A six year and eleven month old girl of non-consanguineous Caucasian parents first presented with a two week history of fever, weight loss, arthralgia and maculopapular rash. She was born at term via Caesarean section with no neonatal concerns. Her medical history was fairly unremarkable, with mild eczema and croup and normal growth. There was no family history of autoimmune conditions. She was up-to-date with her immunizations. She was initially diagnosed with tonsillitis which was positive for Streptococcus on a throat swab. She remained unwell despite recurrent courses of antibiotics over a 6 week period. A comprehensive viral surveillance including Epstein Barr Virus (EBV), Cytomegalovirus (CMV), HIV and Hepatitis B using PCR on blood was negative on admission. She attended her local hospital due to persisting symptoms. She had no clinical features of arthritis or bowel disease. Serum inflammatory markers were prominent including C-Reactive Protein 135 mg/l (0-10 mg/l), thrombocytopenia with a platelet count of 64 × 109/l (150–300 × 109/l), raised alanine transaminase (ALT), 1038 IU/l (10–35 IU/l), raised lactate dehydrogenase (LDH), 8775 IU/L (420–750 IU/l), hyperferritinaemia, 71,378 μg/l (23–76 μg/l), hypofibrinogenaemia, 1 g/l (1.5–4.0 g/l). Her haemoglobin (Hb) and white cell count (WCC) were 80 g/L (115–155 g/l) and 5.1 × 109/l (4.5–13.51 × 109/l) respectively. She was referred for further investigation; her bone marrow biopsy showed occasional haemophagocytosis; flow cytometry perforin expression was present, there was normal granule release (CD107a) on activation of CD8 and NK cells and her CD56 + ve cells were normal (82.4%) compared to the control (71.5%). A basic auto-immune screen was negative (anti-neutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, anti-nuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), and anti-cyclic citrullinated peptide (anti-CCP)). A presumed diagnosis of secondary HLH was made as she fulfilled HLH criteria without any genetic cause with normal granule release. She was treated with dexamethasone (8 weeks), etoposide (12 weeks), cyclosporine A (weaned from 7 months) as per HLH 2004 protocol. She made a good recovery, her biochemical markers normalised (ferritin 42 μg/l, CRP <5 mg/l, ALT 26 IU/ml, platelets 260 x 109/l, Hb 120 g/l) and she remained well for 20 months.
She subsequently represented with a HLH relapse having been unwell for 2 weeks with headaches and lethargy and 5-days of fever. Due to her previous medical history she was screened for a relapse of secondary HLH. Serum ferritin level was 6702 μg/l and LDH 1002 u/l. Repeat bone marrow aspirate showed no evidence of haemophagocytosis. She continued to have quotidian fevers occurring in the evening and night for over a month with other similar symptoms to the initial presentation, arthralgia, a migratory erythematous rash, lethargy and significant weight loss of 2 kg. A skin biopsy showed neutrophilic leucocytoclastic vasculitis therefore she was further investigated by paediatric rheumatology for an underlying systemic condition with an angiogram which showed no specific evidence of vasculitis. Further auto-antibody screening detected a raised anti-tissue transglutaminase (anti-TTG) at 108U/ml (0–6.9U/ml) and positive anti-endomysial antibodies (anti-EMA) indicating a positive coeliac screen. Her HLA typing was positive for HLA-DQ2 but negative for HLA DQ8. She was too unwell to tolerate an endoscopy and jejunal biopsy. There had been no abdominal symptoms and there was no family history of Coeliac Disease. She commenced a gluten-free diet without any Disease Modifying Anti-Rheumatic Drugs (DMARDs) or biological agents, after which her symptoms dramatically improved with her energy levels rising to 90% of normal, however, the rash took longer to fade. Her biochemical markers also improved with her anti TTG level normalising to 4.3U/ml and her ESR reducing from 34 mm/h to 12 mm/h (<13 mm/h) within a month of a gluten free diet. She remained extremely sensitive to gluten, any exposure caused a reaction within a few hours with fevers lasting up to seven days. This suggested that the driving factor for her inflammatory process was due to Coeliac Disease. In light of her hypersensitivity and severe clinical condition, it was felt that a re-challenge with gluten was not appropriate.
Since establishing a gluten-free diet she remained well with no further episodes of MAS. However, after 3 years of commencing a gluten free diet she developed swelling of her joints and was diagnosed with arthritis, mainly affecting the left elbow, which required joint injections and treatment with methotrexate. The family have noted that her symptoms correlate with mistakenly eaten food containing gluten. At no point has she had any bowel symptoms. There was no active arthritis, morning stiffness or limping during either episode of MAS, making SoJIA unlikely. A jejunal biopsy has not been carried out as she has remained on a strict gluten-free diet. Care was provided by a multi-professional team of rheumatologists, gastroenterologists and haematologists.


A 73-year-old, non-smoker Caucasian female presented in the Department of Oral Medicine and Pathology complaining of pain-ful oral lesions of 5-day duration. The lesions had been developed after initiation of a per os ciprofloxacin course (500 mg 1x3) on 5th therapy day for an acute urinary tract Escherichia coli infection diagnosed 10 days ago. Two days before the patient’s visit in our clinic, the urologist recommended ciprofloxacin replacement by metronidazole and cefaclor. According to the patient, similar lesions had appeared in the past after ciprofloxacin intake, though she was not sure regarding the MTX intake at that particular time.
The patient had a known rheumatoid arthritis (RA) history diagnosed 15 years ago. Medication for the RA management consisted of a low-dose methotrexate therapy (2.5mg 1x1/week) supplemented with folic acid (5mg 1x1/week), prednisone 5mg 1x1/day, in addition to a 5-courses of rituximab IV (Mabthera inj.sol 500mg/50ml 1/week x2) administration; the last rituximab IV injection was given 10 months before the lesions presentation. Alendronic acid (5600iu/tab 1x1/weekly) and daily calcium supplementation were taken for osteoporosis management.
The oral examination revealed multiple ulcerative lesions of variable size and irregular shape, located on the dorsal and lateral borders of the tongue, the lower lip, the alveolar maxillary and mandibular mucosa, which were covered by a grey-whitish thick pseudo-membrane (Fig. ), and showed a slightly vegetative ulcer base. There was no evidence of other mucocutaneous lesions or cervical lymphadenopathy. LDMTX-associated oral ulcers, drug-induced oral reaction, drug-induced erythema multiforme and a possible atypical viral or bacterial infection were considered in the differential diagnosis, taking into account the iatrogenic immunosuppression history, the abrupt onset of lesions, and the possible drug reaction (previous report of ciprofloxacin-induced oral lesions).
Tissue swabs from the ulcers were examined for viral, microbial and fungal infection, while a complete laboratory investigation was ordered. PCR tests for HSV, CMV and EBV were negative. A superimposed yeast infection by geotrichum candidum was detected, and interpreted to the long-standing iatrogenic immunosuppression. Complete blood test results were normal, including the folic acid levels. Elevated ESR and CRP levels and significant hypogammaglobulinemia (350 mg/dl, normal range: 700-1600 mg/dl) were noted. A lingual ulcer incisional biopsy was performed under local anesthesia.
Histopathologic examination revealed extensive ulceration of the covering stratified squamous epithelium extended deeply into subjacent striated muscle and adipose tissue that showed degeneration. The ulcer base was widely infiltrated by a dense polymorphous inflammatory cell population consisting of lymphocytes, histiocytes of variable size, along with neutrophils and scarce eosinophils (Fig. a). Among the inflammatory infiltration few scattered large binucleated lymphoid cells with noticeable atypical features were observed similar to Reed-Sternberg cells (Fig. b). Both the polymorphous inflammatory cells and the Re-ed-Sternberg-like cells exhibited positive immunostaining for T-cell markers CD2, CD3, CD4, CD8 and CD15 and negative for B-cell and NK-cell markers (CD20, CD30, Pax-5, CD56, TIA-1 and granzyme) (Figs. c-d). LMP-1 immunostaining and EBER test proved to be negative excluding the EBV presence. The above findings were suggestive of an EBV (-) lymphocytic infiltrate of T-cell phenotype. Based upon the patient’s medical history, the complete laboratory investigation, the clinical and histopathologic findings, a diagnosis of MTX-related non-specific ulcerative stomatitis was rendered, possibly induced by the recent ciprofloxacin administration.
With the rheumatologist’s consent, MTX intake was ceased and 3 weeks later the oral ulcers had healed completely (Fig. ). Two months after MTX withdrawal, the drug was restarted, with no evidence of recurrence of the oral lesions noted so far.
The patient had provided written informed consent for publication of this case report and any accompanying images in a scientific journal, after the authors explained the possible benefits to dental science.


A previously healthy 71-year-old male presented to the cardiac care unit with intermittent chest pain over the previous 24 hours and worsening of discomfort and pain by lying on his left side. Other symptoms consisted of pleuritic pain between the shoulders, a sore throat, and several days of low-grade fever. On presentation, he was not acutely ill despite a temperature of 38.8°C. Clinical examination of heart and lungs showed no abnormalities. He had one painfully enlarged lymph node on the right side of his neck. ECG showed sinus rhythm with normal axis and conduction times and widespread ST-elevation (). Laboratory findings showed troponin-T of 22 ng/l (normal value < 14 ng/l), CRP of 310 mg/l, and leukocytosis (21.1 × 10e9/l) with a left shift (19 × 10e9/l granulocytes). A chest X-ray showed no abnormalities.
We diagnosed our patient with myopericarditis and based on the epidemiology we considered an idiopathic or reactive origin most likely. We hypothesized that a bacterial infection of the throat could explain the infectious parameters. A bacterial myopericarditis was also considered, but anticipated less likely given the absence of acute illness. With this differential diagnosis we took blood cultures and started treatment with amoxicillin and clavulanic acid (1000/200 mg 3 times daily) in combination with acetylsalicylic acid (600 mg 4 times daily) and pantoprazole.
On the second day of admission, the ear, nose, and throat doctor was consulted, who excluded pharyngeal abscess as alternative cause for the elevated infectious parameters. A cardiac ultrasound study showed normal heart function and moderate (<20 mm) pericardial effusion (). During admission to our ward, chest pain remained unchanged and inflammatory parameters increased to CRP 495 mg/l and leukocytes of 27 × 10e9/l. On the third day, 2 blood cultures grew positive of Neisseria meningitidis serotype C (subtype P 1.5, 2, F3-3) sensitive for amoxicillin, rifampicin, and ceftriaxone, and antibiotics were switched to ceftriaxone (2 grams i.v. once daily). The patient's wife was prophylactically treated with azithromycin (500 mg once daily for 3 days).
On the fourth day, our patient had developed paroxysmal atrial fibrillation, and ECG voltages were decreased compared to admission (). A repeat ultrasound showed a substantial increase in pericardial fluid to large (>20 mm) pericardial effusion, with dense structures within the fluid (). Furthermore, it showed diffuse left ventricular hypokinesis with a decreased ejection fraction of ±30%, a mild right ventricular diastolic collapse, and a fixed and unreactive inferior vena cava. Importantly, our patient had no fever and did not show other clinical signs of disease progression.
By all means, the ECG and ultrasound studies clearly indicated early cardiac tamponade and our patient was immediately transferred to a tertiary referral hospital. Sufficient drainage via pericardiocentesis or a pericardial window was considered unlikely given the dense aspect of the pericardial effusion on echocardiography. Therefore, the patient immediately underwent complete pericardiotomy via sternotomy to remove all debris. Upon opening the pericardium, a typical bread and butter appearance was noted (), after which 1100 milliliters of thick purulent fluid was removed and chest tubes were placed to drain the pericardial space. Gram stains were positive for gram-negative diplococcus. Cultures did not grow bacteria, presumably as a result of antibiotic treatment. The patient returned to our hospital after the removal of pericardial drains. Postoperatively he had signs of right-sided decompensation and persisting atrial fibrillation, for which he was treated with furosemide, metoprolol, and acenocoumarol. After completing two weeks of ceftriaxone, infectious parameters were normalized, ultrasound showed no return of pericardial effusion, and the patient was discharged in good health. After three months of follow-up, left ventricle ejection fraction was completely recovered and there were no signs of constrictive pericarditis.


A 69-year-old female (160 cm, 50 kg, ASA I) was scheduled to undergo a vaginal prolapse operation. Her medical history included Sjögren's syndrome and glaucoma. In addition to treatment with timoptol, she occasionally used omeprazol due to gastric complaints. Preoperative physical evaluation showed a normal mouth opening and Mallampati score III with limited neck mobility; a sLMA was chosen to maintain the airway preoperatively. Anesthesia was induced with 15 mcg sufentanil and 300 mg propofol intravenously. A size 4 sLMA was inserted using the standard technique. Insertion of the sLMA was performed by a second-year resident in one attempt. Insertion was without any difficulty and was done under supervision of a Staff Anesthesiologist. After insufflation with about 20 mL air the seal allowed ventilation without leakage. Although cuff pressure is routinely measured in our hospital, in this case it was accidently omitted and not recorded. An inspiratory airway pressure of 18 cm H2O was obtained and maintained throughout the whole operation. The cuff volume was not noted at that time, and the intracuff pressure was not measured on sLMA insertion. Ventilation was set to a 50/50 oxygen/air mixture, ventilatory frequency of 12 bpm, and inspiratory : expiratory ratio of 1 : 2. General anesthesia was maintained with sevoflurane in 50% oxygen. The surgery was completed uneventfully as ventilation and blood pressure were adequate throughout the whole operation. During emergence no complications occurred and total anesthesia time was 1 h and 5 minutes.
Two days postoperatively the patient developed hoarseness and two weeks later she consulted an ENT specialist at our hospital as the complaint got worse. Fiberoptic laryngoscopy showed left vocal cord paralysis and left recurrent laryngeal nerve neuropraxia was diagnosed (). A computed tomography (CT) of the neck and thorax showed no pathological lymphadenopathy or any tumors in the neck or the lungs. Blood analysis showed normal values. The findings were discussed with the patient and she was directed to a logopedist for voice therapy and an appointment was made over 6 weeks.


A 25-year-old female presented to the emergency department with complaints of severe nonradiating epigastric and umbilical pain associated with nausea and vomiting. She was unable to tolerate oral intake. The patient reported this pain to be similar to the abdominal pain that occurred with previous episodes of DKA, although more severe in intensity. Past medical history was significant for type 1 diabetes mellitus with reported noncompliance with insulin and multiple episodes of DKA. Medical history also included asthma, bipolar disorder, ischemic bowel disease status after small bowel resection, methamphetamine abuse, posttraumatic stress disorder, and idiopathic chronic pancreatitis. Her home medications comprised of a long and short acting daily insulin regimen, divalproex, citalopram, and albuterol inhaler. She had no documented allergies.
Vital signs on arrival revealed a heart rate of 115/minute, blood pressure of 132/110 mmHg, respiratory rate of 28/minute, and oxygen saturation of 100% on room air. On physical exam, the patient was noted to be lethargic with dry mucous membranes. Cardiovascular examination revealed sinus tachycardia. Abdominal examination revealed diffuse abdominal tenderness with active bowel sounds with no evidence of guarding or rigidity.
Due to the severity and acuity of her uncontrolled diabetic ketoacidosis with difficulty obtaining IV access, an intraosseous line was obtained in the right humerus for administration of intravenous fluids. A registered nurse, with prior IO access training that included a class and further instruction at hospital orientation when hired, obtained IO access using the EZ-IO system. Initial laboratory studies revealed a blood glucose level of 321 mg/dL, an anion gap of 22, and bicarbonate level of 15 mmol/L. The potassium level was 3.6 without electrocardiographic changes. Urine analysis was positive for ketones and glucose. Arterial blood gas revealed severe metabolic acidosis with the pH being 7.05. Abdominal radiograph was unremarkable. The patient was diagnosed with severe diabetic ketoacidosis and aggressive fluid resuscitation was initiated with normal saline through the intraosseous access, along with insulin infusion as per the hospital's DKA protocol. There were no difficulties with fluid and medication administration through the aforementioned intraosseous needle.
After adequate fluid resuscitation, an attempt at intraosseous line removal in the intensive care unit was unsuccessful due to severe pain in addition to concerns for possible breakage of the needle. A plain radiograph of the right shoulder was significant for an intraosseous needle that appeared bent at the humeral neck, without any evidence of fracture or dislocation on anteroposterior view ().
Orthopedics was consulted and the risks and benefits of surgical and nonsurgical options for intraosseous line removal were thoroughly discussed with the patient. The patient opted to undergo surgical removal of the intraosseous line. Intraoperatively, the right arm was abducted and under C-arm guidance, gentle traction on the intraosseous line was placed directly over the bent portion in order to prevent the needle from breaking off inside the bone. The needle was removed in one piece and C-arm images were taken to confirm no pieces of needle were left behind (). Intraoperative fluoroscopic images demonstrated removal of the intraosseous needle from the proximal humerus, with no evidence of residual foreign body.
Upon further investigation, the nurse reported two prior successful tibial IO placements. However, the nurse denied having placed a humeral IO line prior to this patient interaction. The nurse noted that the patient refused a stabilizing device to keep her arm stable during the placement. The patient had a history of bent intraosseous needles when removing the needles in the past. The prior incidents did not require surgery to remove the intraosseous needle. After the event, the emergency department nurses received training in obtaining IV access via humeral and tibial IO placement.


A 15-year-old Hispanic male presented with severe abdominal pain and distention that progressively worsened over the past 12 hours. The patient was reportedly asymptomatic the day before. He also complained of pain and difficulty moving his legs bilaterally. He had no associated vomiting, diarrhea, or fever.
The patient's mother reported a past medical history of premature birth, developmental delay, and a recent diagnosis of Superior Mesenteric Artery syndrome. The diagnosis of SMA syndrome was made after similar episode of abdominal pain and distention 4 months earlier. According to inpatient records, the patient received nasojejunal tube decompression followed by tube feeds to increase the size of his mesenteric fat pad. No surgical repair was scheduled. The patient's mother denied any other symptoms since that episode ().
On physical exam, the patient was alert and in severe distress. His heart rate was 150 beats/min with a blood pressure of 105/75 mmHg. He was tachypneic with clear lung sounds. His abdomen was massively distended, rigid, and diffusely tender to palpation. His skin was cold and mottled from the waist down and he had decreased motor function and sensation in his legs bilaterally. Femoral pulses were not palpable, but radial pulses were present.
Abdominal X-ray showed massive distention of the stomach without free air. Venous blood gas showed pH 6.9, bicarbonate level 17, and lactate 10.7. Complete blood count showed a white blood cell count of 22000, hemoglobin of 19.3, hematocrit of 57.9, and platelets of 288. His metabolic panel was notable for carbon dioxide level of 14, anion gap of 29, BUN of 24, and creatinine of 2.4. Liver function tests were within normal limits.
The patient was given a 30 mL/kg normal saline bolus. An attempt was made to pass a nasogastric tube for gastric decompression, but the tube could not be advanced past the gastroesophageal junction. Based on clinical exam, severe abdominal compartment syndrome with compression of arterial flow through the aorta was suspected. In consultation with the surgery team, the decision was made to take the patient for emergent decompressive laparotomy without delaying care further for compartment pressures testing. Emergent needle decompression of the stomach would have been another option for the emergency physician if the operating room had not been immediately available or if care was being provided at an outlying facility and transport was indicated. The surgical team wanted to avoid any delay to surgery. The patient was in the operating suite within one hour of arrival to the hospital.
In anticipation of significant reperfusion injury, the patient was given calcium gluconate, sodium bicarbonate, insulin, and dextrose at the start of surgery. Upon opening the abdomen, the patient was noted to have a massively distended stomach with an ischemic appearance. The small bowel was also noted to be dusky from ischemia. The stomach was incised and a large quantity of air and partially digested food was evacuated. With decompression of the stomach, the patient had return of femoral pulses and the lower extremities regained color.
Shortly after decompression of the stomach, the patient's arterial blood gas showed a pH of 6.7, HCO3 of 10, lactate of 13, and potassium of 8.7. Additional bicarbonate, insulin, and dextrose were given. The patient then suffered cardiac arrest second to hyperkalemia and underwent an hour of Advanced Cardiac Life Support (ACLS) protocol resuscitation in the operating room. During the code, the patient's lactate climbed to 15 and the potassium fluctuated between 7 and 8 on multiple serial blood gases despite medical intervention to stabilize it. The patient regained pulses and was moved to the intensive care unit (ICU).
In the ICU, the patient was started on continuous dialysis. Despite resuscitation efforts including high doses of vasopressors to maintain blood pressure as well as sodium bicarbonate, insulin, glucose, albuterol, and calcium, the patient suffered another episode of cardiac arrest. Despite resuming ACLS protocol, the patient was unable to be resuscitated. The patient expired in the intensive care unit 5 hours after arrival to the emergency department.


The patient is a 5-year-old Caucasian boy with an 18-month history of progressive, generalized, nonpruritic hypopigmented lesions, with central lacy erythema and hypopigmented halo, associated with few erythematous papules, within normal overlying skin. The largest lesion was located in the iliac crest ().
The patient's past medical and family history were irrelevant, with no evidence of recent infections, atopy, other inflammatory dermatosis, or relevant environmental exposure.
He was firstly diagnosed with a benign skin condition and prescribed emollients, with no improvement. However, given the persistence and progression of the skin lesions, the patient was submitted to biopsy from a hypopigmented patch that showed typical features of hypopigmented MF (papillary dermal interstitial infiltrate of lymphocytes with mild atypia and epidermotropism; ). Immunophenotyping showed positivity of atypical lymphoid cells for CD2, CD3 (with decreased expression intensity), CD5, and CD8 and an absence of expression of CD20, CD4, and CD30.
On physical examination he had infracentimetric cervical, axillary, and inguinal lymph nodes and no evidence of organomegaly.
Laboratory tests (complete blood count with differential, biochemistry including renal and hepatic function, hemostasis, immunoglobulins, peripheral blood immunophenotyping, and infectious serologies) were unremarkable. Positron emission tomography (PET) scanning was suggestive of metabolically active lymphoproliferative disease with cervical lymph node involvement. Cervical lymph node excisional biopsy did not show involvement by lymphoid neoplasia. Bone marrow aspirate and biopsy were likewise normal.
Therefore, staging tests revealed localized cutaneous disease and the patient was diagnosed with HMF, stage Ib (T2N0M0B0). He initiated treatment with topical corticosteroid 3 times weekly and tacrolimus 2 times weekly and narrow-band ultraviolet B (NBUVB) phototherapy sessions, 2-3 times weekly, with good response.
After the patient began phototherapy sessions, he reported pruritus which significantly improved with continued treatment. Resolution of the central lacy erythema became apparent after a few sessions.
A significant improvement of hypopigmented patches and an absence of new lesions were observed at his last visit (approximately 1 year after diagnosis). Thirty-two NBUVB phototherapy sessions were performed so far, in two different periods of time (cumulative dose 15.8 J/cm2), combined with topical mometasone cream 2 times a week in residual macular lesions.


A 39-year-old gravida nine para two was referred at 30 weeks of gestation for evaluation of MAP. Her history included two uncomplicated low transverse cesarean deliveries, four curettage procedures for pregnancy termination, and two spontaneous abortions. Pelvic imaging showed an anterior placenta with obliteration of the uterine interface, presence of intraplacental vascular lacunae, and increased vascularity proximal to the bladder and loss of the myometrial margin. Findings were suspicious for placenta percreta possibly involving the urinary bladder. The patient was counseled extensively regarding the management of MAP, including conservative management and its associated risks, and comprehensive informed consent was obtained. Planned delivery at 35 weeks and 6 days of gestation occurred under general anesthesia. Immediately prior to delivery, the patient underwent uncomplicated placement of bilateral hypogastric artery balloon catheters and bilateral ureteral stents. At the time of stent placement, systematic inspection of the bladder was noted to be normal on cystoscopy. Intraoperatively, an area of tortuous blood vessels on the uterine serosa was noted extending to a ballooned right broad ligament and to the border of the bladder reflection on the left side, confirming a placenta percreta with broad ligament and possible bladder invasion (). Given the extent of abnormal placentation, conservative management was elected. Uncomplicated cesarean delivery of a neonate weighing 3,150 grams via a fundal hysterotomy then followed. After high ligation of the umbilical cord, the placenta was left adherent to the myometrium. The hysterotomy was repaired in three layers and total estimated blood loss was 1000 cc. The patient was then transferred to the interventional radiology suite in stable condition where balloon catheters were removed followed by bilateral internal iliac embolization using a slurry of absorbable gelatin compressed sponge (gelfoam). Postembolization arteriography was performed showing stasis within the uterine arteries.
Shortly after arrival to the postanesthesia care unit the patient reported buttock numbness but was otherwise asymptomatic. The epidural catheter was removed on postoperative day one and shortly thereafter she reported a burning sensation in the right buttock. Physical exam revealed a tender 9 × 11 cm area of ecchymosis in the medial aspect of right buttock with extension to the gluteal crest. Given recent embolization, there was concern for end-artery compromise and potential soft-tissue and skin necrosis. Interventional radiology, vascular surgery, and plastic surgery teams were consulted. Computed tomography angiogram demonstrated patent internal iliac arteries with patent proximal pelvic branches. Over the following week the lesion blistered, necrosed, and unroofed to reveal healthy tissue beneath. The lesion was treated with topical silver sulfadiazine cream and pressure relief. The patient was discharged home on postoperative day seven with close outpatient follow-up.
The patient was planned for interval hysterectomy at six to eight weeks postpartum but was briefly lost to follow-up. Shortly thereafter, she presented and was admitted to the hospital when she noted umbilical cord tissue prolapsing from the vagina. She subsequently underwent hysterectomy at ten weeks postpartum []. At that time the buttock wound was noted to be healing well with improved epithelialization, scar contraction, and healthy granulation tissue throughout (). She was recommended continued use of daily hydrated polymer dressings until the wound was fully closed.


This is a case of a 62-year-old female who underwent a C2 to the sacrum fusion previously for progressive and worsening idiopathic scoliosis. Her prior surgeries were performed in multiple stages due to proximal junctional kyphosis at various levels. She suffered multiple falls down stairs and presented to the emergency department with severe and worsening neck pain. She also reported bilateral upper extremity numbness and tingling accompanied by balance difficulties while ambulating. Prior to this series of falls, she was living and functioning independently at home.
On examination, our patient had full strength in all muscle groups with a positive right Hoffman’s reflex and 2+ reflexes otherwise. Computed tomography (CT) scan of the neck demonstrated the following: (1) a 7 mm anterior displacement of the C2 vertebral body, (2) multi-comminuted and angulated fracture of C2, (3) anterior subluxation of the C1-2 complex on C3, and (4) subluxation of the foramen magnum (Figure ). She was unable to undergo magnetic resonance imaging (MRI) due to an implanted defibrillator device.
Given the patient’s significant pain and deformity of the C1-2 complex, a posterior occiput to cervical fusion and reduction of the subluxed C1-C2 complex was performed (Figure ). There were no complications with the procedure, and the patient retained full strength with improvement alignment on postoperative x-ray imaging.


A 41-year-old male fell into a freshwater lake. Emergency responders pulled him from the lake and return of spontaneous circulation was achieved after twenty minutes of resuscitation. Subsequent chest radiographs showed development and worsening of bilateral opacities suspicious for pneumonia. Brain death was declared three days after hospital admission.


A 34-year-old Caucasian male was brought to the emergency room following multiple episodes of non-bilious vomiting and non-bloody diarrhea over the previous three days. This was associated with abdominal bloating, listlessness, decreased oral intake and decreased urine output. The patient's history was obtained from his mother as the patient was unable to speak. She did not notice any fever, chills, or sweating. She did not report any recent hospitalization or sick contacts for the patient. His past medical history was significant for developmental delay, club foot, neural deafness and type II diabetes. Family history was unremarkable in terms of any infectious or gastrointestinal illnesses. His mother was his primary carer. The patient did not have a history of alcohol, tobacco or illicit drug use. He was not taking any medications at home and did not have any reported allergies.
Vital signs in the emergency room were significant for a temperature of 38.7°C, heart rate of 153 bpm, blood pressure of 74/43 mmHg, respiratory rate of 55 with 90% oxygen saturation on 2 L of supplemental oxygen via nasal cannula. General examination was remarkable for lethargy, dry mucous membranes, collapsed neck veins, and decreased skin turgor. Abdominal examination revealed a distended abdomen with marked left lower quadrant tenderness. No guarding or rebound tenderness was noted. Bowel sounds were remarkably decreased. Laboratory analysis showed a white blood cell count of 20.9 cells/mL with 10% band neutrophils and 62% mature neutrophils, blood urea nitrogen 57 mg/dL, creatinine 2.75 mg/dL, bicarbonate 13 mmol/L with an anion gap of 26 and lactic acid level of 10.3 mmol/L. Liver enzymes, total bilirubin and coagulation factors were within normal limits. Work-up for sources of infection included blood cultures, stool culture, stool C. difficile toxin polymerase chain reaction (PCR) and urine analysis.
The patient was started on intravenous fluid therapy for dehydration, along with ciprofloxacin and metronidazole for suspected infectious colitis. Abdominal plain films showed a distended colon, suggestive of distal colonic obstruction vs. intestinal ileus. Computed tomography (CT) scan of the abdomen showed thickening of the sigmoid colon with distension of the transverse and descending colon, consistent with colitis. The patient underwent a colonoscopy, which showed severe inflammation with mucosal friability and grey-white exudates extending from the sigmoid to the descending colon (). A sudden transition to fairly normal-looking colon was noted in the transverse colon. Multiple biopsies were taken from the affected and seemingly normal areas.
The patient’s hypotension and lactic acidosis resolved with intravenous fluids and creatinine trended down to normal by hospital day 5, but his diarrhea did not abate. Stool culture was negative for Salmonella, Shigella, Campylobacter, and Yersinia. Blood cultures, urine analysis and stool C. difficile toxin assay were also negative. Colonoscopic biopsies showed mild active colitis with fibrino-purulent exudates. Given the negative work-up for infectious colitis and active inflammation of pathology, the patient was started on intravenous corticosteroids and mesalamine rectal enemas for proctitis from suspected ulcerative colitis. Additionally, a repeat stool specimen was sent for culture. On the sixth day following admission, the repeat stool culture came back positive for heavy growth of MRSA. The patient was subsequently started on vancomycin 125 mg orally QID for 14 days. After the institution of vancomycin, the patient's symptoms promptly resolved. He was taken off the corticosteroids. His repeat stool culture 30 days later was negative for MRSA, indicating cure.


The patient is a 20-years old woman. Her main complaints are primary amenorrhea and abdominal masses. Physical examination showed 156cm in height and 56kg in weight, less subcutaneous fat than a typical woman, hypoplastic breast, and external female genitalia with public hair in inverted triangle. No touchable masses were found in bilateral canalis inguinalis and labium majus. The abdomen was soft and a smooth-surfaced mass was touched one each side which doesn’t show any tenderness or rebound tenderness but a shifting dullness when percussed. A surgery of bilateral ovarian tumor hysterectomy was performed for the patient. The tumors was 10cm×6cm×5cm on right side and 25cm×22cm×10cm on left side, both were attached with streak gonad and normal fallopian tube. Histological examination revealed the tumors belong to dysgerminoma.


A 26-year-old man came to our clinic with a complaint of painless sudden loss of vision in the left eye, which had started 20 hours earlier. On ophthalmic examination, best-corrected visual acuity was 20/200 in the left eye and 20/20 in the right eye (Snellen chart). Intraocular pressure was 12 mmHg in both eyes. Slit-lamp examinations of anterior chambers were normal in both eyes. Funduscopy of the left eye revealed well-demarcated retinal edema centered on a cilioretinal artery adjacent to the fovea (). We diagnosed the disease as CLRAO. After application of topical timolol+dorzolamide+bimatoprost and oral 500 mg acetazolamide, ocular massage was performed. Fundus fluorescein angiography demonstrated an occluded cilioretinal artery ().
HBO therapy was started 22 hours after the onset of symptoms. The patient underwent 5 HBO therapy sessions (2.5 atm, 2 hours). When he returned on the third day after treatment, his visual acuity was unchanged. Five additional HBO treatments were performed, and one week later the visual acuity of the left eye had improved to 20/30. Resolution of the retinal edema was also noted. HBO treatment was discontinued after 20 sessions (total 40 hours). When he returned on the second week after treatment his visual acuity had improved to 20/20. The retinal edema was further resolved. Fundus fluorescein angiography on the second week after the end of treatment demonstrated that the cilioretinal artery was recanalized (, ). Computerized visual field testing also demonstrated a significant decrease in the size of the visual field defect (, ). His blood laboratory findings, systemic physical examination, electrocardiogram, and chest x-ray were all unremarkable. Cryoglobulin, lupus anticoagulant, and anti-cardiolipin antibodies were all negative. Antithrombin III, protein C, and protein S activities were normal.


A 55 year old man was admitted to hospital with a head injury that resulted in hearing loss on the left side with pulsatile tinnitus and a vague feeling of disorientation. A CT scan showed an irregular extra-axial solitary lesion lying adjacent to the falx on the right of the midline measuring 3 × 4 × 6 cm with significant mass-effect and peritumoral oedema involving most of the right frontal lobe. There was evidence of underlying bone remodelling with vascular dural supply and heterogeneous enhancement after contrast administration with a deep cystic component. There were fringes of tumour interdigitating with the brain substance indicating probable brain invasion (Fig. ). The findings were consistent with an aggressive frontal meningioma. Partial surgical removal of the lesion in the right frontal lobe was undertaken. On histological examination, the lesion was classified as an atypical (WHO Grade II) meningotheliomatous meningioma.
A year later, the patient experienced an episode of seizures and a CT scan revealed three new lesions at the site of the previously excised meningioma with extensive perilesional oedema. An MRI confirmed the CT findings indicative of tumour and also detected invasion and occlusion of the anterior part of the superior sagittal sinus (Fig. ). Partial resection of the recurrent mass was again undertaken. Histology of the tumour specimen showed features of an anaplastic (WHO Grade III) meningotheliomatous meningioma with lobules of tumour containing cells with round or oval vesicular nuclei. Focally, there were cells which showed more prominent nuclear pleomorphism. There was increased mitotic activity and extensive tumour necrosis was noted (Fig. ). Post-operative follow-up revealed residual tumour in the anterior part of the superior sagittal sinus, along the falx and the right frontal convexity. Follow-up imaging also confirmed interval progression of the residual meningioma.
The patient completed a course of radiotherapy and, nine months later, a mobile soft tissue lump on his back was noted. A thoracic CT scan revealed a soft tissue lesion superficially located in the inferior portion of the left trapezius muscle. The lesion was lobulated, had a low attenuation centre, showed peripheral enhancement and did not exhibit evidence of matrix calcification (Fig. ). The lesion increased in size and a subsequent MRI scan performed 6 months later confirmed the presence of a solid soft tissue mass up to 5 cm in diameter in the medial left trapezius muscle. The lesion indented the underlying paravertebral muscles but remained well-defined and did not invade the deeper musculature. The lesion returned isointense T1-W signal relative to skeletal muscle and heterogeneous high T2-W signal. There was no internal calcification, haemorrhage or cystic degeneration. Peripheral feeding vessels were present (Fig. ). A PET-CT scan demonstrated that the intramuscular lesion was extremely FDG avid with an SUVmax of 22.1 (Fig. ). PET-CT also revealed disseminated, markedly FDG avid metastases in liver, bone and pleura and residual meningioma in the right frontal lobe.
The lesion was biopsied and showed a largely lobulated tumour containing collections of tumour cells, many of which showed similar features to those seen in the frontal lobe tumour. There were a few whorled collections of tumour cells with round or oval vesicular nuclei (Fig. ). There was prominent nuclear pleomorphism, a high mitotic rate and focal tumour necrosis. Focally there were solid areas of proliferation of pleomorphic tumour cells, some of which had vacuolated cytoplasm. Immunohistochemistry showed strong expression of epithelial membrane antigen (EMA) and P63; there was also focal expression of cytokeratin (CK7+, CK20−), nuclear staining for IN-1, and a high Ki-67 fraction. There was no expression of desmin, S100, CD10, CD30, CD68, myogenin, smooth muscle actin, estrogen receptor, progesterone receptor, chromogranin, carcinoembryonic antigen or TTF1. There was initially some difficulty in establishing the pathological diagnosis as the previous history of recurrent atypical/anaplastic meningioma was not provided to the reporting pathologist whose initial differential diagnosis included a soft tissue metastasis of carcinoma and a primary soft tissue sarcoma expressing the epithelial markers. However, once the history of meningioma and the radiological findings were taken into account, it was clear that the soft tissue mass represented a metastasis of the previously diagnosed anaplastic meningotheliomatous meningioma.
A wide local excision of the lesion, which measured 5 × 3 × 2 cm, was performed; this included a cuff of normal muscle around the lesion and a 1 cm margin of skin around the previous biopsy scar. Histological findings in the resection specimen were similar to those of the biopsy. Further follow up of the patient by CT scan showed no recurrence of the soft tissue lesion but progression of disease in the brain.


We present the case of a 75 year old woman with OC, first diagnosed in 2014. The patient underwent diagnostic laparoscopy with histologic confirmation of a high-grade serous adenocarcinoma of the right ovary. The tumor was not resectable due to extensive small bowel involvement. In addition, due to her clinical condition, the patient declined systemic chemotherapy with carboplatin and paclitaxel. The patient was offered local, intraabdominal chemotherapy with cisplatin and doxorubicin applied as PIPAC as an off-label procedure. The patient provided written informed consent for this treatment and for publication of this case report. We did not obtain Ethics Committee approval, since no approval is required for a singular case report.
From October 2014 to August 2016, the patient underwent 13 cycles q 5–12 weeks of PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 at 12 mmHg. PIPAC was performed as described before (5). Briefly, both drugs were applied into the abdomen via laparoscopy using a 12 mmHg CO2 pneumoperitoneum, an aerosolizer (Capnopen®, Capnomed, Villingen, Germany), and an intravenous high-pressure injector (Arterion Mark 7, MedRad Bayer Healthcare, Berlin, Germany). A video of a PIPAC application is available in the (Additional file 1: Video S1) of the electronic version of the manuscript. Adverse events were graded according to the CTCAE version 4.0. Quality of life was measured by the standardized European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30, version 3.0, questionnaire, a validated tool for assessing quality of life in cancer patients. Between October 2015 and May 2016, tamoxifen 20 mg once daily was taken by the patient. In May 2016 intravenous carboplatin area under the curve (AUC) 3 was added on day 2 after each PIPAC due to local progression diagnosed on a computed tomography scan.
Figure shows screenshots of video-laparoscopies during consecutive PIPACs demonstrating PC and response to PIPAC, evidenced by fibrosis and reticular sclerosis of PC nodules. Histological objective tumor response was noted by grading of tumor cell regression. Figure demonstrates histopathological specimens of the initial tumor specimen sampled during PIPAC #1 with peritoneal manifestations of serous carcinoma with large, pleomorphic nuclei and frequent mitosis and histopathological specimens taken during consecutive PIPACs with residual peritoneal tumor foci with reduced cellularity and fibroelastic connective tissue with inflammatory changes such as fibrinous exudate, fibrosis, foreign-body reaction, and hemosiderin-laden macrophages.
Intraoperative assessment of PCI during repeated PIPACs confirmed stable disease. The PCI noted by laparoscopy during the 13 PIPAC sessions was 25, 19, 10, 15, 15, 13, 14, 10, 8, 10, 15, 6, and 12. The treatment was well tolerated. CTCAE events grade 1 (abdominal pain, fever) were noted within 72 h after 7 PIPAC procedures. A CTCAE event grade 3 was observed twice at the time of PIPAC #11 and #12 (two episodes of symptomatic pleural effusions necessitating pleural puncture and drainage). There was no acute or cumulative renal, hepatic, or hematologic toxicity throughout the whole treatment period. We observed stable or declining values of creatinine, γGT, GOT/ASAT, GPT/ALAT, lactate dehydrogenase, alkaline phosphatase, C-reactive protein, bilirubin, and Quick throughout all PIPAC procedures (Fig. ). Serum levels of CA 125 fluctuated between 1273 and 3486 U/mL. Figure shows EORTC QLQ-C30 quality of life scores indicating a stabilization of the patient’s quality of life during the treatment period. Specifically, scores for pain, vomiting, and obstipation/diarrhea were stable throughout the treatment, suggesting that intraabdominal maintenance chemotherapy with PIPACs does not result in acute or cumulative gastrointestinal toxicity.


A previously healthy 11 year old girl with neurofibromatosis type 1 was diagnosed in 2011 with a large right parietal glioblastoma multiforme following an episode of left sided weakness. She was found to have a hemorrhagic stroke, and despite a partial resection of the tumor, her hemiparesis never resolved. She was started on COG ACNS0822, randomized to Arm A, and she completed the 6 weeks of radiation and vorinostat. In November 2011 she started maintenance chemotherapy with Avastin 10mg/kg Day 1 and 14/Temozolomide 200mg/m2 Days 1-5 for 28 day cycle. She completed 11 out of 12 cycles before coming off protocol for disease progression in October 2012.
She was started on melatonin, metformin, cyclophosphamide and erlotinib based on a proteomic analysis done at Texas Children's. She progressed again within 2 months with leptomeningeal spread to the spine, and was changed to VP-16, vincristine, crizotinib, erlotinib, vorinostat. The regimen resulted in unacceptable toxicities with myelosupression, severe mucositis, and QTc prolongation with cardiac compromise.
She was taken off any disease directed therapy in March 2013 and referred to us for molecular analysis and individualized therapy. The characteristics of the tumor at diagnosis showed activation of a number of pathways associated with cancer growth and progression. The findings and initial pathology are summarized in Figure . The genomic analysis revealed NF1 R1968*, BRCA1 N1355fs*10, CDK4 amplification, TP53 R175H, SOX2 amplification. Because loss of neurofibromin function leads to increase in signaling through the Ras-Raf-MAPK and mTOR pathways, [] she was started on sirolimus 2mg daily and sorafenib to inhibit growth factors downstream from these pathways in addition to metronomic (50 mg/m2) etoposide daily. She remained stable on this regimen until December 2015 (3 years) when she had a radiological progression.
She underwent an excisional biopsy and the molecular analysis of this relapse was consistent with a radiologically, histologically and genetically more aggressive phenotype (Figure ). In addition to the original gene alterations, she now had BRCA2 splice site 67+1G > A, ERBB3 S1074N, TSC1 splice site 364-1G > A, GLI1 amplification, STAG2 Q1167*. Her therapy was therefore changed to everolimus (Ras-Raf-MAPK and mTOR pathways), ceritinib (GLI1/sonic Hedgehog pathway), and trametinib on a metronomic chemotherapy backbone of temozolomide 25 mg/m2, and remains stable.
The case provides a good illustration about the need for multi-agent therapy based on molecular signature. It also stresses the need to consider re-biopsy with relapse as the eco-evolutionary forces within the tumor microenvironment may cause therapeutic resistance and escape from tumor dormancy.[]


A 7-y old previously healthy boy with no family history of cancer was diagnosed with stage III abdominal Burkitt lymphoma in December 2014. He was initially treated standard BFM B-NHL 04 therapy, which included a single initial dose of 375mg/m2 Rituximab followed with 5 cycles of BNHL 04 chemotherapy consisting of dexamethasone, methotrexate, ifosfamide, cyclophosfamide, cytarabine, etoposide, doxorubicine, vincristine as well as intrathecal therapy. After 2 cycles, he had a very good partial response reaching < 5% of the initial tumor volume. An episode of the intestinal obstruction in February 2015 led to excision, and the histology confirmed sclerosing mesenteritis, without histological or rtPCR evidence of lymphoma (the original tissue was positive for cMYC translocation). The FDG PET was borderline positive, but this was thought to be due to inflammation.
Unfortunately the child was found to have an isolated radiological progression in the same region in which the intestinal obstruction had occurred two months after completing chemotherapy. The biopsy in June 2015 confirmed relapsed Burkitt lymphoma, this time with marked areas of sclerosing mesenteritis and mesenteric panniculitis. Mutational analysis of PI3K delta subunit proved germinal mutation/variant outside the classical Activated PI3K-delta syndrome (APDS) 1 or 2 variants. The mutational activation was confirmed by testing the patient's T- lymphocytes, and the S6 (Ser235/236) phosphorylation was found to be 33 fold that of a healthy control.
While undergoing the genomic testing, the boy was started on retrieval therapy with ibrutinib, obinutuzumab and ICE chemotherapy. Unfortunately, after a transient response and disease stabilization, he had an early progression following the first cycle. Based on the finding of germline mutation in PI3K delta subunit, he got 2 weeks of idelalisib (a phosphoinositide 3-kinase inhibitor, which blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase). The single agent therapy led to normalization of the S6 (Ser235/236) phosphorylation in patients peripheral T lymphocytes, but he had further disease progression. It was only when the combination of high dose cytarabine/etoposide (CyVe) with idelalisib and obinutuzumab was used that the disease was stabilized. A biopsy on 9/2015 showed a CD20 positive tumor, with high degree of proliferation and strong expression of PD-1L.
The second biopsy was analyzed using Affy GeneChip ST 1.0 and the whole transcriptome analysis confirmed increased levels of PI3K and revealed additional HR23B. Because HR23B can be used as a good predictor of response to HDAC inhibitors, valproic acid was being considered. Additional tumor specific (somatic) gene alterations in R273C and p53 were also shown.
The child, who had continued on oral ibrutinib + idelalisib and low dose cyclophosphamide since 9/2015, received palliative 21Gy local radiation. In 10/2015, based on the second biopsy findings, the nivolumab, a human IgG4 anti-PD-1 monoclonal antibody, and valproic acid, and HDAC inhibitor, were added. As of March 2016 the boy is doing very well. He has had partial response of the single residual abdominal tumor disease, and remains clinically well with Lansky score 100 and OS > 15 months. He comes to clinic biweekly for nivolumab infusions and assessments, but remains outpatient otherwise. He started his personalized therapy after his second relapse, and this 3rd EFS (7 months) is already the longest EFS, compared to 6 months post his initial standard BFM protocol and just 1 month post ibrutinib, obinutuzumab and ICE chemotherapy.
The case may illustrate a new variant of Activated PI3K-delta syndrome (APDS). At least at present the disease is not tested for and generally not recognized in children with Burkitt's lymphoma. Even if this child had a family history supporting testing for the autosomal dominant form of APDS, he would not have been found. Yet, he had an atypical germinal mutation in the gene that leads to lymphoid hyperplasia, and increases the risk of malignant transformation to B-cell lymphoma. The p110δ protein is a crucial subunit of the PI3K enzyme, and regulates activation of proliferative pathways in B-cells. As such, unless this constitutional activation can be blocked, it will be unlikely that 5 cycles of conventional chemotherapy could successfully prevent a relapse. It may be prudent, in cases where a mutational activation of an important proliferative pathway is found, to use maintenance biological therapy. This could be similar to the 2 years maintenance therapy used in childhood Acute Lymphoblastic Leukemia, which has cure rates of about 90%. It is our hope that this case illustrates a potential for keeping even children with poor prognosis due to genetically complex cancers at home. While not able to eradicate the cancer or it causative mutation, we may be able to keep them well, in school and active by prescribing a combination of low-dose metronomic chemotherapy, an immune checkpoint inhibitor, and a direct inhibitor of the activated pathway(s).


A 69-year-old Caucasian male, with a history of 35 pound weight loss, was found to have a white blood cell (WBC) count of 20.8 × 109/L, with 79% lymphocytes. His brother had died of chronic lymphocytic leukemia (CLL). Flow cytometric analysis revealed two distinct monoclonal B-cell populations. A predominant CD19+/CD20−/CD5+/CD23+/dim surface kappa+/CD25−/CD103− population, consistent with CLL and the second (bright CD20+/bright CD19+/CD11c+/CD25+/CD103+/bright lambda+) smaller population, consistent with hairy cell leukemia (HCL). Bone marrow (BM) biopsy was predominantly involved by HCL, with focal involvement by CLL. Cytogenetic analysis showed a deletion of 7q31. He underwent four treatments of weekly rituximab (375 mg/m2) followed by maintenance rituximab every 3 months for a total of 13 months. Two months after completion of treatment, flow cytometry of the peripheral blood showed involvement by the CLL cell population, but no evidence of HCL. He was then clinically monitored for CLL owing to a lack of symptoms and stable WBC counts between 10 and 16 × 109/L. The patient developed papillary thyroid cancer 51 months after initial diagnosis for which he had successful surgery. Fifty-eight months after initial diagnosis, CT chest was found to have multiple pulmonary and pleural nodules, and while further workup was underway, he was hospitalized with dyspnea and altered mental status and passed away (Table ).


A 49-year-old Caucasian female developed HCL treated with cladribine which led to remission. She relapsed 7 years later and was successfully retreated with cladribine. Seven years thereafter, she presented with cervical lymphadenopathy. WBC count was 11.1 × 109/L with 71% lymphocytes. Biopsy of the lymph node revealed small lymphocytic leukemia (SLL) and a subsequent BM biopsy showed involvement by CLL/SLL occupying 10% of the BM space. At that time, HCL was not detected in the peripheral blood or BM biopsy. Cytogenetic analysis showed trisomy 12. She is being clinically followed up in our clinic and remains asymptomatic and clinically stable at 82 months after CLL diagnosis (nearly 21 years after initial HCL diagnosis).


A 49-year-old Caucasian male was referred for pancytopenia and spontaneous bruising. Complete blood count (CBC) showed a WBC count of 3.1 × 109/L and platelets of 52 × 109/L. A peripheral blood smear and BM biopsy performed at an outside institution were reportedly normal, but flow cytometry revealed a dim CD19+/CD20+/CD5+/CD23+/kappa+ monoclonal B-cell population, consistent with a monoclonal B-cell lymphocytosis of CLL phenotype. Cytogenetic analysis revealed 13q deletion. Clinical expectant management and close follow-up was instituted due to patient preference. Ten months later, he presented with febrile neutropenia. A peripheral blood smear at that time showed circulating lymphoma cells, morphologically consistent with simultaneous involvement by HCL and CLL. A subset of the neoplastic cells showed tartrate resistant acid phosphatase (TRAP) positivity. A BM biopsy showed diffuse involvement by HCL, and no evidence of involvement by CLL. The patient was treated with cladribine for a month with a repeat BM biopsy 2 months after completion showing resolution, and confirmed by normalization of blood counts and flow cytometry. He was clinically followed up for the next 5.5 years, until he started developing thrombocytopenia (hemoglobin 13.0 g/dL, platelets 104 × 109/L, and WBC 7.8 × 109/L). A BM biopsy showed simultaneous involvement by HCL and CLL (20 and 5% of the BM space, respectively). A 13q deletion was present. The patient was managed expectantly.


A 43-year-old male with a family history of leukemia in his grandmother and multiple myeloma in his grandfather experienced night sweats and left upper quadrant abdominal pain, and presented to an outside facility. A CBC showed monocytopenia, and peripheral smear showed rare atypical lymphoid cells, suggestive of CLL. Flow cytometry of the peripheral blood showed a predominant population of mature B-cells (CD19+/CD20+/CD5+/CD23+/moderate-density lambda+) and the second very small population (bright CD19+/bright CD20+/bright CD11c+/CD25+/CD103+/moderate lambda+), consistent with HCL. BM biopsy then demonstrated HCL, involving 20% of the BM space and CLL, involving 1% of the BM space (Figure ). Flow cytometry of the BM aspirate detected the two distinct monoclonal B-cell populations with similar immunophenotypic characteristics to that seen in the peripheral blood. Cytogenetic studies showed trisomy 12 and a partial deletion of the 5′ telomeric 14q32 locus. He was treated with 7 days of intravenous cladribine, resulting in remission of HCL. Just over a year later, he experienced abdominal swelling and right upper quadrant abdominal pain, with computed tomography revealing retroperitoneal and mesenteric lymph nodes that were pathologically demonstrated to be HCL. The patient was subsequently lost to follow-up.


A 79-year-old Caucasian male presented with 1 year history of dry cough and a 15-pound weight loss. Chest imaging revealed multiple lung nodules, which were biopsied and showed adenocarcinoma. CBC showed WBC of 9.0 × 109/L with 68% lymphocytes and hemoglobin of 18.0 g/dL. Peripheral smear showed two distinct neoplastic populations. The majority of lymphocytes showed cytological features of CLL and were admixed with a few hairy cells. The BM aspirate showed a reverse pattern with the majority of cells having cytological and immunophenotypic features of HCL (diffuse interstitial infiltrate of strong CD20+/CD5−/DBA-44+ B-cells). In addition, flow cytometry of the BM aspirate showed two distinct monoclonal B-cell populations, a CD19+/dim CD20+/dim CD5+/CD23+/dim kappa+ population, consistent with CLL and a bright CD19+/bright CD20+/CD11c+/CD25+/CD103+/bright kappa+ population, consistent with HCL. No cytogenetic abnormalities were detected. Given findings of multiple pulmonary nodules and borderline enlarged mediastinal lymph nodes, it was recommended that the patient undergo chemotherapy for lung cancer first. However, the patient was transferred to an outside facility.


A previously well 74-year-old Caucasian woman presented with a 2-week history of jaundice and fatigue. She had no risk factors for viral hepatitis and did not drink alcohol or use herbal or dietary supplements. She had hypertension that was well controlled with irbesartan. Physical examination was significant for jaundice and hepatomegaly. There were no other peripheral signs of chronic liver disease. Laboratory tests at admission were as follows: normal full blood count, serum bilirubin 3.6 mg/dL, alanine aminotransferase (ALT) 1011 U/L, alkaline phosphatase 168 IU/L, albumin 37 g/L, globulin 51 g/L, IgG 31.1 g/L (normal, <16 g/L), and prothrombin time of 16 seconds. Antinuclear antibody titre was 1 : 5120 but smooth muscle, liver-kidney microsomal and mitochondrial antibodies were absent. Serologic tests for hepatitis A, B, and C were negative. A liver ultrasound showed normal sized bile ducts with no features of chronic liver disease.
A liver biopsy on day 6 showed severe interface hepatitis with a mixed inflammatory infiltrates consistent with severe AIH (). She scored 7 on the simplified diagnostic criteria for AIH which is consistent with “definite autoimmune hepatitis” []. Budesonide 9 mg daily was commenced. She began to improve both clinically and biochemically with her ALT dropping to 85 IU/L within 10 days. After this initial response, her ALT rose again to 421 U/L despite remaining budesonide (). On closer questioning, it was later ascertained that irbesartan had been commenced 3 months earlier but had been discontinued 3 days before admission (9 days before her liver biopsy; ALT 834 IU/L at this time). After the initial response to budesonide, a diagnosis of AIH had been established and the irbesartan was recommenced, only to be followed by an ALT rise to 421 (within 2 weeks). A diagnosis of irbesartan-induced hepatitis was considered and the drug was withdrawn and her liver tests returned to normal within 6 weeks. Budesonide was tapered off over a period of 8 months. She remains well with normal liver tests 3 years after her initial presentation. The score for causality assessment for DILI using the updated Roussel Uclaf Causality Assessment Method (RUCAM) was 11 for irbesartan (highly probable) () [].


Patient A: 65-year-old male patient, from Temuco (Southern Chile), with a medical history of arterial hypertension, diabetes mellitus type 2 (DM 2), and cholecystectomy due to cholecystolithiasis. He had a consultation on 16 August 2013 because of an intense stabbing pain in the right hypochondrium. He was given a physical examination when admitted, and there was evidence of a hepatomegaly that was painful on palpation, without any other relevant findings.
A study with echotomography of the abdomen and pelvis was carried out (08-2013), finding a vascularised focal injury on the left liver lobe of 8.5 x 7 cm. A scan of the abdomen and pelvis (09-2013) revealed the presence of a solid substitute liver lesion with a neoplastic appearance in the left liver lobe of 10 x 7 cm, with central areas of necrosis. Alpha feto-protein (AFP) was ordered (09-2013) whose value was reported as greater than 350 ng/ml. The serology test was positive for VHB and VHC.
A liver needle biopsy was performed on the tumour lesion (09-2013) whose microscopic examination showed the morphological appearance of HCC (). The study was completed with immunohistochemistry, with the following results: CD10 (++) cytoplasmatic, hepatocyte (+++), AFP (++), which are consistent with a diagnosis of HCC. A molecular study of the biopsied material was not carried out due to a lack of access to this.
A PET CT (09-2013) was also performed which showed an ill-defined hypermetabolic liver lesion consistent with a history of HCC, 8.9 x 9 cm and SUV max, 11.7 and a hypodense hypermetabolic lesion on the left femoral neck. The biopsy is consistent with a HCC bone metastasis.
Treatment was started with chemoembolisation with the completion of three sessions that were carried out between October 2013 and February 2014. Later, surgery was performed to stabilise the lesion on the left femoral neck (02-2014) and palliative radiotherapy was given, 30 Gy in 10 sessions on this location, achieving a good analgesic response. Treatment was continued with zolendronic acid 4 mg IV every 28 days for 18 months and sorafenib 400 mg, twice a day since May 2014.
A few days after starting the treatment with sorafenib, the patient developed an increase in liver test levels, raised temperature (up to 38.5 °C) and increased blood pressure. The most significant findings of the laboratory tests were: (a) alkaline phosphatase, (b) 223 UI/L, (c) SGOT (AST) 414 UI/L, (d) SGPT (ALT) 670 UI/L, (e) bilirubinemia within the normal range, (f) lactate dehydrogenase 314 U/L and (g) elevated C-reactive protein (265 mg/L). A further abdominal ultrasound scan did not reveal any obstructive liver-biliary pathology. These symptoms were interpreted as drug-induced hepatitis, with the consequent suspension of the antineoplastic treatment, which was later restarted in June 2014 at a 50% dose with good tolerance. Once normal values in the liver tests were achieved, the dose of sorafenib was progressively increased without reaching the maximum recommended dose. Examinations of the thorax, abdomen and pelvis were carried out using a scanner (09-2014). These showed signs of progression in the primary lesion with portal vein thrombosis, signs of peritoneal carcinomatosis and regional lymph node enlargements, ascites and the previously detected secondary bone lesion in the right femur. October 2014 lab tests showed AFP:7865 ng/dl, plasma albumin 2,65 gr/dl, SGOT (AST) 78 U/L, SGPT (ALT) 81 U/L and FA 254 U/L with normal levels of total and direct bilirubin. A scan of the abdomen and pelvis revealed an increase in deep vein thrombosis and the appearance of signs of portal hypertension; therefore, a decision was made to suspend chemotherapy and keep the patient exclusively in palliative care. The patient died at the end of January 2015.


Patient B: Male patient, identical twin of patient A, 61 years old when diagnosed with HCC. He had a history of DM 2 and arterial hypertension; both pathologies were well controlled and being treated with drugs. He also had records of tobacco use and occasional alcohol consumption which were stopped in 1994.
In March 2010, he started showing symptoms of abdominal pain and a weight loss of 20 Kg in three months. The upper endoscopy showed the presence of esophageal varices and hypertensive gastritis. The abdominal ultrasound scan and the MRI of the abdomen showed the presence of tumour lesions of up to 11 cm in the dome of the liver, with satellite nodes consistent with HCC. Metastases were also observed in the right adrenal gland. The serology tests for VHB and VHC were negative. The AFP value was 2200 ng/dL in June 2010. The patient was referred to a centre of reference in Santiago de Chile in July 2010, where, furthermore, new images showed the presence of abdominal lymphadenopathy in the hepatic hilum, retroperitoneal and peritoneal lymph nodes. A biopsy was not taken and, as he had, an ECOG performance status of 1 treatment with Sorafenib was started. Unfortunately, 15 days after starting the treatment, the patient suffered a rapid clinical deterioration secondary to his aggressive underlying illness, leading to the suspension of the drug treatment and his death one month later.


A 42-year-old Moroccan woman was diagnosed with breast cancer in 2008 and underwent right modified radical mastectomy. The tumor was infiltrating ductal carcinoma pT2N1M0 with 2 out of 12 lymph nodes positive. The tumor expressed hormone receptors (estrogen receptor was 90% and progesterone receptor was 70%) and the HercepTest result was negative. Her complete blood count showed a hemoglobin level of 13.7 g/dL (normal range: 12–16 g/dL), a platelet count of 250 × 109/L (normal range: 150–400 × 109/L), a leukocytes count of 7.3 × 109/L (normal range: 4–10 × 109/L) and a neutrophils count of 5.1 × 109/L (normal range: 1.5–7 × 109/L). She received six cycles of adjuvant 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2) and cyclophosphamide (500 mg/m2) (FEC100). The total dose was 960 mg of epirubicin and 4800 mg of cyclophosphamide. Adjuvant chemotherapy was followed by radiation therapy to her chest wall and ipsilateral axillary lymph node metastasis. She was placed on tamoxifen for 5 years.
After completion of 5 years of tamoxifen our patient reported asthenia; a physical examination found hepatomegaly, splenomegaly extending into the umbilicus measuring 21 cm and supraclavicular lymphadenopathy measuring 2 cm, painless and mobile. Her cancer antigen 15-3 (CA15-3) level was 80 UI/mL (normal value less than 25 UI/mL). A thoracoabdominal computed tomography scan showed lung metastases with a hypodense nodule in segment VII of the liver characterized as a metastasis on a magnetic resonance imaging (MRI) scan (Fig. ). A biopsy of this nodule was performed. Morphology and an immunohistochemical profile of this metastasis reveal an adenocarcinoma of mammary origin expressing cytokeratin 7 and mammaglobin (Fig. ). The tumor was triple negative (TN).
Concurrently, our patient’s blood count showed a hyperleukocytosis at 355 × 109/L with a neutrophil count of 152 × 109/L, her hemoglobin level was 10.6 g/dL and platelet count 264 × 109/L. A peripheral smear showed myeloblasts at 4%, promyelocytic at 11%, neutrophilic metamyelocytes at 15%, and neutrophilic myelocytes at 19%. Further investigation by bone marrow aspiration evoked a myeloproliferative disorder (Fig. ); the marrow was very rich with granulocyte elements as blasts (13%), eosinophils (4%) and basophils (4%). Megakaryocytes were rare and multilineage dysplasia signs were observed. Medullary karyotype showed the presence of the translocation (9; 22) (q34; q11) over 20 mitoses analyzed and BCR-ABL by real-time reverse transcriptase polymerase chain reaction (RT-PCR) quantitative assay was positive. She was finally diagnosed as synchronous CML and metastatic relapse of breast cancer.
Our patient then received a dose of 400 mg of imatinib daily taken as four 100 mg tablets, concurrently with chemotherapy-type docetaxel of 100 mg/m2 every 21 days without limiting hematologic toxicity. Liver and lung metastases were stable after nine courses of chemotherapy. The breast cancer progressed 4 months later due to the emergence of new lung metastases, then a treatment based on bevacizumab and capecitabine was introduced.
A major molecular response was achieved after 12 months using the RT-PCR method and maintained after 18 months. She has now completed 2 years of follow-up, still on a major molecular response, and is undergoing imatinib and capecitabine therapy.


A 14-year-old male was admitted to our clinic for treatment of extremely severe spinal deformity associated with progressive late-onset paraplegia. His medical history included the diagnosis of intramedullary astrocytoma at the age of 3 years in another hospital, where he underwent posterior total laminectomy through the thoracic spine (from T4 to T8), with tumor excision performed without fusion. Intramedullary astrocytoma represents 29% of pediatric spinal cord tumors in the literature.[
He reported that kyphosis deformity began to appear 1 year after posterior laminectomy. Later, he underwent posterior spinal fusion without any instrumentation at 9 years of age. However, the deformity gradually progressed over the years. Seven months before admission to our hospital, the patient began to feel lack of strength and sensation in lower extremities bilaterally, with no complains regarding bladder or bowel dysfunction. No improvement in spinal cord function was achieved with conservative measures, and the patient gradually lost the ability to walk and required a wheelchair for movement (Fig. ). The patient and his family denied any recent or remote history of trauma, tuberculosis, or any other infections. The family history was unremarkable; meanwhile, the patient exhibited signs of serious psychosocial problems since he had to use a wheelchair in daily life.
The patient's preoperative coronal and sagittal thoracic kyphosis Cobb's angles were 70° and 170°, respectively (Fig. ). Preoperative whole spine three-dimensional-computed tomography (3-D CT) scans showed extremely severe postlaminectomy thoracic kyphotic deformity; with the apex at T6 vertebra and previous spinal fusion (Fig. ); magnetic resonance imaging (MRI) of the spinal canal revealed spinal cord compression at the apex of the kyphosis (Fig. ). There was no neurological abnormality such as split cord malformation or tethered cord. The electrodiagnostic investigation demonstrated neurological deficit. Pulmonary function tests (PFTs) revealed forced vital capacity (FVC) and forced expiratory volume for 1 second (FEV1) of 31.8% and 33.8%, respectively. Cardiac Doppler ultrasonographic investigation demonstrated mitral and tricuspid regurgitation, with no anomalies of other visceral organs.
Physical examination showed skin hypoesthesia below the T6 level and lower limb spasticity. The patient had weakness of the intrinsic musculature of lower limbs, with left and right lower extremity Grade 3/5 and Grade 1/5 motor strength in all muscle groups, respectively. His Achilles and knee tendons showed hyperreflexia, and the Babinski sign was positive. The overall spinal cord function was classified as Frankel C.
In 2014, the patient underwent preoperative assessment by a team of pediatrics, neurosurgery, anesthesiology, and respiratory specialists, and diagnosis of postlaminectomy rotokyphoscoliosis associated with late-onset paraplegia and severe pulmonary ventilation disorder were confirmed based on the findings. The patient was suggested a revision surgical treatment, and the single stage posterior-only VCR procedure was scheduled. In brief, pedicle screws were inserted using the free-hand technique based on previous studies.[ The patient underwent a VCR at T6 for spinal cord decompression, deformity correction, and posterior spinal fusion from T2 to L3 (Fig. ). The autograft and allograft were used for posterior final spine fusion. During the operation, motor evoked potential (MEP), somatosensory evoked potential (SEP), and wake up test were performed to assess intraoperative complications of spinal cord injury.
The operation time was 450 minutes, and blood loss was 1500 mL. Intraoperatively, a dural tear was noted and repaired; MEP and SEP signals were lost during the entire operation, and the wake-up test was positive. Postoperatively, the patient was transferred to the intensive care unit (ICU) and required positive pressure ventilation support to improve his respiratory condition. On postoperative day 2, he was extubated and transferred to the orthopedic ward, where he received neurotrophic medicines and rehabilitation exercises. The patient required a chest tube for postoperative pleural effusion. The child experienced unplanned return to the operating room for cerebrospinal fluid leak (CSF) on postoperative day 18. The plastic thoracolumbosacral orthosis braces were preserved for 6 months after revision operation.
The spinal cord function improved gradually after the posterior-only VCR procedure. At 3 months, left and right intrinsic musculature of lower limbs both exhibited Grade 3/5 motor strength in all muscle groups. Left and right intrinsic musculature of lower limbs recovered to Grade 4/5 motor strength at 12 months postoperatively. At 18 months postsurgery (follow-up visit), intrinsic musculature of lower limbs displayed Grade 5/5 motor strength, and sensation in lower extremities bilaterally had returned to normal, with the neurological status improving from preoperative Frankel C to Frankel E. At the 24-month follow-up, the good spinal cord function was maintained. Long-standing scoliosis radiographs demonstrated that the major curve at coronal plane was improved to 20° immediately after surgery and 21° (correction rate, 70%) at final follow-up; the thoracic sagittal kyphosis curve was improved to 76° immediately after surgery and 75° (correction rate, 55.9%) at the final follow-up (Fig. ). PFTs revealed FVC and FEV1 of 40.5% and 43.5%, respectively. Postoperative clinical photographs showed overt improvement (Fig. ).


A 27-year-old female, gravida 4 para 3, presented with a persistent umbilical mass from over a year. She had previously undergone three low-transverse cesarean sections and had one miscarriage. She reported constant sharp pain in the mass as well as associated increasing size and worsening discomfort, particularly with her menses. The mass was also reported to have sporadic drainage that ranged from cloudy to clear. Her medical history was remarkable for dyspareunia and intermittent pelvic pain. The patient agreed to participate and was explained the nature and objectives of this study, and informed consent was formally obtained. No reference to the patient's identity was made at any stage during data analysis or in the report.
Physical exam revealed a 2.5 cm firm and indurated subcutaneous mass in the center of her umbilicus, with extreme tenderness to palpation. Ultrasonography revealed an indeterminate solid and cystic lesion in the subcutaneous soft tissues at the umbilicus suggestive of a urachal cyst (Figure ).
A provisional diagnosis of a urachal sinus tract with a cyst was made. The patient consented to an excision of the umbilical cyst with a diagnostic laparoscopy and plans to close off the urachal sinus tract.
Under general anesthesia, laparoscopic exploration revealed a uterus adherent to the anterior abdominal wall consistent with the patient's history of previous cesarean sections. The area around the umbilicus was examined, and no distinct connection to the bladder was noted. The surrounding tissue around the umbilicus was taken down using a tissue sealer. The umbilicus itself was examined, and no intraabdominal connections were noted. As a result, the laparoscopic approach was concluded, and attention was turned to the umbilicus externally where a circumferential incision was made around the mass. The firm mass was encountered subcutaneously and was circumferentially excised. Because of its adherence to the fascia, a 2 x 2 cm circle of fascia was excised along with the mass. This was sent to pathology for specimen analysis. The fascia was then closed, and the umbilicus was reconstructed. On microscopic examination, histologic sections revealed tissue consistent with endometriosis.


A 5-year-old white boy presented with a 1-year history of right shoulder pain and asymmetrical right scapula. His shoulder range of motion was preserved as well as function. Amyotrophy was initially suspected but excluded based on normal neurologic investigation. There was no significant past medical or family history. Imaging revealed a persistent subluxation of the humeral head of unclear genesis (Fig. ). Subsequent investigations by computed tomography (CT) scan and MRI showed a 5×3.5×2.5 cm soft tissue mass with an aggressive appearance within his deltoid muscle but without involvement of his brachial plexus. An initial biopsy failed to determine the exact nature of the lesion but revealed an aggressive biology. Based on the clinical and aggressive appearance of the lesion on imaging, the remaining diagnosis was a malignancy. Consequently, a complete deltoid resection was performed on this child because of the infiltrative pattern of the tumor through the entire muscle (Fig. ). Surgery included a straight lateral, vertical incision from his acromion to the deltoid insertion (Fig. ). The posterior border of his deltoid muscle was prepared and the axillary neurovascular bundle identified. Muscular detachments from the deltoid insertion and then his acromion followed, before his entire muscle was mobilized together with the tumor. No reconstructive procedure was performed at the time of index procedure or later.
Histological analysis of the tumor revealed an angiomatoid fibrous histiocytoma. At the time of diagnosis, this lesion was known as angiomatoid malignant fibrous histiocytoma because initially its metastatic potential was considered much higher than it is now. Angiomatoid fibrous histiocytoma is a low grade lesion with a 1% metastatic rate. Complete surgical resection is usually curative. No adjuvant therapy was performed. His postoperative course was uneventful. Over the first few weeks, physical therapy (PT) assisted in mobilizing his shoulder joint. Six months postoperatively, the child demonstrated near complete range of motion of his right shoulder. Over the years, the growing child participated in normal physical activities and maintained a symmetric range of motion. Ten years after the complete deltoid resection, he is free of disease and his shoulder function remains excellent. When compared to his left side, the range of motion of his right shoulder is symmetrical and normal (Fig. ). Normal rotator cuff muscles and good centralization of the humeral head were observed without degenerative changes on a recent MRI at 11 years of follow-up (Fig. ). His Musculoskeletal Tumor Society Score (MSTS; a score widely used in orthopedic oncology; it addresses pain, function, emotions, hand positioning, manual dexterity, and lifting ability) for upper extremity is excellent (93.3%), his Constant Shoulder Score (a score widely used in shoulder surgery; it addresses pain, activity of daily living, arm positioning, range of motion, and abduction power) is 75.8% on his right side and 80% on his left side. Patient self-assessment of his shoulder function (subjective shoulder value) is excellent (95%) with only slight weakness noted when heavy objects are carried. Despite excellent function reported, a slight difference to the opposite side is observed. Objectively, his shoulder strength in forward elevation is 54.6 kg, internal rotation is 20.8 kg, and external rotation is 15.8 kg compared to 76kg, 23.4 kg, and 24.1 kg respectively for his contralateral shoulder. MRI revealed an intact rotator cuff without atrophy of his supraspinatus, infraspinatus, and subscapularis muscles (Fig. ).


A 3-year-old North African boy was admitted to our Pediatric Nephrology Unit with a 4-day history of haematuria and burning urination. The physical examination was negative for pain, palpable mass in pelvic region, or other genitourinary (GU) symptoms. Blood tests showed white blood cell count (WBC) of 8,700/mm3 with lymphocytic predominance (68%); haemoglobin of 12.4 g/dl; platelet count of 339,000/mm3; C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) within normal limits. Urinalysis revealed a gold yellow colour; pH 5.5; specific gravity 1.020; proteins 30 mg/dl; plenty of red blood cells/High Power Field, pus cells 7–10/High Power Field. Urine culture was sterile. Ultrasound (US) scan of the bladder () documented a vegetating mass in the lumen with maximum size of about 40 × 41 mm, polylobed morphology and irregular contours, characterized by solid heterogeneous echogenicity and weak vascular signs at Colour-Doppler evaluation. Close to the above described mass, another sessile formation of about 6 mm was projected in the lumen. In light of that US aspect, an explorative cystoscopy was performed (). It revealed a nonbleeding lesion, white-coloured, apparently pedunculated, projecting into the lumen next to the left anterolateral wall of the bladder, and associated with a satellite formation of brown colour. Because the cystoscopic features were not clear and an infective origin could not be excluded, the patient underwent an open biopsy. The histological report showed a pseudocystic, multilocular gelatinous, and moderately fluctuating formation of 52 × 45 × 11 mm and a brownish minute fragment of solid tissue of 7 × 7 mm. Both findings displayed features of mixed Botryoid and Spindle Cell type of Embryonal Rhabdomyosarcoma. The child was transferred to the pediatric oncology department to start on a chemotherapy cycle, according to RMS 2005 protocol of European Pediatric Soft Tissue Sarcoma Group (EPSSG) [] in patients with standard risk, using IVA (ifosfamide, actinomycin D, and vincristine) associations.


A previously healthy, 48-years-old mexican woman was admitted at the Hospital de Oncologia, Centro Medico Nacional Siglo XXI, with left “pelvic limb” as well as back pain, with loss of strength and balance. Physical examination on admission revealed an ECOG of 1 and difficulty ambulating. Muscle strength of the left lower extremity was 3/5. No adenopathies were found in the head and neck areas, and no tumor was identified in the abdomen. Computed tomography (CT) scan revealed a solid, heterogeneous, non-encapsulated, vascularized intra-axial mass at the L3-L5 lumbar level, measuring 5.0x4.5 cm, that invaded the spinal canal and was fixed to deep planes (Fig. -). Chest, abdominal and pelvic CT scan revealed no abnormalities. A sagittal magnetic resonance imaging (MRI) of the filum terminale confirmed the presence of a large, expansive and infiltrative spinal mass with associated bone remodeling conditioning image reinforcement. The T2-weighted MRI sequence showed a hyperintense tumor (Fig. ), and the gadolinium-enhanced MRI scan revealed a large infiltrative mass with highly heterogeneous signal (Fig. ). Also, bilateral compression of the L3-L5 nerve roots was evident. Neurologic examination uncovered no other abnormalities. The imaging differential diagnosis included that of a metastatic tumor. No laboratory abnormalities were reported. Laboratory thyroid function was found T3 89.37 ng/dL (NL 80.00–200.00); T4 9.17 mcg/dL (5.10–12.80); T4L 1.43 ng/dL (NL 0.90–1.70); TSH 0.764 uI/mL (NL 0.270–4.200); TG 9.26 ng/mL (NL 0.10–78.00), vanillylmandelic acid 1.50 ng/mL (NL 1.50–4.8). Serum epinephrine 113 pg/mL (NL 50.00–100.00), serum norepinephrine 596 pg/mL (110.00–658.00), urinary epinephrine of 17.00 μg/day (NL 0.10–20.00), serum dopamine 12.00 pg/mL (NL 10.00–20.00), urinary dopamine of 0.60 μg/day (NL 0.29–1.87 μg/24 h), urinary norepinephrine of 96.00 μg/day (NL 10.00–70.00) and acid 5-hidroxindolacetic of 3.00 mg/24 h. An octreoscan was performed without evidence of involvement other than in the lumbar region. Pre-operatively, the tumor was considered completely unresectable and only incisional biopsy was performed.
Incisional biopsy was obtained for intraoperative evaluation. Macroscopically heterogeneous solid tumor gray-white with areas of congestive appearance of brown-reddish color was observed. Frozen sections revealed a hypercellular tumor with solid growth and encompassing two cell populations. The most striking population consisted of atypical giant cells with irregular hyperchromatic nuclei, with pseudoinclusions and abundant eosinophilic cytoplasm. These cells were intermingled with polygonal intermediate size cells with no atypia, with hyperchromatic nuclei and scant eosinophilic cytoplasm. Due to the observed degree of nuclear atypia and pleomorphism, the intraoperatory diagnosis was reported as consistent with a poorly differentiated neuroendocrine carcinoma, metastatic to the lumbar spine. However, in definitive sections a diagnosis of GCE was rendered.
Microscopically, the tumor showed diffuse, solid, festooned, trabecular, nodular areas with increased cellularity and a focal myxopapillary growth pattern (Fig. -). At lower power, numerous non-cohesive pleomorphic giant cells with abundant eosinophilic cytoplasm were observed. Nuclei were large, round, hyperchromatic and displayed intranuclear eosinophilic inclusions. They alternated with polygonal medium-sized cells (Fig. -), forming perivascular pseudorosettes and true rosettes (Fig. -). No mitoses, microvascular proliferation nor necrosis in pseudopalisading were observed.
The tissue was fixed in 10% buffered formaldehyde and paraffin embedded. Hematoxylin and eosin–stained sections were used for diagnosis. For immunohistochemistry (IHC) analysis, 5-μm sections of a representative block were obtained. The following antibodies were used: CD34, c-Kit (CD117), inhibin, S100 protein, CD56, chromogranin, synaptophysin, cytokeratin AE1/AE3, epithelial membrane antigen (EMA), glial fibrillary acidic protein (GFAP), CD99, bcl-2, HMB45, Melan A, PAX5, cytokeratin 20, GATA3, uroplakin III, TTF-1, thyroglobulin, cyclin-D1, p53 and Ki-67, which were performed on an automated immunostainer (Ventana, Biotek System, Tucson, Ariz) with appropriate positive and negative control run concurrently. Briefly, paraffin sections were mounted on charged glass slides, air-dried over-night, and then deparaffinized. To enhance the immunostaining, a heat-induced epitope-retrieval procedure was performed. After incubation with bloking serum, sections were incubated with primary antibodies (Table ), followed by a biotinylated polyvalent secondary antibody solution. Sections were then incubated with horseradish peroxidase-conjugated avidin-biotin complex, followed by 3,3-diaminobenzidine and hydrogen peroxidase.


A 60-year-old man, shopkeeper by occupation, presented with history of fever for the last two months. The fever was low grade, intermittent, without any diurnal variation, not associated with chills or rigors, night sweats, headache, rashes, and weight loss. He was a smoker for the last 10 years, nonalcoholic, and vegetarian by diet. His past medical and surgical history was unremarkable. Only medication that he took on and off was an antipyretic for fever. His travel history was noncontributory. He also denied any personal and family history of any major illness. His general physical examination revealed pallor while his systemic examination was normal. Abnormal laboratory parameters were dimorphic anemia with hemoglobin level of 8.5 gm/dl, a peripheral blood leukocyte count of 2500/µl, and a platelet count of 40,000/µl, revealing pancytopenia. The erythrocyte sedimentation rate was 15 cumm/hr. Urine and blood cultures were negative. Mantoux's test was negative. Serological tests for human immunodeficiency virus and hepatitis virus were nonreactive. Liver and kidney function tests were within normal limits.
A posterior superior iliac spine bone marrow biopsy was done to detect the cause of pancytopenia. Histopathological sections of the trephine biopsy showed an extensive involvement of bone marrow by sheets, clusters, and cords of poorly differentiated tumor cells with indistinct cell borders, high nuclear to cytoplasmic ratio, moderate amount of eosinophilic cytoplasm, round to oval vesicular nucleus, indistinct nucleoli, and high mitosis. At places, desmoplastic reaction was seen (Figures , , , and ). Based on these features, a diagnosis of a metastatic malignant tumor was made.
A panel of immunohistochemical markers were put for tumor characterization. Tumor cells exhibited strong positive expression for pan cytokeratin (CK) [AE1 and AE3], epithelial membrane antigen (EMA) [E29], CD5 [4C7], Bcl-2 [100/D5], p53 [D07], CD117 [YR145], and p63 [4A4] (Figures , , , and ) and negative expression for leukocyte common antigen (LCA) [PD7/26/16 and 2B11], CD3 [PS1], CD1a [O10], CD99 [HO36-1.1], CD20 [L26], CD30 [CON6D/B5], CD15 [BRA4F1], thyroid transcription factor (TTF-1) [8G7G3/1], Wilm's tumor suppressor gene 1 protein (WT-1) [CAN-R9(IHC)-56-2], placental alkaline phosphatase (PLAP) [PL8/F6], CK7 [OV-TL 12/30], CK20 [EPR1622Y], estrogen receptor (ER) [SP1], progesterone receptor (PR) [SP2], Muc-1 [EPR1023], synaptophysin [Snp88], chromogranin [LK2H10], CD34 [QBend/10], vimentin [V-9], desmin [33], S100 [15E2E2], prostate specific antigen (PSA) [ErPr8], antimelanoma [HMB-45], and terminal deoxynucleotidyl transferase (TdT) [polyclonal].
Considering the morphological and immunohistochemical findings, a diagnosis of poorly differentiated thymic epithelial tumor metastasis to the bone marrow was made. Following this, a detailed clinical and radiological workup was advised to find the primary. Computed tomography (CT) scan and Magnetic Resonance Imaging (MRI) of the chest revealed an ill-defined, approximately 58 × 45 × 38 mm in size heterogenously enhancing mass in the anterior mediastinum ().
CT-guided core biopsy of this mediastinal mass showed histopathological and immunohistochemical features of poorly differentiated thymic carcinoma with tumor cells showing CK, EMA, CD5, p53, CD117, p63, and Bcl-2 positivity. Based on these findings, a final diagnosis of clinically occult poorly differentiated thymic carcinoma metastatic to the bone marrow was made. The tumor at initial diagnosis presented in stage IVb according to the Masaoka staging system. The patient underwent surgical excision followed by postoperative radiotherapy and four cycles of cisplatin, doxorubicin, vincristine, and cyclophosphamide (ADOC) chemotherapy. However, he succumbed to the disease eight months after the diagnosis.