Commentary case

By :

Prof. Dr.: Fawzy Megahed

The patient had been well until 2 yearsbefore this presentation, when anemia wasnoted on routine examination at anotherhospital. During the next 7 months,endoscopic and colonoscopic screeningexaminations were negative.

Pathological examination of a bone marrow–biopsy specimen and aspirate revealed 30%plasma cells; flow-cytometric studiesrevealed an IgG lambda M component.

Skeletal radiographs reportedly revealedmultiple lytic lesions.

He had hyperlipidemia, hypertension, low-back pain, and gastroesophageal refluxdisease; he had undergone colonicpolypectomies and had a history of prostatecancer for which radical prostatectomy wasperformed 11 years earlier.

Medications included rosuvastatin, andomeprazole. He lived with his wife andworked in an office. He had stopped smoking20 years earlier, drank alcohol in moderation,and did not use illicit drugs. His mother andmaternal uncle had rheumatoid arthritis.

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A diagnosis of multiple myeloma wasmade.

Lenalidomide, bortezomib, anddexamethasone were administered, followedby cyclophosphamide. Nine months beforethis presentation, the patient was admittedto this hospital; melphalan hydrochloride wasadministered, and autologous stem-celltransplantation was performed.

Results of follow-up studies were consistentwith complete remission.

Two months before this presentation,swelling and pain in the hands occurred,followed by pedal edema, tightening of theskin of the hands and feet, and diffusehyperpigmentation on the trunk, arms, andlegs.

Maintenance therapy with lenalidomide wasbegun, but it was stopped during the firstcycle because of worsening symptoms.Diffuse joint pain occurred andhyperpigmentation increased.

One month before this presentation, resultsof liver-function tests were normal, as wereblood levels of electrolytes, thyrotropin, iron,iron-binding capacity, ferritin, and folate .

What is your differential diagnosis ?

Which of the following can explainthis new presentation ?

1- Multiple Myeloma and Systemic Amyloidosis

2- paraneoplastic syndrome

3- nephrogenic systemic fibrosis

4- Eosinophilic fasciitis (Shulman’s syndrome)

5- Lenalidomide toxicity

6- Scleroderma

7- Scleromyxedema

Total urine protein was 90 mg per liter . Fine-needle aspiration biopsy of a fat pad wasperformed, and pathological examination ofthe specimen revealed no evidence ofmalignant cells or amyloid.

A TTE showed trace mitral regurgitation,trace tricuspid insufficiency, and a leftventricular ejection fraction of 64% andshowed that the ascending aorta was 41 mmin diameter (reference diameter, <36 mm);.Urinalysis was normal.

On presentation, the patient rated the

joint pain at 6 on a scale of 0 to 10, with 10indicating the most severe pain.

On examination, the blood pressure was112/63 mm Hg and the pulse 100 beats perminute; the temperature, respiratory rate,and oxygen saturation were normal. Asystolic murmur, grade 2/6, was heard at theright and left upper sternal borders.

There was swelling and tenderness in theMCP and proximal IP joints bilaterally andswelling below the knees to the toes, withouterythema or warmth. The range of motionwas decreased in the MCP and ankle joints.

The skin on the MCP joints and legs belowthe knees to the toes was hyperpigmented.Testing for antibodies to Ro , La , Sm, RNP, Jo-1, Scl-70 (topoisomerase I), and CCP wasnegative, and the level of creatine kinase wasnormal.

Can we review our diagnosis?

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Which of the following is the themost appropriate diagnosis ?

1- Sclerederma

2- paraneoplastic syndrome

3- nephrogenic systemic fibrosis

4- Eosinophilic fasciitis (Shulman’s syndrome)

5- Lenalidomide toxicity

6- Scleroderma

7- Scleromyxedema

8- other diagnosis to be pursued.

A tapering course of prednisone wasadministered.

Five weeks later, after returning from avacation in Aruba, the patient was seen forfollow-up appointments at the hematologyclinic of the other hospital and therheumatology clinic of this hospital.

He reported severe fatigue, decreasedexercise tolerance, and weight loss ofapproximately 3.5 kg. He rated the joint painat 2 out of 10, but substantial stiffnesspersisted while he was taking prednisone.

On examination, the blood pressure was110/70 mm Hg, the pulse 100 to 111 beatsper minute, and the oxygen saturation 96%while he was breathing ambient air; thetemperature was normal.

The MCP and proximal IP joints remainedswollen but were less tender, and the wristswere slightly full. There was 1+ pitting edemabelow the knees; the skin was deeply tannedand firm in a manner that was out ofproportion to the degree of pitting edema.

The stool was dark brown and positive (3+)for blood. The administration of omeprazolewas increased to twice daily .

One week later (six weeks after thispresentation), the patient was admitted tothe other hospital because of worseninganemia . The hematocrit rose to 27.9% afterleukocyte-reduced red cells were transfused.

Next step!!!!!!!!

Endoscopy revealed severe acute gastritiswith marked erythema and friability. He wasdischarged on the third day.

IVIG was administered monthly, with someimprovement in joint pain and stiffness.

Skin tightness persisted, and a skin biopsywas performed.

Hematoxylin and eosin staining of histologic sections of a skin-biopsy specimen from the dorsum of the left hand :

revealed a normalepidermis withdermal collagenexpansion involvingthe subcutaneoustissue (Panel A,asterisk); there isadnexal atrophy withperiadnexal fat loss(Panel A, arrow).

A sparselymphoplasmacytic infiltrate wasidentified at thejunction of thedermis and thesubcutaneous fat(Panel B, arrow).

There were areas ofreticular dermal fibroblasthypocellularity (Panel C).

An immunohistochemicalstain for CD34 shows adiffuse loss of CD34expression in dermalspindle cells (Panel C,inset).

A colloidal ironstain showsinterstitial mucindeposits (Panel D).

An elastic tissue stainshows preservationof dermal elasticfibers, with parallelarrangement andstraightening (PanelE, arrow).

Three months after this presentation,prednisone was administered for persistentstiffness. The patient reported extremefatigue and increasing dyspnea on exertionduring the preceding 3 months.

Chest imaging was performed because of theworsening shortness of breath.

A CT scan of the chest withlung windows, obtained

through the lung baseswith the patient in theprone

position, shows subpleuralreticulation, ground-glass

opacities, andbronchiolectasis (Panel A).

A scan with soft-tissuewindows, obtainedwith the patient in thesupine position, showsa small pleural effusionon the right side,diffuse distention ofthe esophagus with air

and liquid, anddilatation of the mainpulmonary artery

(measuring 3.5 cm indiameter) (Panel B).

A scan with bonewindows,obtained in thesagittal plane,shows diffuseosteopenia,multiple lyticlesions in thespine, and ahealed fracture ofthe body of thesternum

(Panel C).

The patient was admitted 3.5 months afterthis presentation. On examination, therewere bilateral bronchial breath sounds,crackles at the base of the left lung, extensivehardening of the skin from the hands to theelbows and from the toes to above theknees, and deep bronze discoloration on thetrunk, arms, and legs .

Joint motion was limited by skin thickening.

An endoscopic examination was performed.During the endoscopy, a gastric biopsyspecimen was obtained from the antrum.

Gastric-Biopsy Specimen(Hematoxylin andEosin).

Examination of a gastric-biopsy specimen from the

antrum reveals expansionof the lamina propria and

prominent fibromuscularhyperplasia. There wereectatic mucosal capillarieswith occasional fibrinthrombi (inset). Thisconstellation of findings isconsistent with gastricantral vascular ectasia(“watermelon

stomach”).

IVIG and bortezomib were administered.

The patient was discharged on the fourth day.

Five days later, the patient reportedincreased discomfort and inability to bend hisjoints and was using a wheelchair. During thenext 4 days, confusion developed and he haddifficulty with word-finding. Oral intake waspoor.

Four months after this presentation, he wasbrought to the emergency department of thishospital; on examination, he was alert,oriented to person only, and had difficultywith word-finding and verbal expression.

The blood pressure was 98/63 mm Hg, andthere was periorbital and facial edema; theremainder of the examination wasunchanged.

Urinalysis showed 2+ albumin by dipstick, aspecific gravity of 1.015, and a pH of 6.0; theurinary sediment was packed withpigmented, coarsely granular casts and had10 non dysmorphic erythrocytes /HPF and nocellular casts. The ratio of total spot-urineprotein to creatinine was 4.0.

The peripheral blood smear showed 2 to 4schistocytes /HPF . CT of the head, performedwithout the administration of contrastmaterial, was negative. The patient wasreadmitted to this hospital.

What is your finaldiagnosis?

Which of the following is the themost appropriate diagnosis ?

1- Sclerederma

2- paraneoplastic syndrome

3- nephrogenic systemic fibrosis

4- Eosinophilic fasciitis (Shulman’s syndrome)

5- Lenalidomide toxicity

6- Scleroderma

7- Scleromyxedema

8 – thrombotic thrombocytopenic purpura

The correct answer is ……………….

Scleroderma

Discussion The differential diagnosis narrows to twosimilar but discrete clinical syndromes:scleroderma and scleromyxedema . Thefinding of mucin deposition on examinationof the skin-biopsy specimen argues against adiagnosis of scleroderma.

However, scleroderma is likely, given theoverall clinical features (including interstitiallung disease, bleeding due to GAVE ,inflammatory joint disease with limitations ofmotion, and rapidly emerging diffuse,hyperpigmented, fibrotic skin diseasewithout papules).

The event that led to his last presentation tothe hospital was probably scleroderma renalcrisis. Normotensive scleroderma renal crisishas been reported, but this patient wasprobably dehydrated, and cardiacdysfunction could have accounted in part forhis hypotension.

A subset of patients with scleroderma andanti-RNA polymerase III antibodies presentwith rapid diffuse skin disease, fibrosis ofdeep soft tissue, friction rubs, and jointcontractures and are at high risk forscleroderma renal crisis (20%).

They often have primary scleroderma-relatedheart disease and are at increased risk forconcomitant cancer .

A positive test of anti-RNA polymerase IIIantibodies would confirm the clinicaldiagnosis of scleroderma.

TTP was considered as an explanation of thepatient’s central nervous system and renaldisease, but this diagnosis would not explainthe previous findings of the skin, joints, andother organ systems.

In making a diagnosis of scleromyxedema, itwould be necessary to perform a kidneybiopsy to look for mucin deposition in renalvessels.

Thank you