A Collection of Cancerous Conditions
Spontaneous Tumor Lysis Syndrome in Breast Cancer
LeAnn Nguyen, MD, and Gabriel Marcelo Aisenberg, MD
University of Texas McGovern School of Medicine, Houston, Texas
Nguyen L, Aisenberg GM. Spontaneous tumor lysis syndrome in breast cancer. Consultant. 2017;57(7):429-430.
A 29-year-old woman presented to the hospital with a rapidly enlarging left breast mass, which initially had been indolent for approximately 6 months, along with dyspnea.
History. Less than 1 month prior to admission, she had been diagnosed with stage IV invasive ductal carcinoma of the left breast (estrogen receptor weakly positive, progesterone receptor negative, ERBB2 negative). The proliferative rate of the tumor as measured by the cellular marker protein Ki-67 was 95%.
Physical examination. On admission, she was normotensive but tachycardic. The entire left breast was firm and red, with a large, fungating lesion superior to the areola with serosanguineous discharge. There was a palpable 4-cm left axillary node. Breath sounds were decreased at the left lung base. The liver was enlarged. Heart sounds were normal, with no gallops. There was no edema and no visible focal neurologic deficit.
Diagnostic tests. Computed tomography (CT) showed a massive necrotic-appearing mass involving the entire left breast, measuring 10.8 × 8.4 × 11.1 cm; several bilateral pulmonary nodules; diaphragmatic pleural metastases; moderate loculated left pleural effusion; and innumerable necrotic liver metastases, with replacement of the entire left hepatic lobe (Figures 1 and 2). The proximal pulmonary arteries were free of clots.
Laboratory test results revealed renal insufficiency and elevated levels of potassium, uric acid, and lactate dehydrogenase (LDH). These findings were concerning for tumor lysis syndrome, so chemotherapy was delayed. Urinalysis results were normal.
Treatment. She received intravenous normal saline and 1 dose of rasburicase. Daily therapy with allopurinol was also started, as well as ceftriaxone, vancomycin, and metronidazole (for suspected secondary breast necrotizing infection) and morphine for pain control. Her laboratory test results improved after treatment, and on the second day of admission, she started her chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), without hormonal therapy due to the weak estrogen receptor positivity.
Outcome of the case. The patient’s clinical course was complicated by a rapidly accumulating pleural effusion leading to hypoxia and cardiac arrest, resulting in death on hospital day 6.
Discussion. Acute tumor lysis syndrome (ATLS) is an oncologic emergency that can be fatal if untreated. ATLS most frequently occurs in hematologic malignancies after initiation of cytotoxic therapy but can occur spontaneously in malignancies with large burden of disease and high proliferative rate. Cases of spontaneous tumor lysis syndrome (STLS), defined as ATLS not induced by chemotherapy or radiation, are well documented in association with lymphoma and leukemia. STLS has been rarely described in solid nonhematologic malignancies such as germ cell tumors; gastric, colon, liver, prostate, lung, and maxillary sinus cancer; pheochromocytoma; and undifferentiated metastatic carcinoma of unknown primary (Table).1-6 Only 1 case has been reported in a patient with metastatic breast cancer.1
ATLS is the result of rapid tumor necrosis, with the release of cellular contents into the bloodstream leading to metabolic derangements such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Hyperuricemia increases the risk of uric acid crystallization in renal tubules and can lead to renal failure. The release of potassium increases the risk of hyperkalemia, the most dreaded complication of which is cardiac arrhythmias and death. The release of phosphate can result in hyperphosphatemia. Phosphate precipitation together with calcium can worsen preexisting renal failure and result in hypocalcemia. The presence of these metabolic derangements should prompt the rapid recognition of this oncologic emergency.
Risk factors for ATLS include rapidly proliferating or chemosensitive malignancies, preexisting renal insufficiency, elevated uric acid level at baseline, and extensive tumor burden (bulky disease > 10 cm, elevated LDH greater than 2 times the upper limit of normal, or an elevated white blood cell count above 25,000/µL).7 The factors making some but not all patients with those features more prone to STLS are poorly understood. Therefore, current recommendations are lacking on which patients should be screened for STLS, particularly patients without hematologic malignancies.8
Our patient had multiple risk factors, including extensive tumor burden with massive necrosis seen on CT imaging, highly proliferative cancer, and elevated LDH. Obstruction of the urinary tract was ruled out by imaging, and other causes of kidney failure were deemed unlikely. Additionally, with the administration of fluids and rasburicase, her laboratory data improved. Her death was attributed to rapidly accumulating pleural effusion resulting in hypoxia and cardiac arrest.
The therapeutic management of ATLS and STLS includes fluid resuscitation and restoration of threatening metabolic derangements such as hyperkalemia, hypocalcemia, and hyperphosphatemia. The role of hemodialysis for refractory cases, particularly those with associated kidney failure, should be individualized considering the overall prognosis.9
STLS can be life-threatening; therefore, awareness and early recognition are important. Although based on expert guidelines, solid nonhematologic tumors are classified as having a low or intermediate risk of STLS, it is important to maintain an elevated index of suspicion in patients with risk factors and weigh the benefit of prophylactic interventions.7
- Sklarin NT, Markham N. Spontaneous recurrent tumor lysis syndrome in breast cancer. Am J Clin Oncol. 1995;18(1):71-73.
- Crittenden DR, Ackerman GL. Hyperuricemic acute renal failure in disseminated carcinoma. Arch Intern Med. 1977;137(1):97-99.
- Feld J, Mehta H, Burkes RL. Acute spontaneous tumor lysis syndrome in adenocarcinoma of the lung: a case report. Am J Clin Oncol. 2000;23(5):491-493.
- Vaisban E, Braester A, Mosenzon O, Kolin M, Horn Y. Spontaneous tumor lysis syndrome in solid tumors: really a rare condition? Am J Med Sci. 2003;325(1):38-40.
- Woo IS, Kim JS, Park MJ, et al. Spontaneous acute tumor lysis syndrome with advanced gastric cancer. J Korean Med Sci. 2011;16(1):115-118.
- Saini N, Lee KP, Jha S, et al. Hyperuricemic renal failure in nonhematologic solid tumors: a case report and review of the literature. Case Rep Med. 2012;2012:314056.
- Coiffier B, Altman A, Pui C-H, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26(16):2767-2778.
- Wilson PF, Berns JS. Tumor lysis syndrome: new challenges and recent advances. Adv Chronic Kidney Dis. 2014;21(1):18-26.
- Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004:116(8):546-554.
Jillian A. Weissman, MD; Joseph M. Mazziotta, MD; and Lisa M. Jernigan, MD
Tallahassee Memorial Hospital Family Medicine Residency Program, Tallahassee, Florida
Weissman JA, Mazziotta JM, Jernigan LM. Metastatic melanoma. Consultant. 2017;57(7):431-432.
A 42-year-old man without a significant past medical history was admitted with pancreatitis and lower-extremity edema. Two months prior, the patient had experienced generalized weakness, fatigue, intermittent nausea, and vomiting. He also had noted some nodules on his abdomen, which had begun to quickly spread toward his head, face, buttocks, and extremities. The patient stated that for several years he had noted changes (darkening and enlargement) in a birthmark on his back.
Physical examination. The patient appeared to be in no acute distress. Multiple nontender subcutaneous and cutaneous hyperpigmented nodules of varying size were noted on the head, trunk, and extremities, including a dark asymmetric lesion measuring 2 cm in diameter with an irregular border on the upper back (Figure 1). Tender lymphadenopathy was present in the posterior cervical, bilateral axillary, and inguinal chains. The patient exhibited tenderness to palpation in the left epigastric region. The external genitalia were mildly edematous. The presence of bilateral lower-extremity pitting edema was noted.
Diagnostic tests. An excisional biopsy of 2 cutaneous nodules was obtained, the results of which revealed malignant melanoma consistent with a skin metastasis. Diagnostic magnetic resonance imaging was performed to assess the severity of disease. (Figure 2). The results showed diffuse metastatic disease of the soft tissues, the brain, the cervical, thoracic, and lumbar marrow, the pelvis, and the retroperitoneum. There was also a posterior metastasis involving the medulla.
Outcome of the case. Given the degree of metastasis, the patient was determined not to be a candidate for chemoradiation. He was transferred to hospice for pain management and died 1 month after receiving the diagnosis.
Discussion. Melanoma is a malignant tumor of melanocytes. Although it is less common than other skin cancers, if undiagnosed melanoma may spread rapidly and is responsible for 75% of deaths from skin cancer.1 The recurrence rate of dermal metastasis with melanoma is generally less than 5%.2 The majority of local recurrences occur early, but delayed recurrences do occur, more commonly with thinner lesions than with thicker ones.2
Definitive diagnosis is made based on biopsy results. A full-thickness biopsy is recommended over a superficial shave biopsy, since the latter may have less diagnostic accuracy.3 This can subsequently affect tumor staging, prognosis, and follow-up recommendations. Punch biopsies can also lead to a missed diagnosis if the lesion is large and adequate sampling is not performed. Excisional biopsy may be appropriate if the lesion is large or irregular but for cosmetic reasons may not be ideal for people with many moles. However, numerous reviews have shown that the type of biopsy does not negatively influence overall melanoma survival rates.3
After the melanoma diagnosis has been made, surgical excision of the entire lesion with clear margins is recommended. A 2009 Cochrane review found no statistically significant difference in survival between wide (3-5 cm) and narrow (1-2 cm) surgical margins.4
Primary care providers should emphasize the early recognition of melanoma. While the US Preventive Services Task Force guidelines state that insufficient evidence exists to support routine skin examination in primary care for the early detection of melanoma in adults,5 studies have shown the melanoma risk to be 2.24-fold higher in patients with a first-degree relative with melanoma.6 A preferred method for screening moles is using the familiar mnemonic ABCDE (asymmetry, borders, color, diameter, evolution/enlargement).7 For patients with many moles, photographic mapping of the body may be helpful to delineate new or changing moles from older stable ones.
Many lesions that are removed will not be malignant, but a significant proportion may be true melanoma precursors. The removal of these moles interrupts tumor progression.8 The prognosis for patients with early disease (melanoma in situ) is excellent; melanoma at this stage is often curable with simple surgical excision. The main components of staging (in accordance with TNM staging system) include the thickness of the primary tumor (Breslow depth), the presence or absence of ulceration of the overlying epithelium, and the mitotic rate.9
Melanoma treatment can range from simple surgical excision to chemotherapy, radiotherapy, or immunotherapy combinations.10 Until recently, metastatic melanoma had very limited treatment options. Cytotoxic chemotherapy has been used for more than 3 decades.10 Dacarbazine is one of the most common antineoplastic chemotherapeutic agents used in the treatment of a variety of cancers, including malignant melanoma.
In 2011, ipilimumab and vemurafenib were approved following advances in the understanding of melanoma biology and tumor immunology involving the B-Raf protein.11 These drugs slow the growth of tumors in some people whose metastatic melanoma is associated with a BRAF gene change. The B-Raf protein is involved in directing cell growth. Almost 50% of melanomas harbor mutations in BRAF.12 Use of these agents has improved progression and overall survival in patients with metastatic disease compared with chemotherapy alone. Despite this robust antitumor activity, most responses to these agents are partial, and disease progression is typically seen at a median of 5 to 7 months.11 Chronic therapy with a specific B-Raf inhibitor has been shown to lead to the development of drug resistance to multiple selective B-Raf inhibitors in melanomas associated with B-Raf mutations that had been initially highly sensitive to these compounds.13
Nivolumab is a monoclonal antibody developed for the treatment of advanced melanoma and other cancers.14 It was initially approved for use in the United States in 2014 and is now considered the first-line treatment for metastatic melanoma. Nivolumab as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab if the patient is positive for the B-Raf mutation.15 It is also indicated in combination with ipilimumab in patients with a B-Raf wild-type melanoma.15 The potential for durable antitumor immune responses coupled with a favorable toxicity profile make nivolumab an attractive therapeutic option as a single agent.14
Agents targeting the programmed death-1 (PD-1) receptor and its ligand (PD-L1) are a new and promising class of agents that inhibit a critical negative regulator of T-cell activation and thereby promote antitumor immunity.16,17
- Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ. Early detection and treatment of skin cancer. Am Fam Physician. 2000;62(2):357-368.
- Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol. 1996;3(5):446-452.
- Pickett H. Shave and punch biopsy for skin lesions. Am Fam Physician. 2011;84(9):995-1002.
- Sladden MJ, Balch C, Barzilai DA, et al. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst Rev. 2009;(4):CD004835. doi:10.1002/14651858.CD004835.pub2
- US Preventive Services Task Force. Screening for skin cancer: US Preventive Services Task Force recommendation statement. JAMA. 2016;316(4):429-435.
- Ford D, Bliss JM, Swerdlow AJ, et al. Risk of cutaneous melanoma associated with a family history of the disease. Int J Cancer. 1995;62(4):377-381.
- What to look for: ABCDEs of melanoma. American Academy of Dermatology. https://www.aad.org/public/spot-skin-cancer/learn-about-skin-cancer/detect/what-to-look-for. Accessed June 20, 2017.
- Edman RL, Wolfe JT. Prevention and early detection of malignant melanoma. Am Fam Physician. 2000;62(10):2277-2284.
- Gershenwald JE, Soong S-j, Balch CM; American Joint Committee on Cancer (AJCC) Melanoma Staging Committee. 2010 TNM staging system for cutaneous melanoma … and beyond. Ann Surg Oncol. 2010;17(6):1475-1477.
- Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology (Williston Park). 2009;23(6):488-496.
- Jang S, Atkins MB. Which drug, and when, for patients with BRAF-mutant melanoma? Lancet Oncol. 2013;14(2):e60-e69.
- Ilieva KM, Correa I, Josephs DH, et al. Effects of BRAF mutations and BRAF inhibition on immune responses to melanoma. Mol Cancer Ther. 2014;13(12):2769-2783.
- Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683-695.
- Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: latest evidence and clinical potential. Ther Adv Med Oncol. 2015;7(2):97-106.
- Opvido [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2015.
- Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65(3):1089-1096.
- Ott PA, Hodi F, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19(19):5300-5309.
Polypoid Pedunculated Amelanotic Melanoma
Jane Clark, MD, and Emily Jorge, DCNP, FNP-BC
Skin Cancer and Cosmetic Dermatology Centers, Dalton, Georgia
Clark J, Jorge E. Polypoid pedunculated amelanotic melanoma. Consultant. 2017;57(7):433-434.
A 74-year-old woman presented with a large, ulcerated, and fungating mass on her left cheek (Figure 1). She stated that the lesion had begun 1 year ago as a slow-growing, pinto bean-sized, pink macule on her left cheek, and had since grown into a large nodule that bled occasionally. She denied any prior surgery or trauma to the affected area. Her family history was negative for melanoma or other skin cancers. Her past medical history was significant for hypertension.
Physical examination. At the initial consultation, an exophytic, pedunculated, ulcerated mass measuring 3.5 cm in diameter was present on her left cheek. Induration and erythema were present at the base of the growth. The lesion was suspected most likely to be a squamous cell carcinoma.
Diagnostic tests. A shave biopsy was performed, removing the lesion at its base, and was sent for pathology examination. The biopsy revealed an ulcerated malignant melanoma (MM) invading to a depth of at least 15 mm (Clark level IV, Breslow depth stage III). The neoplasm extended diffusely to the base of the specimen, with extensive ulceration of the surface. No definite regression was present, and numerous dermal mitotic figures were identified (10 mitoses/mm2) (Figures 2 and 3). Immunohistochemistry results for S100 protein (a common marker for melanoma) were strongly positive.
Treatment. She was immediately referred to a surgical oncologist for the management of melanoma, and she subsequently underwent a modified excision around the prior scar site. A modified nasal flap was constructed; the final closure measured 1.7 × 2.4 cm. The margins from the excision site, examined via frozen section, were clear. No nodal involvement was seen in 2 sentinel nodes, which had been removed via careful dissection along the facial and marginal mandibular lymphatics.
The final tumor-node-metastases (TNM) classification of the patient’s melanoma stage was T4bN0M0, or stage III. Results of serum indices and chest radiograph findings were unremarkable. The patient declined the recommended adjuvant interferon treatment.
Outcome of the case. After surgery, the patient was instructed to follow up for wound care. At a follow-up visit several months later, examination of the surgical site revealed a well-healed scar (Figure 4). She has had a 3-year disease-free period and has regular follow-up visits at our dermatology clinic.
Discussion. Melanoma is generally classified into 4 subtypes: nodular, acral lentiginous, lentigo maligna, and superficial spreading. This classification was devised after observation of variable and characteristic patterns on histology that could be correlated with distinctive clinical presentations.
The polypoid pedunculated melanoma (PPM) subtype was first described in 1958 by Vogler and colleagues,1 but the literature continues to be scant regarding polypoid, pedunculated, or exophytic melanomas. Most authors who have researched polypoid, pedunculated, or exophytic skin melanomas consider this entity a variant of nodular melanoma.2 Reports of a polypoid morphology in melanomas range from approximately 2% to 43%.3 One large retrospective study showed that the prevalence of a pedunculated morphology of melanoma to be 5.8%,4 while another study showed the prevalence to be higher, at 21.5%.5 The reported occurrence rate of polypoid melanoma is extremely variable in the literature, likely due to different clinical and pathologic criteria used to characterize it.
This neoplasm may mimic benign and malignant variants of both melanocytic and nonmelanocytic lesions. PPM may mimic clinical features of cutaneous squamous cell carcinoma, keratoacanthoma, nodular basal cell carcinoma, and Merkel cell carcinoma. These conditions were included among our patient’s differential diagnoses due to her history of a nonhealing growth in a sun-exposed area. Cutaneous lymphoma, large pyogenic granuloma, and ulcerative melanoma were also considered.
The amelanotic PPM variant occurs much less frequently than its pigmented counterpart, and as such, diagnosis and treatment are often delayed.6 Histologic examination of our patient’s biopsy specimen showed a strongly positive S100 immunostain, a stain that is immunoreactive in 96% to 99% of cases of melanoma.7 This finding supported the final diagnosis of MM in our patient.
Although several cases have been reported, PPM (and particularly the amelanotic variant) certainly is not common. Amelanotic melanoma is a subtype of cutaneous melanoma with little or no pigment on visual inspection. The prevalence of the amelanotic subtype has been estimated between 1.8% and 8.1% of all melanomas,8 and this subtype is difficult to diagnose due to the lack of the melanin pigment typically found in melanomas.
MM tumors grow rapidly and are prone to metastasis at an early stage of disease. Hematogenously spread, MM can metastasize to regional lymph nodes as well as the gastrointestinal tract, lungs, brain, paratesticular tissue, and bone marrow. Furthermore, PPMs have a poor prognosis, which is related to the unusually large thickness and ulceration and not to the pedunculated shape of the lesion.9
In an analysis of 17,600 cutaneous melanomas for TNM staging, Balch and colleagues demonstrated that tumor thickness and ulceration were the most powerful predictors of survival in the T (tumor) category.10 Our patient had a T4bN0M0 or resectable stage III melanoma. T4b describes melanomas of greater than 4.0 mm in thickness with ulceration. According to Balch and colleagues’ study, a stage III melanoma has a 5-year survival rate of 13% to 69%.
Wide local excision of the primary tumor with 2-cm margins remains the first-line therapy in such cases.11 No survival advantage is demonstrated with wider resection margins. Because stage III melanoma represents nodal disease, performing a regional lymph node dissection is also recommended. Additional standard treatment options for a resectable stage III melanoma include adjuvant chemotherapy such as high-dose interferon alfa-2b and pegylated interferon.12 However, prospective, randomized, multicenter trials have demonstrated that such treatments improve relapse-free survival but do not improve overall survival.
Immunotherapy with checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab, which are undergoing further investigative clinical trials, have been approved by the Food and Drug Administration for the treatment of resectable stage III disease as well as unresectable stage III, stage IV, and recurrent melanoma.
- Vogler WR, Perdue GD, Wilkins SA Jr. A clinical evaluation of malignant melanoma. Surg Gynecol Obstet. 1958;106(5):586-594.
- Knezević F, Duancić V, Sitić S, et al. Histological types of polypoid cutaneous melanoma II. Coll Antropol. 2007;31(4):1049-1053.
- Cutler K, Chu P, Levin M, Wallack M, Don PC, Weinberg JM. Pedunculated malignant melanoma. Dermatol Surg. 2000;26(2):127-129.
- Manci EA, Balch CM, Murad TM, Soong SJ. Polypoid melanoma, a virulent variant of the nodular growth pattern. Am J Clin Pathol. 1981;75(6):810-815.
- McGovern VJ, Shaw HM, Milton GW. Prognostic significance of a polypoid configuration in malignant melanoma. Histopathology. 1983;7(5):663-672.
- Morton CA, Mackie RM. Clinical accuracy of the diagnosis of cutaneous malignant melanoma. Br J Dermatol. 1998;138(2):283-287.
- Aisner DL, Maker A, Rosenberg SA, Berman DM. Loss of S100 antigenicity in metastatic melanoma. Hum Pathol. 2005;36(9):1016-1019.
- Koch SE, Lange JR. Amelanotic melanoma: the great masquerader. J Am Acad Dermatol. 2000;42(5 pt 1):731-734.
- Agostini P, Rivero A, Parra Martin JA, Soares-de-Almeida L. Pedunculated polypoid melanoma: a case report of a rare spindle-cell variant of melanoma. Dermatol Online J. 2015;21(4):10.
- Balch CM, Soong S-J, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622-3634.
- Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol. 1998;5(4):322-328.
- PDQ Adult Treatment Editorial Board. Melanoma Treatment (PDQ®): Health Professional Version. Bethesda, MD: National Cancer Institute. https://www.ncbi.nlm.nih.gov/books/NBK66034. Published January 26, 2017. Accessed June 20, 2017.