Inflammatory Malignant Fibrous Histiocytoma Associated with Leukemoid Reaction or Leukocytosis: A Comprehensive Review

Table 1

Shows the characteristics and relevant aspects of the patients with IMFH associated with LR or leukocytosis.

Study	Patient characteristics	Tumor characteristics	WBC (highest)	Treatment	Survival	Comments
Hisaoka et al.; Pathology international  (1997); Case report	Sex: male (on hemodialysis); Age: 69; Patient presented c/o dull pain in the left loin and thigh for 1 month; no constitutional complaints.	Tumor located within the left Iliopsoas muscle 2.5 cm in diameter; originally misdiagnosed as an intramuscular abscess. No metastasis.	WBC: 73.9 K/mm^3 range ( 18–73.9); (no differential reported); After the first surgery WBC returned to normal and it increased again once tumor recurred.	Surgery done twice due to local recurrence. Patient received chemotherapy after the second surgery (details not reported.)	Death: Approx. 180 days after diagnosis due to severe emaciation and liver dysfunction.; Patient passed away approx. 150 days after the onset of leukemoid reaction.	This group suggested that retroperitoneal IMFHs could originate from dediffenciated Liposarcomas. Elevated serum concentration of G-CSF = 109.0 pg/mL, IL-6 = 95.8 pg/mL were seen after the first surgery due to tumor relapse, and they declined after the second one.
Melhem et al.; Blood (1993); Primary article	Patient no. 1; Sex: male; Age: 63; Patient presented with 1 year history of a growing abdominal mass and weight lost.; Patient no. 2; Sex: male; Age: 67; Patient presented with anorexia, fatigue, and a 10 kg weight loss for the past month	Patient no. 1: Tumor located in the retroperitoneum from L (lumbar) 3 to posterior mediastinum, 11 × 22 cm in diameter. No metastasis.; Patient no. 2: Tumor located in the retroperitoneum involving the right kidney with wide spread metastasis to the liver and the omentum (dimensions not specified.)	Patient no. 1: WBC 164 K/mm^3 range (58–164); Bands N: 75.44 K/mm^3; Eos: 39.36 K/mm^3 Meta: 16.4 K/mm3; Myel: 9.84 K/mm^3; Promy: 8.2 K/mm^3; Blast: 1.64 K/mm^3; Patient no. 2: WBC 156 K/mm^3 range (62–156); Bands N: 106.8 K/mm^3; Neut: 43.68 K/mm^3; Meta: 3.12 K/mm^3	Patient no. 1: Partial resection with 5–10 % of tumor left. Radiation therapy given (details not reported.) Re-admitted 1 year after with increase residual mass.; Patient no. 2: Patient deteriorated and emergency laparotomy was performed with finding as described in the tumor characteristics section. No other treatment was done secondary to patient’s rapid demise.	Patient no. 1 Death: Approx. 489 days after diagnosis.; Patient passed away about 180 days after the onset of leukemoid reaction. Immediate cause of death not reported.; Patient no. 2; Death 14 days after diagnosis.; Patient passed away 14 days after the onset of leukemoid reaction.; Immediate cause of death not reported.	BM biopsy of both patients showed hypercellularity, no cytogenetic abnormalities, and no evidence of hematological malignancy. Alkaline phosphatase score was elevated in both patients.; IL-6, IL-7, IL-8, TGF-beta, SCF, and KGF were detected in IMFH tumors with leukemoid reaction only. Researchers concluded that these cytokines could promote the growth and metastasis of this malignancy.
Kyriakos and Kempson; Cancer (1976); Case series	Patient no. 1; (case 2); Sex: female; Age: 47; Patient presented with a left lower quadrant mass that has been progressively growing, and subsequently became painful; no constitutional complaints.; Patient no. 2 (case 6); Sex: Male; Age: 60; Patient presented with weakness, night sweats, decrease exercise tolerance, and 22 lbs weight lost for 4 months. Fever develops shortly after disease onset.	Patient no. 1; Left lower quadrant abdominal mass with multiple recurrences. Patient was misdiagnosis several times including granulomatous inflammatory reaction unknown type, and pseudotumor inflammatory type. At autopsy a 3.5×4×2cm mass was found on the mesentery of the small intestine, 100 cm distal to the ligament of Treitz with wide spread metastasis and bowel necrosis.; Patient no. 2 Misdiagnosed with anemia, and then with leukemia before the diagnosis of neoplastic disease was entertained. Tumor found in the left upper quadrant measuring 8.5 cm in diameter adjacent to the left kidney. The neoplasm recurred in the right lower lung lobe, invading the chest wall, and extending into the retroperitoneum with wide spread metastasis and areas of necrosis.	Patient no. 1: WBC 30 K/mm^3 (no other reported), no differential.; Patient no. 2; WBC 86 K/mm^3 range (17.1–86); Bands N: 63 K/mm^3; Neut: 31 K/mm^3; WBC normalized after first surgery and then increased once the tumor recurred.	Patient no. 1: A total of 4 surgeries done. First, an excisional biopsy reported as granulomatous inflammatory reaction undetermined type. Second was an exploratory laparotomy which showed an abdominal abscess, a dermoid cyst, and uterine myomas; no malignancy diagnosed at this time. Third surgery revealed an abdominal mass situated between the rectus muscle sheet and the peritoneum; it was diagnosed as inflammatory pseudotumor.; Fourth surgery done due to recurrent of the abdominal mass. Patient received maximum dose of nitrogen mustard, and radiation therapy with1040 rads to the lower abdomen, and 632 rads to the upper which caused symptoms relieve.; Patient no. 2; Surgical resection of the mass follow by radiation with 3800 rads to the tumor bed and para-aortic lymph nodes. Second surgery due to recurrence with right lower lung lobectomy along with preoperative radiation of 2025 rads; tumor partially removed. Tumor recurred and chemotherapy with adriamycin, dactinomycin, vincristine, and cyclophosphamide was attempted but failed.	Patient no. 1; Death Approx. 562 days after diagnosis.; (Death occurred 114 days after leukocytosis onset.) Patient final days marked by neurological dysfunction associated with seizure, jaundice, low platelet and decrease WBC with a left shift, along with generalized weakness and cachexia. Immediate cause of death not reported.; Patient no. 2; Death Approx.; 2225 days after diagnosis.; (Death occurred 36 days after leukemoid reaction onset.) Final clinical course characterized by persistent hypoglycemia, elevated alkaline phosphatase, oliguria, and pneumonia. Immediate cause of death not reported	Patient no. 1 At the onset of leukemoid reaction patient complained of fever, chills, and abdominal pain. During his last relapse, Patient was treated with Amphoteracin B because the mass was thought to be of infectious origin due to a positive serum complement fixation test for blastomycosis. BM aspiration showed myeloid hyperplasia. Thus, clinical course highlighted by multiple misdiagnoses which delayed treatment.; Patient no. 2; At presentation misdiagnosed multiple times; fist with anemia and subsequently with leukemia. After the first surgery misdiagnosed as having Hodgkin’s Lymphoma. BM biopsy showed granulocytic hyperplasia. Once more, patient’s clinical course characterized by several misdiagnoses which delayed treatment.
Asirwatham et al.; Cancer  (1978); Case report	Sex: Male; Age: 47; Patient presented with a 7 months history of left thigh pain which began after trauma, at first intermittent and then became progressively worse.	Tumor measured 10×7×4cm and was located in the left thigh involving the muscles. After biopsy, diagnosis was not clear; nodular tenosynovitis, dermatofibroma, pigmented villonodular synovitis, atypical xanthogranuloma; among others, were some of the differentials.	WBC: 38 K/mm^3 Range (10–38); Neut: 80%; WBC returned to normal after amputation.	Initially patient got a total of 4 biopsies without a definitive diagnosis. Patient got excisional biopsy of the mass follow by radiation for a total amount of 6138 rads in 26 cycles over a period of 38 days. He develops ulcerations at the site of treatment which resulted in erosion of the femoral artery with massive hemorrhage; urgent amputation was done.	Amputation resulted in total remission for a period of over 18 years. Patient was alive and well at last follow up.	WBC returned to normal after amputation. No palpable mass seen in the amputated specimen, surgical margins were tumor free, and 2 saphenous lymph nodes were free of metastasis as well. However, positive tumor foci identify during microscopy. Since residual tumor was found in the amputated specimen, these researchers concluded that this malignancy is not completely eliminated by radiotherapy.
Vilanova et al.; Virchows Arch. (1980); Case report	Sex: Female; Age: 71; Presented with left upper quadrant abdominal pain for 3 weeks.	Tumor in the left retroperitoneal space, above the kidney, partially adherent to spleen, and to the larger gastric curvature.; Rounded, soft centrally necrotic mass, measuring 10 cm in diameter.; No metastatic foci found anywhere.	WBC: 43 K/mm^3 (range 24–43 K/mm^3); Neut-30%; Baso-35%; Eos-22%; Meta: 5%	Exploratory laparotomy with biopsy and frozen section; diagnosed it as fibrosarcoma.	Death: on the 7th post-operative day, 7 days after the onset of leukemoid reaction. Immediate cause of death not reported	These researchers concluded that the leukocytic reaction observed was likely secondary to tumor production of granulopoietic growth factor. BM aspiration disclosed granulocytic hyperplasia with depressed erythropoiesis. This researchers concluded that this malignancy 6+follows a rapid, aggressive course and more so in patients with a blood reaction.
Ballestri et al.; European; journal of ultrasound (2011); Case report	Sex: Male; Age: 65; Presented with intermittent fever for 1 month, and 10 kg weight loss associated with an upper abdominal discomfort/pain and dysphagia.	Tumor located in the retroperitoneum at the level of the right iliac fossa, next to the right iliac vessels and anterior to the psoas muscle. It had a; multinodular appearance with regions of hemorrhage and necrosis; measuring 12.5 cm in diameter.	WBC: 24.1 K/mm^3 (no range reported); Eos: 3.5 K/mm^3; WBC, constitutional symptoms, and inflammatory markers returned to normal values after surgery.	Surgical removal of the mass via laparotomy followed by chemotherapy and radiation. (no other details specified)	Patient was recurrence free 180 days after diagnosis.	First description of retroperitoneal IMHF assessed with real time ultrasound, frequency-encoded color Doppler and Spectral Doppler, and contrast enhanced ultrasound.
Singh et al.; International journal of urology; (2006); Case report	Sex: Male; Age: 58; Presented with left flank pain and fever for 2 months.	First mass was located in the superior pole of the kidney measuring 10×12cm.; Second lesion consisted of three masses, the first in the left posterior thoracic cavity (10×10cm), the second in the lesser sac (6×6cm overlying the aorta and inferior vena cava), and the third in the left renal fossa (8×8cm).	WBC: 105 K/mm^3 (WBC: 70–105/mm^3; Neut: 90–98%; Raised LAP score)	Initial radical nephrectomy showed xanthogranulomatous pyelonephritis without evidence of malignancy.; Subsequently patient present with left sided chest pain, fever, and cough. He underwent open drainage of a left lower lung loculated empyema. Analysis of the fluid showed non-specific inflammation.; Finally patient present with left flank pain, decrease appetite, and weight lost. Exploratory laparotomy revealed unresectable tumors.	Death within 30 days of diagnosis of IMFH.; Patient passed away Approx 30 days after the onset of leukemoid reaction.; Immediate cause of death not reported.	This group concluded that this malignancy has a very strong predilection for local recurrence, and distant metastasis.; Chemotherapy has been try in few patient with negligent improve in overall survival. Radiotherapy has shown no obvious benefit. In this case the patient had a very poor performance status and could not tolerate any adjuvant chemotherapy.; A high index of suspicion is absolutely required for early diagnosis of this rare entity.
Kato et al.; Surgery today; (2002); Case report	Sex: Male; Age: 70; Patient presented with a palpable large elastic hard mass in the right upper quadrant of the abdomen. No constitutional symptoms.	Ct-scan of the abdomen demonstrated a well defined mass measuring 12×10cm. It extended from the hepatic hilum to the liver bed, and it appeared to involve the gallbladder.; Ct-scan of the abdomen 4 months later showed a lesion 6.5×5.5cm in the ascending colon.; Ct-scan of the abdomen 29 months later disclosed another 4 cm mass in the gastric antrum.	WBC: 50.7 K/mm^3 (range 11–50.7 K/mm^3); Neut: 88%; Leukemoid reaction subsided after surgery.	Initial the mass was excised completely along with the gallbladder and part of the liver.; Tumor recurred 4 months later; a 6.5×5.5cm mass was seen in Ct-scan located in the ascending colon. Right hemicolectomy with regional lymph node dissection was done; no evidence of metastasis.; Tumor recurred once more 29 months later; a 4 cm mass was detected by Ct-scan in the antrum of the gastric wall. Distal partial gastrectomy with regional lymph node dissection was performed; no evidences of metastasis.	Patient has survived more than 1095 days since he was originally diagnosed and was disease free at last follow up.	Pathology report of initial surgery disclosed a lesion with biomorphic make up: typical IMFH histology and xanthogranulomatous. Thus researchers concluded that the entity known as malignant xanthogranuloma are in fact IMFH.; WBC, inflammatory makers (CRP) and serum G-CSF were elevated before surgery. Tumor cells stained diffusely for G-CSF.; This article suggested that since a major part of the tumor had xanthogranulomatous histology and only a small portion of it consist of classic IMFH, multiple biopsies must be taken when the diagnosis of IMFH is suspected.
Roques et al.; American cancer society; (1979); Case report	Sex: Female; Age: 53; Patient presented with a history of tiredness, backache, ankle edema, anorexia, and weight loss.; Patient was afebrile but cachectic with a mass that resembled an enlarged spleen extending 6 cm below the costal margin.	Large (dimensions not specify) soft tissue tumor overlying the left kidney behind the pancreas. This lesion was adherent to left kidney, left adrenal gland, spleen, and pancreas.	WBC: 32.6 K/mm^3 (range 22.6–32); Neut:88–90%; Band N: 9%; Mono: 3%; WBC count fell to normal levels, but toxic granulations and ALP remained elevated after first surgery. Once tumor relapsed the WBC increased again.	Patient misdiagnosed with chronic neutrophilic leukemia, thus she was treated with Busulphan 4 mg/day. Left upper quadrant mass decreasing in size but Busulphan was discontinued due to pancytopenia.; Previous treatment unsuccessful and patient remained symptomatic and she developed fever. Exploratory laparotomy resulted in the resection of a large soft tissue tumor together with the spleen, left adrenal, left kidney and distal third of the pancreas.; Five months later, patient developed hepatomegaly and leukocytosis. A subsequent laparotomy revealed widespread peritoneal and hepatic metastases which could not be resected but were biopsied.	Death: Approx 334 days after she first seek medical attention.; Patient passed away 334 days after the onset of leukemoid reaction.; Immediate cause of death not reported.	Base on a negative Philadelphia chromosome and an increase leukocyte alkaline phosphatase, patient was diagnosed with IMFH associated with leukemoid reaction.; The fatal course seen in this case supports the observation that IMFH associated with leukemoid reaction follows an accelerated lethal course.; These researches hypothesized that the mechanism responsible for the granulocytic reaction is unlikely to be related to necrosis since this is not a major feature of these tumors.; It is probable that IMFH produces a granulopoietic factor.
Takahashi et al.; Pathology, research and practice; (1989); Case report	Sex: Male; Age: 77; Patient had a history of recurrent soft tissue tumor in the right scapula that has been surgically removed twice. During his second recurrence he was being closely followed as outpatient, but he fell, bruised his right chest and was admitted to the hospital with severe dyspnea.	On physical exam a non-tender, ill-defined mass was palpated in the right scapular region. Surgical specimen consisted of an elastic, soft, white yellow mass measuring 10×7×5cm which was located within the subcutaneous tissue.	WBC: 38 K/mm^3 (range 22.6–38 K/mm) Neut: 78%; Bands N: 8%; Blast: 1%; Myel: 3%; Meta: 2%; Fever, increase inflammatory markers, and elevated WBC were elevated when the tumor recurred, and they subsided after the tumor was removed.	Tumor was surgically removed. Originally the patient developed a hen’s egg-sized tumor in the right scapula which was excised 10 years before presentation without any further interventions.; Five years after the original surgery, tumor recurred and was surgically removed once more.	Death: Occurred 35 days after admission, and the leukemoid reaction begun around the same time.; Patient’s course complicated with severe respiratory distress secondary to a pneumothorax.; Immediate cause of death resulted from cardiac failure.	It is known that the inflammatory infiltrate seen in this tumor occurs with or without necrosis; making the latest an unlikely cause.; These researchers demonstrated neutrophil chemotactic activity in tumor extract samples; suggesting that this malignancy can produce this biomolecules.
Algabra et al.; Hystopatho-logy; (1989); Brief Report	Sex: male; Age: 67; Patient presented with fever and right epididymis mass. Ultrasound showed a mass extending from the head of the epididymis to the spermatic cord.	Tumor described as a lobulated grey-white mass, measuring 5×4.5×4cm that was displacing the vessels and ductus deferens.	WBC 32.5 K/mm^3  Range (not available); Eos: 7.8%; After surgery WBC returned to normal, and the fever subsided.	After radical orchiectomy patient received 10 cycles of chemotherapy (agents not specified) and local radiation with Cobalt 60.	Patient was last since disease free 335 days after surgery.	This is the first case of IMFH of the spermatic cord. This group concluded that the prognosis of spermatic cord IMFH is favorable, with disease free intervals of up to 5 years.
Serke et al.; Oncology; (1986); Case report	Sex: Female; Age: 63; Patient presented with progressive hoarseness over 6 weeks. A right 2×2×2cm thyroidal mass was palpated.; Four week after the first surgery patient presented with a rapid enlarging mass in the right jugulum and hoarseness.	Tumor located in the right thyroid 2×2×2cm mass.; Tumor (found 4 weeks after surgery) extending from the right thyroid to the aortic arch measuring 3×3×3cm.; The histopathology of both specimens was exactly the same.	WBC 35 K/mm^3 (range 6–35); Eos: 40–50%; At initial presentation the WBC was normal. It increased after the tumor relapsed.	First surgery was a right sided hemithyroidectomy. Patient refused radiation.; Second tumor resected with dimensions as described.; After first surgery patient refuse radiation therapy. Patient got a tracheostomy tube after second surgery secondary to an episode of severe shortness of breaths.	Death: 49 days after presentation.; Patient died 21 days after the onset of leukocytosis.; Immediate cause of death not specified	Eosinophilopoietic factor activity was confirmed in both the serum and IMFH specimen of the patient.; These researchers concluded that the tumor was capable of producing growth factors that stimulated the proliferation of eosinophils.
Hurtado-Cordovi et al.; Case Report in Medicine; (2012); Case report	Sex: Male; Age: 60; Patient presented to the general medicine clinic complaining of a rapid growing ulcerative mass in the left arm, just distal to the deltoid muscles. However, patient did not complaint of any significant pain or constitutional symptoms.	Tumor was located in the lateral aspect of the left arm; described as a fungating, necrotic mass measuring 4.4×3×3cm.; Pre-surgical chest X-ray showed no metastasis.	WBC 109 K/mm^3 (range 93.6–109); AbsN: 64.5–94.4 K/mm^3; Abs Bands: 8.6–25.2 K/mm^3; Abs Mono: 2.1–12 K/mm^3	Surgery consisted of wide excision of the mass. Specimen’s margins were disease free.; Patient was evaluated for palliative chemotherapy but due to his critical condition treatment could not be given.	Death occurred Approx 38 days after surgery and 3 days after the onset of leukemoid reaction.	This is the first time that subcutaneous IMFH has been associated with leukemoid reaction. This group concluded that the overproduction of growth factors and cytokines by this malignancy, and their interactions with the tumor’s microenvironment seem to be responsible for the aggressive nature of this neoplasm. In addition, they observed that the depth of tumor invasion does not necessarily correlate with metastatic potential.
Liarmakopou-los et al.; Case report in oncology (2011); Case Report	Sex: Female; Age: 65; Patient presented complaining of a painful lumbar mass that develop few days after a fall. On physical exam her temperature was 39°C, and there was palpable, fluctuating, erythematous mass in the lumbar area.	A contrast-enhanced ultrasound showed a heterogeneous mass measuring 9.8×8×11cm with a rich vascular supply.	WBC 41.3 K/mm^3 (range not reported); Neut: 87%; (no other differential reported)	Patient was misdiagnosed with paraspinal abscess and underwent 3 unsuccessful drainage attempts which were associated with bleeding and significant morbidity.; Biopsy confirmed the diagnosis of IMFH and MRI deemed the tumor inoperable. Neoadjuvant radiotherapy was given and was complicated with excessive bleeding requiring multiple blood transfusions. Patient did not benefit from this treatment.	Death occurred Approx 180 days after patient first seek medical attention.; Patient passed away 180 days after the onset of leukocytosis.; Immediate cause of death not reported.	Even with the availability of modern imaging, the diagnosis of IMFH can be challenging. This case provides evidences that surgical intervention, which is currently the main treatment for MFH, is not always possible secondary to tumor location and/or patient’s brittle clinical condition.

Note: The WBC reported correspond to the highest value observed during the course of the illness, the differential WBC count described illustrates abnormally high parameters only.
Abbreviations: Approx. (approximate), c/o (complaining of), Kg (kilogram), lbs (pounds) IMFH (inflammatory malignant fibrous histiocytoma), BM (bone marrow), LR (leukemoid reaction), IL (interleukin), KGF (keratinocyte growth factor), GSF (granulocyte colony stimulating factor), STC (stem cell growth factor), TGF-beta (transforming growth factor beta), rads (absorbed radiation dose), WBC (white blood cell count), Eos (eosinophils), Baso (basophils), Mono (monocytes), AbsN (absolute neutrophil), Neut (neutrophils), Abs Bands (absolute band neutrophils), Band N (band neutrophils), Abs Mono (absolute monocytes), Blast (blastocytes), Myel (myelocytes), Meta (metamyelocytes), Promy (promyelocytes), LAP (Leukocyte alkaline phosphatase), ESR (erythrocyte sedimentation rate), CRP (C-reactive protein).