usually work for patients who have hepatitis C and mild or moderate cryoglobulinemia. However, the condition can return when treatment stops.
Severe cryoglobulinemia (involves vital organs or large areas of skin) is treated with corticosteroids and other medications that suppress the immune system.
Treatment may also involve plasmapheresis. Plasmapheresis is a procedure in which blood plasma is removed from the circulation and replaced by fluid, protein, or donated plasma.


Outlook (Prognosis)   
Cryoglobulinemia is not usually deadly. However, if the kidneys are affected, the outlook is poor.

Possible Complications   
Complications include:
• Bleeding in the digestive tract (rare)
• Heart disease (rare)
• Infections of ulcers
• Kidney failure
• Liver failure
• Skin death
• Death
  
Prevention   
There is no known prevention. Avoiding exposure to cold temperatures may prevent some symptoms.
Because so many cases of mixed cryoglobulinemia are associated with hepatitis C, prevention of hepatitis C infection may reduce your risk of cryoglobulinemia.

diagnosis of case 1

Given the patient's history of immunoproliferative disorder, and the atypical presentation of her lesions, consideration was given to a vasculitic or vasculopathic etiology. A panel of additional laboratory studies was sent. Lupus anticoagulant was not detected, and anticardiolipin was also negative. Antinuclear antibodies (ANA) and antibodies to neutrophil cytoplasmic antigens (ANCA) were not detected. All hepatitis markers were negative, including for hepatitis C. The test for rheumatoid factor was negative. The cryoglobulin test was positive, and quantified as primarily immunoglobulin G (IgG). This was subsequently confirmed on a separate test several months later.

Cryoglobulins are single or mixed immunoglobulins that reversibly precipitate at low temperatures. Cryoglobulinemia is defined as the presence of cryoglobulins in the serum. This can lead to a syndrome of systemic inflammation caused by immune complexes associated with the cryoglobulins. The mechanism of precipitation is poorly understood. The solubility of cryoglobulins is partially related to the structure of the immunoglobulin heavy and light chains. Alteration in protein conformation resulting from temperature changes may cause decreased solubility and subsequent vasculitic damage. The ratio of antibody to antigen in circulating cryoglobulin aggregates affects the rate of clearance from the circulation and the resultant location of tissue deposition.[2,4]

Cryoglobulins are reported in otherwise healthy individuals, so their true prevalence is unknown. While cryoglobulinemia is thought to be rare, it may be underdiagnosed because of the diversity of clinical presentations. The prevalence of mixed cryoglobulinemia is approximately 1:100,000. The female-to-male ratio is 3:1. The mean age reported is 42-52 years.

Cryoglobulinemia is classified based on cryoglobulin type using the Brouet classification. Type I cryoglobulinemia is monoclonal, usually immunoglobulin M (IgM). Types II and III are immunocomplexes formed by monoclonal or polyclonal IgM, respectively. Types II and III have rheumatoid factor (RF) activity and bind to polyclonal immunoglobulins. These two types are referred to as "mixed cryoglobulinemia". Type I accounts for 10-15% of cases, type II is seen in 50-60%, and type 3 is found in 25-30%. Atypical cryoglobulins with a microheterogeneous composition that does not fit into any of the classifications have prompted suggestion of a classification called Type II-III variant.[2,3,4]

Type I cryoglobulinemia is usually related to an underlying lymphoproliferative disease and may be difficult to distinguish from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Type I cryoglobulinemia may result in hyperviscosity as a result of high levels of circulating monoclonal cryoglobulins, leading to physical obstruction of vessels. In addition, immune complex deposition may cause an inflammatory vasculitis. Specific clinical manifestations include acrocyanosis, retinal hemorrhage, Raynaud phenomenon with digital ulceration, livedo reticularis, purpura, and arterial thrombosis.[1,2,3,4]

Types II and III cryoglobulinemia are associated with chronic inflammatory states, such as systemic lupus erythematosus, Sjögren syndrome, and viral infections (particularly hepatitis C). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states. Tissue damage results from immune complex deposition and complement activation. Specific clinical manifestations associated with types II and III cryoglobulinemia include arthralgia (usually of the leg, ankle and foot), fatigue, myalgia, renal immune-complex disease, cutaneous vasculitis, and peripheral neuropathy. The Meltzer triad of purpura, arthralgia, and weakness is seen in 25-30% of patients.[1,2,4,5]

Mortality and morbidity in individuals with cryoglobulinemia often depends on the underlying associated disease, if present. The overall prognosis is worse in patients with associated disease. The mean survival is approximately 50% at 10 years after diagnosis. The risk of renal failure appears to be greater in those with hepatitis C virus—associated disease.[2,4]

Lymphoproliferative disease is more common in individuals with cryoglobulinemia. Patients with mixed cryoglobulinemia may develop benign lymphoid infiltrates in the spleen and bone marrow. Less frequently, patients may develop B-cell non-Hodgkin lymphoma. The incidence of malignant lymphoma in mixed cryoglobulinemia varies from 10-40%, with an onset of 5-10 years after disease diagnosis.[2,3]

Cutaneous manifestations are almost always present in cryoglobulinemia. Lesions are most often seen in dependent areas (especially the lower extremities), and they include erythematous macules and purpuric papules (90-95%), as well as ulcers (10-25%). Lesions in nondependent areas (head and mucosa) are more common in type I cryoglobulinemia, as are livedo reticularis, Raynaud phenomenon, and ulcers. Nail fold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.[1,3]

Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always seen in mixed cryoglobulinemia. Renal involvement is one of the most serious complications of cryoglobulinemia, and it typically manifests early in the course of the disease (within 3-5 years of diagnosis). This may progress to complete renal failure. Hypertension and nephritic-range proteinuria with resultant edema are characteristically seen in cryoglobulinemia.[2,4]

A reduction in forced expiratory flow rates and the presence of interstitial infiltrates are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic, with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare. Neuropathy is common in types II and III disease, affecting 70-80% of patients. Sensory neuropathy is more common than motor neuropathy (5% of patients). Abdominal pain has been reported in 2-22% of patients. Vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported. Splenomegaly may be seen in these patients.

The differential diagnosis of cryoglobulinemia includes antiphospholipid syndrome, chronic lymphocytic leukemia, Churg-Strauss syndrome, cirrhosis, giant cell arteritis, glomerulonephritis, Goodpasture syndrome, hemolytic-uremic syndrome, hepatitides, non-Hodgkin lymphoma, microscopic polyangiitis, multiple myeloma, polyarteritis nodosa, sarcoidosis, serum sickness, systemic lupus erythematosus, and Waldenström hypergammaglobulinemia.[2,3]

Key lab studies include evaluation for serum cryoglobulins. The specimen must be obtained in warm tubes (98.6°F or 37°C) without anticoagulants and then allowed to clot before centrifugation. The serum is then incubated at 39.2°F (4°C). Type I tends to precipitate within 24 hours. Type III may require 7 days to precipitate. Specific immunologic assays may be used to identify cryoglobulin components (immunoglobulins, light chains, clonality).

Urinalysis, serum creatinine, and electrolytes are important to evaluate for evidence of renal disease. A complete blood cell (CBC) count should be done to screen for infection, anemia, or leukemia. Abnormal liver function studies and transaminases may suggest underlying hepatitis. If so, hepatitis serologies are indicated. If hepatitis C virus test results are negative and clinical suspicion remains high, serologies may be performed on the cryoprecipitate. Rheumatoid factor is positive in types II and III. ANA is indicated upon clinical suspicion of underlying connective-tissue disease. ESR elevation is nonspecific, and it may occur in the presence of a number of associated inflammatory disorders. Patients may display hypocomplementemia (especially low C4 levels). The clinician should consider serum protein electrophoresis, urine protein electrophoresis, and quantitative immunoglobulin if there is suspicion for underlying gammopathy.[3]

Clinical imaging should be ordered as warranted based on suspected underlying disease. Tissue biopsy may be required for diagnosis in patients with vasculitis and/or renal disease. Purpura is characterized by dermal vasculitis that extends variably to the subcutaneous tissue. Hepatitis C virus—associated proteins have been found in vasculitic skin biopsy specimens. Although samples generally exhibit inflammatory vascular changes, intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli.

The management of cryoglobulinemia should be focused on treating underlying conditions, as well as limiting the precipitation of cryoglobulins and the resultant inflammatory effects. Asymptomatic cryoglobulinemia does not require treatment. When treatment is required, it is based on suppression of the immune response.[2]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in patients with arthralgia and fatigue, but may be contraindicated in patients with renal disease. Immunosuppressive medications (eg, corticosteroids, cyclophosphamide, azathioprine) are indicated in cases with evidence of organ involvement, such as vasculitis, renal disease, progressive neurologic findings, or severe skin manifestations.[2]

Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for the reduction of immunoglobulin production.[2]

Pegylated interferon alfa combined with ribavirin has been demonstrated to be effective in patients with cryoglobulinemia associated with hepatitis C, and efficacy in patients with chronic myelogenous leukemias and low-grade lymphomas has been reported.

Rituximab (anti-CD20 chimeric monoclonal antibody) has shown promise in controlling vasculitis, peripheral neuropathy, arthralgias, low-grade B-cell lymphomas, renal disease, and fever, specifically in patients with hepatitis C virus—related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral therapy. Studies have not yet been published on its efficacy and safety in the setting of other types of cryoglobulinemia.[2,4]

The patient in this case was referred to rheumatology and prescribed a course of oral corticosteroids. She was also referred to dermatology and had azathioprine added to her treatment. The lesions began to slowly shrink and lift at the edges (see Figure 2). Serial debridements were performed. Appropriate wound care was provided by her caregiver under instruction and supervision of the wound center. Following this care plan, the patient has had nearly complete resolution of most of her lesions (see Figure 3). She developed a persistent pancytopenia despite discontinuation of the azathioprine. She was referred to a hematologist and now has evidence of multiple myeloma based on bone marrow biopsy, with continued positive cryoglobulins.

Necrotic Skin Lesions in a 61-Year-Old Woman

A 61-year-old woman presents to the wound center for continued treatment of venous leg ulcers complicated by diabetes mellitus. Her past medical history is remarkable for essential hypertension and obesity. The patient also has a history of angioimmunoblastic lymphadenopathy, which occurred over 15 years ago. The patient can not remember any details of this diagnosis; consultation with her primary care clinician reveals that this was a benign/peripheral presentation. No records are available for review. According to the primary care clinician, the condition went into complete remission following a course of prednisone. The patient notes that she has developed new wounds on both of her thighs. The lesions are black, with surrounding redness and tenderness. There is no itching. She states that the lesions have been enlarging slowly over the past several days, and many are now several centimeters in diameter. She denies having any fever or chills. Her fasting serum glucose readings have been stable in the 100-200 mg/dL (5.55-11.1 mmol/L) range. She denies experiencing any easy bruising or bleeding. She has not had any recent trauma or procedures in the area of the lesions, and she has not had any recent changes in her medications. She has no history of smoking, alcohol or illicit drug use.

On physical examination, her oral temperature is 97.8°F (36.6°C). Her pulse is 86 bpm and regular, and her blood pressure is 128/81 mm Hg. Her respiratory rate is 14 breaths/min. She is in no acute distress, but she does note that the wounds are causing her discomfort. The examination of her head, neck, lungs, heart and abdomen is unremarkable. The skin of the upper extremities and torso is also unremarkable. She has a nonhealing venous ulcer on each of her medial malleolar areas, which are unchanged from previous examination. She has multiple black eschars on her thighs, each surrounded by a centimeter of erythema with a slightly reticular pattern, as well as induration. She has trace edema to her ankles, but no edema in her legs or thighs. The lesions are tender. There are no vesicles or pustules. No confluent or ascending erythema is noted. The largest lesion measures 4.4 × 2.6 cm (see Figure 1).

Laboratory testing shows a white blood cell (WBC) count of 10.1 × 103/µL (10.1 × 109/L; normal range, 4.1- 10.9 × 103/µL), a hemoglobin of 10 g/dL (100 g/L; normal range, 12.0-15.2 g/dL), platelets of 492 × 103/µL (492 × 109/L; normal range, 140-450 × 103/µL), and a normal WBC differential. The basic metabolic panel is normal. The hemoglobin A1c finding is 6.6% (0.066; normal range, 3.8-6.4%). The albumin is normal at 3.5 g/dL (35 g/L), and the erythrocyte sedimentation rate (ESR) is elevated at 80 mm/hr (normal range, 1-25 mm/hr).

Biopsies are obtained of representative lesions at their edges. They demonstrate acute and chronic inflammation in the dermis and subcutaneous fat. No viral cytopathic changes are seen. Small vessel microthrombi are limited to the base of the ulcer and are not identified in vessels away from the ulcer, which suggests a secondary thrombotic reaction. No specific changes of vasculitis or malignancy are identified.

What is the diagnosis?

Hint: Her current diagnosis is associated with her remote past medical history.

Multiple myeloma

Cryoglobulinemia

Non-Hodgkin lymphoma

Giant cell arteritis